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Badralmaa Y, Natarajan V. Aberrant Wnt/β-catenin signaling in the mesenchymal stem cells of LZTFL1-depleted mice leads to increased adipogenesis, with implications for obesity. J Biol Chem 2025; 301:108057. [PMID: 39662832 PMCID: PMC11770550 DOI: 10.1016/j.jbc.2024.108057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
Obesity is one of the main clinical characteristics associated with the heterogeneous genetic disorder Bardet-Biedl syndrome (BBS). Leucine zipper transcription factor like 1 (LZTFL1) is a member of the BBS gene family. Our work showed that Lztfl1knockout (LZKO) mice display the obesity phenotype as early as 3 months of age. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into various cell types, including adipocytes. To understand the role of LZTFL1 in adipogenesis, we analyzed MSCs isolated from LZKO mouse compact bones (CB-MSCs). Compared to wildtype (WT), LZKO CB-MSCs had elongated primary cilia with tapered tips and increased levels of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor that favors adipogenesis, and nuclear glucocorticoid receptor (GR), a transcription factor involved in Pparg activation. Also, LZKO CB-MSCs had a lower level of total β-catenin, a core factor of the antiadipogenic canonical Wnt/b-catenin signaling pathway involved in limiting the nuclear localization of GR. Interaction between caveolin1 (CAV1) and LRP6, the main receptor for canonical Wnt signaling, is known to be critical for Wnt pathway activation and β-catenin stabilization. Compared to WT cells, LZKO cells had elevated total, cell-surface, and lipid-raft-associated LRP6 and reduced CAV1, strongly indicating alterations in the components of the Wnt-signaling pathway. We show that in the absence of LZTFL1, adipogenesis-restraining Wnt/β-catenin signaling is inhibited, and adipogenesis-favorable factors are stimulated in CB-MSCs, leading to enhanced adipogenesis. Evidence provided here could help in understanding the mechanism and molecular basis of obesity in LZTFL1-defective patients.
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Affiliation(s)
- Yunden Badralmaa
- Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Ven Natarajan
- Laboratory of Molecular Cell Biology, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
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2
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Cheng J, Cui J, Li Y, Liu X, Jiang Y, Liu Q, Liu C, Feng H, Jiao Z, Shao X, Gao Y, Sun D, Zhang W. The RAAS system SNPs polymorphism is associated with essential hypertension risk in rural areas in northern China. Int J Med Sci 2024; 21:2694-2704. [PMID: 39512695 PMCID: PMC11539379 DOI: 10.7150/ijms.98724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/19/2024] [Indexed: 11/15/2024] Open
Abstract
Objectives: Epidemiological evidence has shown that genetics and environment are associated with the risk of hypertension. However, the specific SNP effects of a cluster of crucial genes in the RAAS system on the risk of hypertension are unclear. Methods: A case-control study was performed on the baseline participants of Environment and Chronic Disease in Rural Areas of Heilongjiang China (ECDRAHC) study. According to the inclusion and exclusion criteria, 757 subjects (428 hypertensive patients) were enrolled. A total of 32 SNP sites and related haplotypes, involved in AGT (angiotensinogen), ACE (angiotensin-converting enzyme), AGTR1, CYP11B2 (aldosterone-synthase), LDLR (low-density lipoprotein receptor), LRP5 (low-density lipoprotein receptor associated protein 5), LRP6 (low-density lipoprotein receptor associated protein 6), PPARG (peroxisome proliferator-activated receptor gamma) and ACE2 (angiotensin-converting enzyme 2) genes which exert important roles in renin-angiotensin-aldosterone system (RAAS) system were analyzed. Furthermore, a polygenic scoring model was established to assess individual risk of developing hypertension based on the comprehensive SNPs effects in genes related the RAAS system. Results: After controlling the impact of confounding factors, multivariate logistic regression analysis revealed that the distribution of AGT/rs5046, LRP6/rs12823243 and ACE2/rs2285666 was associated with susceptibility to essential hypertension. In genetic score model, the score > -0.225 had a higher risk, the OR (95%CI) was 1.229 (1.110, 1.362). Conclusions: To the best of our knowledge, this is the first time a hypertension risk scoring model on RAAS associated gene cluster has been constructed, which will provide a novel approach for prevention and control of essential hypertension.
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Affiliation(s)
- Jin Cheng
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Jing Cui
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
- Harbin Center for Disease Control and Prevention, Harbin, Heilongjiang, People's Republic of China
| | - Yuanyuan Li
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Xiaona Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Yuting Jiang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Qiaoling Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Chang Liu
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Hongqi Feng
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
| | - Zhe Jiao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
| | - Xinhua Shao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
| | - Yanhui Gao
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
| | - Dianjun Sun
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University, Harbin, People's Republic of China
| | - Wei Zhang
- Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, People's Republic of China
- National Health Commission & Education Bureau of Heilongjiang Province, Key Laboratory of Etiology and Epidemiology, Harbin Medical University (23618504), Harbin, People's Republic of China
- Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Harbin Medical University, Harbin, People's Republic of China
- Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, People's Republic of China
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Le A, Peng H, Golinsky D, Di Scipio M, Lali R, Paré G. What Causes Premature Coronary Artery Disease? Curr Atheroscler Rep 2024; 26:189-203. [PMID: 38573470 DOI: 10.1007/s11883-024-01200-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
PURPOSE OF REVIEW This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD). RECENT FINDINGS pCAD refers to coronary artery disease (CAD) occurring before the age of 65 years in women and 55 years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research.
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Affiliation(s)
- Ann Le
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
| | - Helen Peng
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Danielle Golinsky
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- School of Nursing, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Matteo Di Scipio
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
- Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Ricky Lali
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada
| | - Guillaume Paré
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
- Department of Medical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, L8L 2X2, Canada.
- Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8L 4K1, Canada.
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Mehvari S, Karimian Fathi N, Saki S, Asadnezhad M, Arzhangi S, Ghodratpour F, Mohseni M, Zare Ashrafi F, Sadeghian S, Boroumand M, Shokohizadeh F, Rostami E, Boroumand R, Najafipour R, Malekzadeh R, Riazalhosseini Y, Akbari M, Lathrop M, Najmabadi H, Hosseini K, Kahrizi K. Contribution of genetic variants in the development of familial premature coronary artery disease in a cohort of cardiac patients. Clin Genet 2024; 105:611-619. [PMID: 38308583 DOI: 10.1111/cge.14491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/04/2024] [Accepted: 01/18/2024] [Indexed: 02/05/2024]
Abstract
Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one-third of patients with CAD have a positive family history, and individuals with such history are at ~1.5-fold increased risk of CAD in their lifespans. Accordingly, the long-recognized familial clustering of CAD is a strong risk factor for this disease. Our study aimed to identify candidate genetic variants contributing to CAD by studying a cohort of 60 large Iranian families with at least two members in different generations afflicted with premature CAD (PCAD), defined as established disease at ≤45 years in men and ≤55 years in women. Exome sequencing was performed for a subset of the affected individuals, followed by prioritization and Sanger sequencing of candidate variants in all available family members. Subsequently, apparently healthy carriers of potential risk variants underwent coronary computed tomography angiography (CCTA), followed by co-segregation analysis of the combined data. Putative causal variants were identified in seven genes, ABCG8, CD36, CYP27A1, PIK3C2G, RASSF9, RYR2, and ZFYVE21, co-segregating with familial PCAD in seven unrelated families. Among these, PIK3C2G, RASSF9, and ZFYVE21 are novel candidate CAD susceptibility genes. Our findings indicate that rare variants in genes identified in this study are involved in CAD development.
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Affiliation(s)
- Sepideh Mehvari
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Nahid Karimian Fathi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Sara Saki
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Asadnezhad
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Sanaz Arzhangi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Fatemeh Ghodratpour
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Marzieh Mohseni
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Farzane Zare Ashrafi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Saeed Sadeghian
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadali Boroumand
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Shokohizadeh
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Rostami
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Rahnama Boroumand
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Najafipour
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Reza Malekzadeh
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammadreza Akbari
- Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada
| | | | - Hossein Najmabadi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Kaveh Hosseini
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kimia Kahrizi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
- McGill Genome Centre, Montreal, Quebec, Canada
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Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
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Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Mani A. Update in genetic and epigenetic causes of hypertension. Cell Mol Life Sci 2024; 81:201. [PMID: 38691164 PMCID: PMC11062952 DOI: 10.1007/s00018-024-05220-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 05/03/2024]
Abstract
Hypertension is a heritable disease that affects one-fourth of the population and accounts for about 50% of cardiovascular deaths. The genetic basis of hypertension is multifaceted, involving both monogenic and most commonly complex polygenic forms. With the advent of the human genome project, genome-wide association studies (GWAS) have identified a plethora of loci linked to hypertension by examining common genetic variations. It's notable, however, that the majority of these genetic variants do not affect the protein-coding sequences, posing a considerable obstacle in pinpointing the actual genes responsible for hypertension. Despite these challenges, precise mapping of GWAS-identified loci is emerging as a promising strategy to reveal novel genes and potential targets for the pharmacological management of blood pressure. This review provides insight into the monogenic and polygenic causes of hypertension. Special attention is given to PRDM6, among the earliest functionally characterized GWAS-identified genes. Moreover, this review delves into the roles of genes contributing to renal and vascular forms of hypertension, offering insights into their genetic and epigenetic mechanisms of action.
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Affiliation(s)
- Arya Mani
- Department of Internal Medicine, Yale University School of Medicine, Yale Cardiovascular Research Center, 300 George Street, New Haven, CT, 06511, USA.
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
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7
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Sandforth L, Brachs S, Reinke J, Willmes D, Sancar G, Seigner J, Juarez-Lopez D, Sandforth A, McBride JD, Ma JX, Haufe S, Jordan J, Birkenfeld AL. Role of human Kallistatin in glucose and energy homeostasis in mice. Mol Metab 2024; 82:101905. [PMID: 38431218 PMCID: PMC10937158 DOI: 10.1016/j.molmet.2024.101905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 02/20/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2024] Open
Abstract
OBJECTIVE Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. METHODS Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. RESULTS In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. CONCLUSIONS KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.
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Affiliation(s)
- Leontine Sandforth
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Sebastian Brachs
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
| | - Julia Reinke
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany
| | - Diana Willmes
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany
| | - Gencer Sancar
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Judith Seigner
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - David Juarez-Lopez
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Arvid Sandforth
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jeffrey D McBride
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Sven Haufe
- Department of Rehabilitation and Sports Medicine, Hannover Medical School (MHH), Hannover, Germany
| | - Jens Jordan
- Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas L Birkenfeld
- Internal Medicine IV, Endocrinology, Diabetology and Nephrology, University Hospital of Tuebingen, Tuebingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tuebingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section of Metabolic Vascular Medicine, Department of Medicine III, University Clinic Dresden, TU Dresden, Germany; Department of Diabetes, Life Sciences & Medicine, Cardiovascular Medicine & Life Sciences, King's College London, UK.
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Katsi V, Papakonstantinou I, Tsioufis K. Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management. Int J Mol Sci 2023; 24:11786. [PMID: 37511551 PMCID: PMC10381022 DOI: 10.3390/ijms241411786] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.
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Affiliation(s)
- Vasiliki Katsi
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
| | | | - Konstantinos Tsioufis
- Department of Cardiology, Hippokration Hospital, 11527 Athens, Greece
- School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Xie XM, Cao QL, Sun YJ, Zhang J, Liu KL, Qin YF, Long WJ, Luo ZJ, Li XW, Liang XH, Yuan GD, Luo XP, Xuan XP. LRP6 Bidirectionally Regulates Insulin Sensitivity through Insulin Receptor and S6K Signaling in Rats with CG-IUGR. Curr Med Sci 2023; 43:274-283. [PMID: 36913109 DOI: 10.1007/s11596-022-2683-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 10/27/2022] [Indexed: 03/14/2023]
Abstract
OBJECTIVE Intrauterine growth restriction followed by postnatal catch-up growth (CG-IUGR) increases the risk of insulin resistance-related diseases. Low-density lipoprotein receptor-related protein 6 (LRP6) plays a substantial role in glucose metabolism. However, whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear. This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR. METHODS The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction. The mRNA and protein expression of the components in the insulin pathway, LRP6/β-catenin and mammalian target of rapamycin (mTOR)/S6 kinase (S6K) signaling, was determined. Liver tissues were immunostained for the expression of LRP6 and β-catenin. LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling. RESULTS Compared with the control rats, CG-IUGR rats showed higher homeostasis model assessment for insulin resistance (HOMA-IR) index and fasting insulin level, decreased insulin signaling, reduced mTOR/S6K/ insulin receptor substrate-1 (IRS-1) serine307 activity, and decreased LRP6/β-catenin in the liver tissue. The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age (AGA) rats led to reductions in insulin receptor (IR) signaling and mTOR/S6K/IRS-1 serine307 activity. In contrast, LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity. CONCLUSION LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways, IR and mTOR-S6K signaling. LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.
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Affiliation(s)
- Xue-Mei Xie
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Qiu-Li Cao
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Yu-Jie Sun
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Jie Zhang
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
| | - Kai-Li Liu
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Ying-Fen Qin
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Wen-Jun Long
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zuo-Jie Luo
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Xiao-Wei Li
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Xing-Huan Liang
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Guan-Dou Yuan
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Xiao-Ping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiu-Ping Xuan
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
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Puente N, Vega AI, Hernandez JL, Fernandez-Luna JL, Riancho JA. An LRP6 mutation (Arg360His) associated with low bone mineral density but not cardiovascular events in a Caucasian family. Osteoporos Int 2022; 33:2445-2448. [PMID: 35840698 PMCID: PMC9568478 DOI: 10.1007/s00198-022-06494-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/04/2022] [Indexed: 11/29/2022]
Abstract
UNLABELLED We present a family with a rare mutation of the LRP6 gene and for the first time provide evidence for its association with low bone mineral density. INTRODUCTION The Wnt pathway plays a critical role in bone homeostasis. Pathogenic variants of the Wnt co-receptor LRP6 have been associated with abnormal skeletal phenotypes or increased risk of cardiovascular events. PATIENT AND METHODS Here we report an index premenopausal patient and her family carrying a rare missense LRP6 pathogenic variant (rs141212743; 0.0002 frequency among Europeans). This variant has been previously associated with metabolic syndrome and atherosclerosis, in the presence of normal bone mineral density. However, the LRP6 variant was associated with low bone mineral density in this family, without evidence for association with serum lipid levels or cardiovascular events. CONCLUSION Thus, this novel association shows that LRP6 pathogenic variants may be involved in some cases of early-onset osteoporosis, but the predominant effect, either skeletal or cardiovascular, may vary depending on the genetic background or other acquired factors.
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Affiliation(s)
- Nuria Puente
- Servicio de Medicina Interna, Hospital UM Valdecilla, Universidad de Cantabria, IDIVAL, Avda Valdecilla sn, 39008, Santander, Spain
| | - Ana I Vega
- Servicio de Genética, Hospital UM Valdecilla, IDIVAL, Santander, Spain
| | - José L Hernandez
- Servicio de Medicina Interna, Hospital UM Valdecilla, Universidad de Cantabria, IDIVAL, Avda Valdecilla sn, 39008, Santander, Spain
| | | | - Jose A Riancho
- Servicio de Medicina Interna, Hospital UM Valdecilla, Universidad de Cantabria, IDIVAL, Avda Valdecilla sn, 39008, Santander, Spain.
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Keskin G, Karaer K, Uçar Gündoğar Z. Targeted next-generation sequencing (NGS) analysis of mutations in nonsyndromic tooth agenesis candidate genes : Analysis of a Turkish cohort. J Orofac Orthop 2022; 83:65-74. [PMID: 33725141 DOI: 10.1007/s00056-021-00284-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 02/06/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE The goal of this study was to assess genes known to be associated with tooth agenesis with next-generation sequencing (NGS) and analyze the relationship between these mutations and tooth agenesis phenotypes. METHODS The study included 49 individuals aged between 6 and 13 years. A total of 14 genes related to nonsyndromic tooth agenesis were selected for targeted NGS. Mutations in Msh homeobox 1 (MSX1), Wnt family member 10A (WNT10A), axis inhibition protein 2 (AXIN2), keratin 17 (KRT17), lipoprotein receptor 6 (LRP6), and secreted protein, acidic and rich in cysteine (SPARC)-related modular calcium-binding protein 2 (SMOC2) genes were investigated. RESULTS Mutations in six genes were detected in 12 of 49 subjects. Fifteen variants were identified, including the unknown variants c.657G > C in MSX1, c.2029C > T in AXIN2, and c.1603A > T in LRP6. Second premolar tooth agenesis was observed in 43.3% of all tooth agenesis cases with mutations, and it was the predominant phenotype observed for each mutated gene, followed by tooth agenesis of the lateral incisors (20%). CONCLUSIONS Variations in MSX1, WNT10A, AXIN2, KRT17, LRP6, and SMOC2 may be a risk factor for hypodontia or oligodontia in the Turkish population.
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Affiliation(s)
- Gül Keskin
- Department of Pediatric Dentistry, Gaziantep University, 27310, Gaziantep, Turkey.
| | - Kadri Karaer
- Department of Medical Genetics, Pamukkale University, 20070, Denizli, Turkey
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12
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Desita SR, Hariftyani AS, Jannah AR, Setyobudi AK, Oktaviono YH. PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis. J Basic Clin Physiol Pharmacol 2022; 33:529-534. [PMID: 35429418 DOI: 10.1515/jbcpp-2021-0291] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/09/2022] [Indexed: 06/14/2023]
Abstract
Coronary artery disease (CAD) is a disease characterized by atherosclerosis formation which causes sudden cardiac death. The prevalence of CAD is expected to increase by 2030. Atherosclerosis started from accumulation of LDL in the blood vessels, followed by endothelial cell activation and dysfunction. PCSK9 is a gene that plays an important role in the creation of atherosclerotic plaque through induced degradation of LDLRs. Inhibition of PCSK9 gene resulted in a decrease of LDLRs degradation and reduction in LDL-C levels. LRP6, as well as its mutation, is a coreceptor that contributes to atherosclerosis through the canonical Wnt/β-catenin pathway. By employing EMPs mediated miRNA-126, third-generation antisense against miR-494-3p (3 GA-494), and recombinant Wnt mouse Wnt3a (rmWnt3a), the inhibition of LRP6 could reduce VSMCs proliferation, enhancing anti-inflammatory macrophages, and diminished bioactive lipids component, respectively. Those mechanisms lead to the stabilization and reduction of atherosclerosis plaques.
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Affiliation(s)
- Saskia R Desita
- Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | - Ayik R Jannah
- Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | - Yudi H Oktaviono
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Dr. Soetomo General Hospital, Surabaya, Indonesia
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Yue H, Liang J, Song G, Cheng J, Li J, Zhi Y, Bian Z, He M. Mutation analysis in patients with nonsyndromic tooth agenesis using exome sequencing. Mol Genet Genomic Med 2022; 10:e2045. [PMID: 36017684 PMCID: PMC9544223 DOI: 10.1002/mgg3.2045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/05/2022] [Accepted: 08/15/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Tooth agenesis (TA) is a congenital abnormality that may present as syndromic or nonsyndromic. Considering its complex genetic aetiology, the aim of this study was to uncover the pathogenic mutants in patients with nonsyndromic TA and analyse the characteristics of these mutants. METHODS Exome sequencing was performed to detect pathogenic variants in 72 patients from 43 unrelated families with nonsyndromic TA. All candidate variants were validated using Sanger sequencing. Bioinformatics and conformational analyses were performed to determine the pathogenic mechanisms of the mutants. RESULTS The following eight mutations (six novel and two known) in six genes were identified in eight families: WNT10A [c.742C > T (p.R248*)], LRP6 [c.1518G > A (p.W506*), c.2791 + 1G > T], AXIN2 [c.133_134insGCCAGG (p.44_45insGQ)], PAX9 [c.439C > T (p.Q147*), c.453_454insCCAGC (p.L154QfsTer60)], MSX1 [c.603_604del (p.A203GfsTer10)] and PITX2 [c.522C > G (p.Y174*)]. Bioinformatics and conformational analyses showed that the protein structures were severely altered in these mutants, and indicated that these structural abnormalities may cause functional disabilities. CONCLUSIONS Our study extends the mutation spectrum in patients with nonsyndromic TA and provides valuable data for genetic counselling. The pathogenic mechanisms of TA in patients/families with unknown causative variants need to be explored further.
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Affiliation(s)
- Haitang Yue
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jia Liang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Guangtai Song
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jing Cheng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jiahui Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yusheng Zhi
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhuan Bian
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Miao He
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther 2022; 7:131. [PMID: 35459215 PMCID: PMC9033871 DOI: 10.1038/s41392-022-00955-7] [Citation(s) in RCA: 475] [Impact Index Per Article: 158.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023] Open
Abstract
Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis. Several signaling pathways, that are associated with the inflammatory response, have been implicated within atherosclerosis such as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt signaling pathways, which are of importance for atherosclerosis development and regression. Targeting inflammatory pathways, especially the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β, could represent an attractive new route for the treatment of atherosclerotic diseases. Herein, we summarize the knowledge on cellular participants and key inflammatory signaling pathways in atherosclerosis, and discuss the preclinical studies targeting these key pathways for atherosclerosis, the clinical trials that are going to target some of these processes, and the effects of quelling inflammation and atherosclerosis in the clinic.
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Affiliation(s)
- Peng Kong
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Zi-Yang Cui
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Xiao-Fu Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Dan-Dan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Rui-Juan Guo
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Mei Han
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China.
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Activation of LRP6 with HLY78 Attenuates Oxidative Stress and Neuronal Apoptosis via GSK3β/Sirt1/PGC-1α Pathway after ICH. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7542468. [PMID: 35419167 PMCID: PMC9001077 DOI: 10.1155/2022/7542468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/09/2022] [Accepted: 02/12/2022] [Indexed: 12/14/2022]
Abstract
Background Oxidative stress and neuronal apoptosis have important roles in the pathogenesis after intracerebral hemorrhage (ICH). Previous studies have reported that low-density lipoprotein receptor-related protein 6 (LRP6) exerts neuroprotection in several neurological diseases. Herein, we investigate the role of LRP6 receptor activation with HLY78 to attenuate oxidative stress and neuronal apoptosis after ICH, as well as the underlying mechanism. Methods A total of 199 CD1 mice were used. ICH was induced via injection of autologous blood into the right basal ganglia. HLY78 was administered via intranasal injection at 1 h after ICH. To explore the underlying mechanism, LRP6 siRNA and selisistat, a Sirt1 selective antagonist, were injected intracerebroventricularly at 48 h before ICH induction. Neurobehavioral tests, Western blot, and immunofluorescence staining were performed. Results The expression of endogenous p-LRP6 was gradually increased and expressed on neurons after ICH. HLY78 significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased oxidative stress and neuronal apoptosis, as well as increased expression of p-GSK3β, Sirt1, and PGC-1α, as well as downregulation of Romo-1 and C-Caspase-3. LRP6 knockdown or Sirt1 inhibition abolished these effects of HLY78 after ICH. Conclusion Our results suggest that administration of HLY78 attenuated oxidative stress, neuronal apoptosis, and neurobehavioral impairments through the LRP6/GSK3β/Sirt1/PGC-1α signaling pathway after ICH.
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Long W, Zhou T, Xuan X, Cao Q, Luo Z, Qin Y, Ning Q, Luo X, Xie X. IUGR with catch-up growth programs impaired insulin sensitivity through LRP6/IRS-1 in male rats. Endocr Connect 2022; 11:EC-21-0203.R1. [PMID: 34825892 PMCID: PMC8789020 DOI: 10.1530/ec-21-0203] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/26/2021] [Indexed: 11/11/2022]
Abstract
Intrauterine growth restriction combined with postnatal accelerated growth (CG-IUGR) could lead to long-term detrimental metabolic outcomes characterized by insulin resistance. As an indispensable co-receptor of Wnt signaling, LRP6 plays a critical role in the susceptibility of metabolic disorders. However, whether LRP6 is involved in the metabolic programing is still unknown. We hypothesized that CG-IUGR programed impaired insulin sensitivity through the impaired LRP6-mediated Wnt signaling in skeletal muscle. A CG-IUGR rat model was employed. The transcriptional and translational alterations of the components of the Wnt and the insulin signaling in the skeletal muscle of the male CG-IUGR rats were determined. The role of LRP6 on the insulin signaling was evaluated by shRNA knockdown or Wnt3a stimulation of LRP6. Compared with controls, the male CG-IUGR rats showed an insulin-resistant phenotype, with impaired insulin signaling and decreased expression of LRP6/β-catenin in skeletal muscle. LRP6 knockdown led to reduced expression of the IR-β/IRS-1 in C2C12 cell line, while Wnt3a-mediated LRP6 expression increased the expression of IRS-1 and IGF-1R but not IR-β in the primary muscle cells of male CG-IUGR rats. The impaired LRP6/β-catenin/IGF-1R/IRS-1 signaling is probably one of the critical mechanisms underlying the programed impaired insulin sensitivity in male CG-IUGR.
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Affiliation(s)
- Wenjun Long
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tuo Zhou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiuping Xuan
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qiuli Cao
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zuojie Luo
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuemei Xie
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Correspondence should be addressed to X Xie:
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17
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Cao Q, Li X, Xuan X, Huang S, Xie X. Changes of LRP6/β-catenin pathway in adipose tissue of rats with intrauterine growth restriction with catch-up growth. Zhejiang Da Xue Xue Bao Yi Xue Ban 2021; 50:755-761. [PMID: 35347917 PMCID: PMC8931619 DOI: 10.3724/zdxbyxb-2021-0178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/30/2021] [Indexed: 06/14/2023]
Abstract
To investigate the expression of low-density lipoprotein receptor-related protein 6 (LRP6)/β-catenin pathway related proteins in adipose tissue of rats with intrauterine growth restriction with catch-up growth SD rats were randomly divided into nutrition-restriction rats and normal feed rats during pregnancy. CG-IUGR model was established by reducing the number of offspring in the nutrition-restriction rats (CG-IUGR group); while the rats in the control group were offspring of the normal feed pregnant rats. In order to exclude the interference of gender, male offspring mice were selected in both the CG-IUGR group and the control group in the following studies. The CG-IUGR group and the control group were subjected to glucose tolerance test at 12 weeks of age, and the perirenal adipose tissue samples were taken to observe the adipose structure by HE staining. Expression of LRP6, β-catenin and insulin receptor substrate 1 (IRS-1) in adipocytes were examined by confocal microscopy. Protein expression of LRP6, β-catenin and IRS-1 were measured by Western blotting. Blood glucose level and the area under the cure of CG-IUGR group were significantly higher than that of control group (both <0.05). Adipocyte size in the CG-IUGR group was significantly larger than that of control group, and the expression of LRP6, β-catenin and IRS-1 protein in adipose tissue of the CG-IUGR group was significantly lower than that of control group (all <0.05). : The expression of LRP6/β-catenin pathway related proteins is reduced in the adipose tissue in CG-IUGR rats, probably contributing to the insulin resistance in these rats.
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18
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Jeong W, Jho EH. Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond. Front Cell Dev Biol 2021; 9:714330. [PMID: 34589484 PMCID: PMC8473786 DOI: 10.3389/fcell.2021.714330] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/25/2021] [Indexed: 11/13/2022] Open
Abstract
Wnt signaling plays crucial roles in development and tissue homeostasis, and its dysregulation leads to various diseases, notably cancer. Wnt/β-catenin signaling is initiated when the glycoprotein Wnt binds to and forms a ternary complex with the Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Despite being identified as a Wnt co-receptor over 20 years ago, the molecular mechanisms governing how LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered. Due to its role as one of the main Wnt signaling components, the dysregulation or mutation of LRP6 is implicated in several diseases such as cancer, neurodegeneration, metabolic syndrome and skeletal disease. Herein, we will review how LRP6 is activated by Wnt stimulation and explore the various regulatory mechanisms involved. The participation of LRP6 in other signaling pathways will also be discussed. Finally, the relationship between LRP6 dysregulation and disease will be examined in detail.
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Affiliation(s)
- Wonyoung Jeong
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, Seoul, South Korea
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19
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Chow H, Sun JK, Hart RP, Cheng KK, Hung CHL, Lau T, Kwan K. Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2004993. [PMID: 34180138 PMCID: PMC8373092 DOI: 10.1002/advs.202004993] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 05/06/2021] [Indexed: 05/07/2023]
Abstract
Early changes in astrocyte energy metabolism are associated with late-onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated with diminished LRP6 gene expression in the frontal cortex region. The authors show that LRP6 is a unique Wnt coreceptor on astrocytes, serving as a bimodal switch that modulates their metabolic landscapes. The Wnt-LRP6 mediated mTOR-AKT axis is essential for sustaining glucose metabolism. In its absence, Wnt switches to activate the LRP6-independent Ca2+ -PKC-NFAT axis, resulting in a transcription network that favors glutamine and branched chain amino acids (BCAAs) catabolism over glucose metabolism. Exhaustion of these raw materials essential for neurotransmitter biosynthesis and recycling results in compromised synaptic, cognitive, and memory functions; priming for early changes that are frequently found in LOAD. The authors also highlight that intranasal supplementation of glutamine and BCAAs is effective in preserving neuronal integrity and brain functions, proposing a nutrient-based method for delaying cognitive and memory decline when LRP6 cell surface levels and functions are suboptimal.
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Affiliation(s)
- Hei‐Man Chow
- School of Life Sciences, Faculty of ScienceThe Chinese University of Hong Kong999077Hong Kong
| | - Jacquelyne Ka‐Li Sun
- School of Life Sciences, Faculty of ScienceThe Chinese University of Hong Kong999077Hong Kong
| | - Ronald P. Hart
- Department of Cell Biology and NeuroscienceRutgers UniversityPiscatawayNJ08854USA
| | - Kenneth King‐Yip Cheng
- Department of Health Technology and InformaticsThe Hong Kong Polytechnic University999077Hong Kong
| | - Clara H. L. Hung
- The University Research Facility in Life SciencesThe Hong Kong Polytechnic University999077Hong Kong
| | - Tsun‐Ming Lau
- School of Life Sciences, Faculty of ScienceThe Chinese University of Hong Kong999077Hong Kong
| | - Kin‐Ming Kwan
- School of Life Sciences, Faculty of ScienceThe Chinese University of Hong Kong999077Hong Kong
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20
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Huang YX, Gao CY, Zheng CY, Chen X, Yan YS, Sun YQ, Dong XY, Yang K, Zhang DL. Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis. Front Genet 2021; 12:688241. [PMID: 34306029 PMCID: PMC8292820 DOI: 10.3389/fgene.2021.688241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/16/2021] [Indexed: 01/13/2023] Open
Abstract
Background The low-density lipoprotein receptor-related protein 6 (LRP6) gene is a recently defined gene that is associated with the autosomal-dominant inherited tooth agenesis (TA). In the present study, a family of four generations having TA was recruited and subjected to a series of clinical, genetic, in silico, and in vitro investigations. Methods After routine clinical evaluation, the proband was subjected to whole-exome sequencing (WES) to detect the diagnostic variant. Next, in silico structural and molecular dynamics (MD) analysis was conducted on the identified novel missense variant for predicting its intramolecular impact. Subsequently, an in vitro study was performed to further explore the effect of this variant on protein maturation and phosphorylation. Results WES identified a novel variant, designated as LRP6: c.2570G > A (p.R857H), harbored by six members of the concerned family, four of whom exhibited varied TA symptoms. The in silico analysis suggested that this novel variant could probably damage the Wnt bonding function of the LRP6 protein. The experimental study demonstrated that although this novel variant did not affect the LRP6 gene transcription, it caused a impairment in the maturation and phosphorylation of LRP6 protein, suggesting the possibility of the disruption of the Wnt signaling. Conclusion The present study expanded the mutation spectrum of human TA in the LRP6 gene. The findings of the present study are insightful and conducive to understanding the functional significance of specific LRP6 variants.
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Affiliation(s)
- Yan-Xia Huang
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Chun-Yan Gao
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Chun-Yan Zheng
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Xu Chen
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - You-Sheng Yan
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yong-Qing Sun
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Xing-Yue Dong
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Kai Yang
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Dong-Liang Zhang
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
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21
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Bagchi DP, MacDougald OA. Wnt Signaling: From Mesenchymal Cell Fate to Lipogenesis and Other Mature Adipocyte Functions. Diabetes 2021; 70:1419-1430. [PMID: 34155042 PMCID: PMC8336005 DOI: 10.2337/dbi20-0015] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/20/2021] [Indexed: 12/14/2022]
Abstract
Wnt signaling is an ancient and evolutionarily conserved pathway with fundamental roles in the development of adipose tissues. Roles of this pathway in mesenchymal stem cell fate determination and differentiation have been extensively studied. Indeed, canonical Wnt signaling is a significant endogenous inhibitor of adipogenesis and promoter of other cell fates, including osteogenesis, chondrogenesis, and myogenesis. However, emerging genetic evidence in both humans and mice suggests central roles for Wnt signaling in body fat distribution, obesity, and metabolic dysfunction. Herein, we highlight recent studies that have begun to unravel the contributions of various Wnt pathway members to critical adipocyte functions, including carbohydrate and lipid metabolism. We further explore compelling evidence of complex and coordinated interactions between adipocytes and other cell types within adipose tissues, including stromal, immune, and endothelial cells. Given the evolutionary conservation and ubiquitous cellular distribution of this pathway, uncovering the contributions of Wnt signaling to cell metabolism has exciting implications for therapeutic intervention in widespread pathologic states, including obesity, diabetes, and cancers.
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Affiliation(s)
- Devika P Bagchi
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
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22
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Weerackoon N, Gunawardhana KL, Mani A. Wnt Signaling Cascades and Their Role in Coronary Artery Health and Disease. JOURNAL OF CELLULAR SIGNALING 2021; 2:52-62. [PMID: 33969358 PMCID: PMC8098721 DOI: 10.33696/signaling.2.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The Wnt signaling is classified as two distinct pathways of canonical Wnt/β-catenin signaling, and the non-canonical pathways of planar cell polarity and Wnt/Ca2+ pathways. However, the scientific discoveries in recent years have shown that canonical and non-canonical Wnts pathways are intertwined and have complex interaction with other major signaling pathways such as hedgehog, Hippo and TOR signaling. Wnt signaling plays important roles in cell proliferation, differentiation and migration during embryonic development. The impairment of these pathways during embryonic development often leads to major congenital defects. In adult organisms Wnt expression is more restricted to proliferating tissues, where it plays a key role in tissue regeneration. In addition, the disruption of homeostatic processes of multicellular organisms may give rise to reactivation and/or altered activation of Wnt signaling, leading to development of malignant tumors and chronic diseases such as type-2 diabetes and adult cardiovascular diseases. Coronary artery disease (CAD) is the leading cause of death in the world. The disease is the consequences of two distinct disease processes: Atherosclerosis, a primarily inflammatory disease and plaque erosion, a disease process associated with endothelial cell defect and smooth muscle proliferation with only modest contribution of inflammatory cells. The atherosclerosis is itself a multifactorial disease that is initiated by lipid deposition and endothelial dysfunction, triggering vascular inflammation via recruitment and aggregation of monocytes and their transformation to foam cell by the uptake of modified low-density lipoprotein (LDL), culminating in an atheromatous plaque core formation. Further accumulation of lipids, infiltration and proliferation of vascular smooth muscle cells (VSMCs) and extracellular matrix deposition result in intimal hyperplasia. Myocardial infarction is the ultimate consequence of these processes and is caused by plaque rupture and hypercoagulation. In vivo studies have established the role of the Wnt pathway in all phases of atherosclerosis development, though much remains unknown or controversial. Less is known about the mechanisms that induce plaque erosion. The limited evidence in mouse models of Wnt coreceptor LRP6 mutation and heterozygous TCF7L2 knock out mice implicate altered Wnt signaling also in the pathogenesis of plaque erosion. In this article we focus and review the role of the Wnt pathway in CAD pathophysiology from clinical and experimental standpoints.
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Affiliation(s)
- Nadisha Weerackoon
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Kushan L Gunawardhana
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.,Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Arya Mani
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.,Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
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23
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Mineo C. Lipoprotein receptor signalling in atherosclerosis. Cardiovasc Res 2021; 116:1254-1274. [PMID: 31834409 DOI: 10.1093/cvr/cvz338] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/01/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022] Open
Abstract
The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis. Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor, and apolipoprotein E receptor 2. The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL. Among these are cluster of differentiation 36, scavenger receptor class B type I and lectin-like oxidized low-density lipoprotein receptor-1. In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signalling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells, and platelets. Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.
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Affiliation(s)
- Chieko Mineo
- Department of Pediatrics and Cell Biology, Center for Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA
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24
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Yu M, Fan Z, Wong SW, Sun K, Zhang L, Liu H, Feng H, Liu Y, Han D. Lrp6 Dynamic Expression in Tooth Development and Mutations in Oligodontia. J Dent Res 2020; 100:415-422. [PMID: 33164649 DOI: 10.1177/0022034520970459] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Genes associated with the WNT pathway play an important role in the etiology of tooth agenesis. Low-density lipoprotein receptor-related protein 6 encoding gene (LRP6) is a recently defined gene that is associated with autosomal dominant inherited tooth agenesis. Here, we aimed to identify novel LRP6 mutations in patients with tooth agenesis and investigate the significance of Lrp6 during tooth development. Using whole-exome sequencing, we identified 4 novel LRP6 heterozygous mutations (c.2292G>A, c.195dup, c.1095dup, and c.1681C>T) in 4 of 77 oligodontia patients. Notably, a patient who carried a nonsense LRP6 mutation (c.2292G>A; p.W764*) presented a hypohidrotic ectodermal dysplasia phenotype. Preliminary functional studies, including bioinformatics analysis and TOP-/FOP-flash reporter assays, demonstrated that the activation of WNT/β-catenin signaling was compromised as a consequence of LRP6 mutations. RNAscope in situ hybridization revealed dynamic and special changes of Lrp6 expression during murine tooth development from E11.5 to E16.5. It was noteworthy that Lrp6 was specifically expressed in the epithelium at E11.5 to E13.5 but was expressed in both dental epithelium and dental papilla from E14.5 and persisted in both tissues at later stages. Our study broadens the mutation spectrum of human tooth agenesis and is the first to identify a LRP6 mutation in patients with hypohidrotic ectodermal dysplasia and reveal the dynamic expression pattern of Lrp6 during tooth development. Information from this study is conducive to understanding the functional significance of Lrp6 on the biological process of tooth development.
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Affiliation(s)
- M Yu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Z Fan
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - S W Wong
- Division of Comprehensive Oral Care-Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - K Sun
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - L Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - H Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - H Feng
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Y Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - D Han
- Department of Prosthodontics, Peking University School and Hospital of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, Beijing, China
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25
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Liu Y, Neogi A, Mani A. The role of Wnt signalling in development of coronary artery disease and its risk factors. Open Biol 2020; 10:200128. [PMID: 33081636 PMCID: PMC7653355 DOI: 10.1098/rsob.200128] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/23/2020] [Indexed: 02/05/2023] Open
Abstract
The Wnt signalling pathways are composed of a highly conserved cascade of events that govern cell differentiation, apoptosis and cell orientation. Three major and distinct Wnt signalling pathways have been characterized: the canonical Wnt pathway (or Wnt/β-catenin pathway), the non-canonical planar cell polarity pathway and the non-canonical Wnt/Ca2+ pathway. Altered Wnt signalling pathway has been associated with diverse diseases such as disorders of bone density, different malignancies, cardiac malformations and heart failure. Coronary artery disease is the most common type of heart disease in the United States. Atherosclerosis is a multi-step pathological process, which starts with lipid deposition and endothelial cell dysfunction, triggering inflammatory reactions, followed by recruitment and aggregation of monocytes. Subsequently, monocytes differentiate into tissue-resident macrophages and transform into foam cells by the uptake of modified low-density lipoprotein. Meanwhile, further accumulations of lipids, infiltration and proliferation of vascular smooth muscle cells, and deposition of the extracellular matrix occur under the intima. An atheromatous plaque or hyperplasia of the intima and media is eventually formed, resulting in luminal narrowing and reduced blood flow to the myocardium, leading to chest pain, angina and even myocardial infarction. The Wnt pathway participates in all different stages of this process, from endothelial dysfunction to lipid deposit, and from initial inflammation to plaque formation. Here, we focus on the role of Wnt cascade in pathophysiological mechanisms that take part in coronary artery disease from both clinical and experimental perspectives.
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Affiliation(s)
- Ya Liu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Arpita Neogi
- Yale Cardiovascular Genetics Program, Yale University, New Haven, CT, USA
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale University, New Haven, CT, USA
- Yale Cardiovascular Research Center, Department of Medicine, Yale University, New Haven, CT, USA
- Department of Genetics, Yale University School of Medicine, Yale University, New Haven, CT, USA
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26
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Wang Y, Chen Z, Li Y, Ma L, Zou Y, Wang X, Yin C, Pan L, Shen Y, Jia J, Yuan J, Zhang G, Yang C, Ge J, Zou Y, Gong H. Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3β. Redox Biol 2020; 37:101699. [PMID: 32905882 PMCID: PMC7486456 DOI: 10.1016/j.redox.2020.101699] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/17/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Low density lipoprotein receptor-related protein 6 (LRP6), a Wnt co-receptor, induces multiple functions in various organs. We recently reported cardiac specific LRP6 deficiency caused cardiac dysfunction in mice. Whether cardiomyocyte-expressed LRP6 protects hearts against ischemic stress is largely unknown. Here, we investigated the effects of cardiac LRP6 in response to ischemic reperfusion (I/R) injury. Tamoxifen inducible cardiac specific LRP6 overexpression mice were generated to build I/R model by occlusion of the left anterior descending (LAD) coronary artery for 40 min and subsequent release of specific time. Cardiac specific LRP6 overexpression significantly ameliorated myocardial I/R injury as characterized by the improved cardiac function, strain pattern and infarct area at 24 h after reperfusion. I/R induced-apoptosis and endoplasmic reticulum (ER) stress were greatly inhibited by LRP6 overexpression in cardiomyocytes. LRP6 overexpression enhanced the expression of heat shock transcription factor-1(HSF1) and heat shock proteins (HSPs), the level of p-glycogen synthase kinase 3β(GSK3β)(S9) and p-AMPK under I/R. HSF1 inhibitor deteriorated the apoptosis and decreased p-GSK3β(S9) level in LRP6 overexpressed -cardiomyocytes treated with H2O2. Si-HSF1 or overexpression of active GSK3β significantly attenuated the increased expression of HSF1 and p-AMPK, and the inhibition of apoptosis and ER stress induced by LRP6 overexpression in H2O2-treated cardiomyocytes. AMPK inhibitor suppressed the increase in p-GSK3β (S9) level but didn't alter HSF1 nucleus expression in LRP6 overexpressed-cardiomyocytes treated with H2O2. Active GSK3β, but not AMPK inhibitor, attenuated the inhibition of ubiquitination of HSF1 induced by LRP6-overexpressed-cardiomyocytes treated with H2O2. LRP6 overexpression increased interaction of HSF1 and GSK3β which may be involved in the reciprocal regulation under oxidative stress. In conclusion, cardiac LRP6 overexpression significantly inhibits cardiomyocyte apoptosis and ameliorates myocardial I/R injury by the crosstalk of HSF1 and GSK3β signaling.
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Affiliation(s)
- Ying Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhidan Chen
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yang Li
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Leilei Ma
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yan Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Xiang Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Chao Yin
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Le Pan
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yi Shen
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Jianguo Jia
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Jie Yuan
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Guoping Zhang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Chunjie Yang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yunzeng Zou
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
| | - Hui Gong
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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Bagchi DP, Nishii A, Li Z, DelProposto JB, Corsa CA, Mori H, Hardij J, Learman BS, Lumeng CN, MacDougald OA. Wnt/β-catenin signaling regulates adipose tissue lipogenesis and adipocyte-specific loss is rigorously defended by neighboring stromal-vascular cells. Mol Metab 2020; 42:101078. [PMID: 32919095 PMCID: PMC7554252 DOI: 10.1016/j.molmet.2020.101078] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/14/2020] [Accepted: 09/06/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Canonical Wnt/β-catenin signaling is a well-studied endogenous regulator of mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting adipogenesis. However, emerging genetic evidence in humans links a number of Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway also functions in adipocytes. Recent studies in mice have uncovered compelling evidence that the Wnt signaling pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions. However, complexities in Wnt signaling and differences in experimental models and approaches have thus far limited our understanding of its specific roles in this context. METHODS To investigate roles of the canonical Wnt pathway in the regulation of adipocyte metabolism, we generated adipocyte-specific β-catenin (β-cat) knockout mouse and cultured cell models. We used RNA sequencing, ChIP sequencing, and molecular approaches to assess expression of Wnt targets and lipogenic genes. We then used functional assays to evaluate effects of β-catenin deficiency on adipocyte metabolism, including lipid and carbohydrate handling. In mice maintained on normal chow and high-fat diets, we assessed the cellular and functional consequences of adipocyte-specific β-catenin deletion on adipose tissues and systemic metabolism. RESULTS We report that in adipocytes, the canonical Wnt/β-catenin pathway regulates de novo lipogenesis (DNL) and fatty acid monounsaturation. Further, β-catenin mediates effects of Wnt signaling on lipid metabolism in part by transcriptional regulation of Mlxipl and Srebf1. Intriguingly, adipocyte-specific loss of β-catenin is sensed and defended by CD45-/CD31- stromal cells to maintain tissue-wide Wnt signaling homeostasis in chow-fed mice. With long-term high-fat diet, this compensatory mechanism is overridden, revealing that β-catenin deletion promotes resistance to diet-induced obesity and adipocyte hypertrophy and subsequent protection from metabolic dysfunction. CONCLUSIONS Taken together, our studies demonstrate that Wnt signaling in adipocytes is required for lipogenic gene expression, de novo lipogenesis, and lipid desaturation. In addition, adipose tissues rigorously defend Wnt signaling homeostasis under standard nutritional conditions, such that stromal-vascular cells sense and compensate for adipocyte-specific loss. These findings underscore the critical importance of this pathway in adipocyte lipid metabolism and adipose tissue function.
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Affiliation(s)
- Devika P Bagchi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Akira Nishii
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ziru Li
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Jennifer B DelProposto
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Callie A Corsa
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Hiroyuki Mori
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Julie Hardij
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Brian S Learman
- Department of Microbiology and Immunology, University of Buffalo, Buffalo, NY, USA.
| | - Carey N Lumeng
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ormond A MacDougald
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
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Bagchi DP, Li Z, Corsa CA, Hardij J, Mori H, Learman BS, Lewis KT, Schill RL, Romanelli SM, MacDougald OA. Wntless regulates lipogenic gene expression in adipocytes and protects against diet-induced metabolic dysfunction. Mol Metab 2020; 39:100992. [PMID: 32325263 PMCID: PMC7264081 DOI: 10.1016/j.molmet.2020.100992] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/27/2020] [Accepted: 04/02/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular disease. Canonical Wnt/β-catenin signaling is established as an important endogenous inhibitor of adipogenesis. This pathway is operative in mature adipocytes; however, its roles in this context remain unclear due to complexities of Wnt signaling and differences in experimental models. In this study, we used novel cultured cell and mouse models to investigate functional roles of Wnts secreted from adipocytes. METHODS We generated adipocyte-specific Wntless (Wls) knockout mice and cultured cell models to investigate molecular and metabolic consequences of disrupting Wnt secretion from mature adipocytes. To characterize Wls-deficient cultured adipocytes, we evaluated the expression of Wnt target and lipogenic genes and the downstream functional effects on carbohydrate and lipid metabolism. We also investigated the impact of adipocyte-specific Wls deletion on adipose tissues and global glucose metabolism in mice fed normal chow or high-fat diets. RESULTS Many aspects of the Wnt signaling apparatus are expressed and operative in mature adipocytes, including the Wnt chaperone Wntless. Deletion of Wntless in cultured adipocytes results in the inhibition of de novo lipogenesis and lipid monounsaturation, likely through repression of Srebf1 (SREBP1c) and Mlxipl (ChREBP) and impaired cleavage of immature SREBP1c into its active form. Adipocyte-specific Wls knockout mice (Wls-/-) have lipogenic gene expression in adipose tissues and isolated adipocytes similar to that of controls when fed a normal chow diet. However, closer investigation reveals that a subset of Wnts and downstream signaling targets are upregulated within stromal-vascular cells of Wls-/- mice, suggesting that adipose tissues defend loss of Wnt secretion from adipocytes. Interestingly, this compensation is lost with long-term high-fat diet challenges. Thus, after six months of a high-fat diet, Wls-/- mice are characterized by decreased adipocyte lipogenic gene expression, reduced visceral adiposity, and improved glucose homeostasis. CONCLUSIONS Taken together, these studies demonstrate that adipocyte-derived Wnts regulate de novo lipogenesis and lipid desaturation and coordinate the expression of lipogenic genes in adipose tissues. In addition, we report that Wnt signaling within adipose tissues is defended, such that a loss of Wnt secretion from adipocytes is sensed and compensated for by neighboring stromal-vascular cells. With chronic overnutrition, this compensatory mechanism is lost, revealing that Wls-/- mice are resistant to diet-induced obesity, adipocyte hypertrophy, and metabolic dysfunction.
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Affiliation(s)
- Devika P Bagchi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ziru Li
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Callie A Corsa
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Julie Hardij
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Hiroyuki Mori
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Brian S Learman
- Department of Microbiology and Immunology, University of Buffalo, Buffalo, NY, USA.
| | - Kenneth T Lewis
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Rebecca L Schill
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Steven M Romanelli
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Ormond A MacDougald
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
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Montazeri-Najafabady N, Dabbaghmanesh MH, Mohammadian Amiri R. The rs2302685 polymorphism in the LRP6 gene is associated with bone mineral density and body composition in Iranian children. J Gene Med 2020; 22:e3245. [PMID: 32573887 DOI: 10.1002/jgm.3245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/25/2020] [Accepted: 03/15/2020] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Some 60-80% of the variability in bone mineral density (BMD) is determined by genetic factors. In the present study, we investigated the impact of the rs2302685 polymorphism of LRP6 on BMD and body composition in Iranian children. METHODS In total, 200 children (101 boys and 99 girls) were enrolled in the study. Body composition and BMD were computed using the Hologic DXA System (Hologic, Marlborough, MA, USA). The single nucleotide polymorphism of LRP6 rs2302685 (V1062I) was determined using a polymerase chain reaction/restriction fragment length polymorphism. A generalized linear model was performed to find the association between LRP6 polymorphisms, BMD and body composition in two adjusted models. RESULTS In model 1, a significant difference was found between LRP6 (rs2302685) polymorphism, trochanteric BMD (p = 0.007), intertrochanteric BMD (p = 0.007), total fat (p = 0.001), total fat (%) (p = 0.034), total lean mass (p = 0.031), total Lean + BMC (p = 0.036) and total mass (p = 0.001). In model 2, LRP6 (rs2302685) polymorphisms showed a significant effect on the trochanteric BMD (p = 0.005), intertrochanteric BMD (p = 0.005), total fat (p = 0.001), total fat (%) (p = 0.013) and total mass (p = 0.01). Total fat, total fat (%) and total body mass were higher in subjects with the CC genotype compared to the TT/CT genotype, whereas total lean mass and total Lean + BMC were higher in the TT/CT genotype. CONCLUSIONS The present study shows that the LRP6 polymorphism may be associated with body composition and BMD in Iranian children.
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Affiliation(s)
- Nima Montazeri-Najafabady
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hossein Dabbaghmanesh
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Rajeeh Mohammadian Amiri
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Boucher P, Matz RL, Terrand J. atherosclerosis: gone with the Wnt? Atherosclerosis 2020; 301:15-22. [PMID: 32289618 DOI: 10.1016/j.atherosclerosis.2020.03.024] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/19/2020] [Accepted: 03/26/2020] [Indexed: 12/11/2022]
Abstract
Atherosclerosis, a pathology affecting large and medium-sized arteries, is the major cause of cardiovascular morbidity/mortality in industrialized countries. During atherosclerosis, cells accumulate large amounts of cholesterol through the uptake of modified low-density lipoprotein particles to form foam cells. This accumulation forms the basis for the development of the disease and for a large spectrum of other diseases in various organs. Massive research efforts have yielded valuable information about the underlying molecular mechanisms of atherosclerosis. In particular, newer discoveries on the early stage of lesion formation, cholesterol accumulation, reverse cholesterol transport, and local inflammation in the vascular wall have opened unanticipated horizons of understanding and raised novel questions and therapeutic opportunities. In this review, we focus on Wnt signaling, which has received little attention so far, yet affects lysosomal function and signalling pathways that limit cholesterol accumulation. This occurs in different tissues and cell types, including smooth muscle cells, endothelial cells and macrophages in the arterial wall, and thus profoundly impacts on atherosclerotic disease development and progression.
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Affiliation(s)
- Philippe Boucher
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France.
| | - Rachel L Matz
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France
| | - Jérôme Terrand
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France
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Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine. Sci Rep 2020; 10:5186. [PMID: 32198362 PMCID: PMC7083857 DOI: 10.1038/s41598-020-61869-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/24/2020] [Indexed: 12/15/2022] Open
Abstract
The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway.
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Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities. Hum Genet 2020; 139:447-459. [PMID: 32076828 DOI: 10.1007/s00439-020-02124-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/31/2020] [Indexed: 12/15/2022]
Abstract
Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptors (LDLRs) family and accumulating evidence points to the critical role of LRP6 in cardiovascular health and homeostasis. In addition to presenting the well-appreciated roles in canonical signaling regulating blood pressure, blood glucose, lipid metabolism, atherosclerosis, cardiac valve disease, cardiac development, Alzheimer's disease and tumorigenesis, LRP6 also inhibits non-canonical Wnt signals that promote arterial smooth muscle cell proliferation and vascular calcification. Noticeably, the role of LRP6 is displayed in cardiometabolic disease, an increasingly important clinical burden with aging and obesity. The prospect for cardiovascular diseases treatment via targeting LRP6-mediated signaling pathways may improve central blood pressure and lipid metabolism, and reduce neointima formation and myocardial ischemia-reperfusion injury. Thus, a deep and comprehensive understanding of LRP6 structure, function and signaling pathways will contribute to clinical diagnosis, therapy and new drug development for LRP6-related cardiovascular diseases.
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Affiliation(s)
- Andreas W Heumüller
- From the Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Germany
| | - Stefanie Dimmeler
- From the Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Germany
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34
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Whyte MP, McAlister WH, Zhang F, Bijanki VN, Nenninger A, Gottesman GS, Lin EL, Huskey M, Duan S, Dahir K, Mumm S. New explanation for autosomal dominant high bone mass: Mutation of low-density lipoprotein receptor-related protein 6. Bone 2019; 127:228-243. [PMID: 31085352 DOI: 10.1016/j.bone.2019.05.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/01/2019] [Accepted: 05/03/2019] [Indexed: 01/10/2023]
Abstract
LRP5 encodes low-density lipoprotein receptor-related protein 5 (LRP5). When LRP5 with a Frizzled receptor join on the surface of an osteoblast and bind a member of the Wnt family of ligands, canonical Wnt/β-catenin signaling occurs and increases bone formation. Eleven heterozygous gain-of-function missense mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching to LRP5's first β-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder "high bone mass" (HBM). LRP6 is a cognate co-receptor of LRP5 and similarly controls Wnt signaling in osteoblasts, yet the consequences of increased LRP6-mediated signaling remain unknown. We investigated two multi-generational American families manifesting the clinical and routine laboratory features of LRP5 HBM but without an LRP5 defect and instead carrying a heterozygous LRP6 missense mutation that would alter the first β-propeller of LRP6. In Family 1 LRP6 c.602C>T, p.A201V was homologous to LRP5 HBM mutation c.641C>T, p.A214V, and in Family 2 LRP6 c.553A>C, p.N185H was homologous to LRP5 HBM mutation c.593A>G, p.N198S but predicting a different residue at the identical amino acid position. In both families the LRP6 mutation co-segregated with striking generalized osteosclerosis and hyperostosis. Clinical features shared by the seven LRP6 HBM family members and ten LRP5 HBM patients included a broad jaw, torus palatinus, teeth encased in bone and, reportedly, resistance to fracturing and inability to float in water. For both HBM disorders, all affected individuals were taller than average for Americans (Ps < 0.005), but with similar mean height Z-scores (P = 0.7606) and indistinguishable radiographic skeletal features. Absence of adult maxillary lateral incisors was reported by some LRP6 HBM individuals. In contrast, our 16 patients with AD osteopetrosis [i.e., Albers-Schönberg disease (A-SD)] had an unremarkable mean height Z-score (P = 0.9401) lower than for either HBM group (Ps < 0.05). DXA mean BMD Z-scores in LRP6 HBM versus LRP5 HBM were somewhat higher at the lumbar spine (+7.8 vs +6.5, respectively; P = 0.0403), but no different at the total hip (+7.9 vs +7.7, respectively; P = 0.7905). Among the three diagnostic groups, only the LRP6 HBM DXA BMD values at the spine seemed to increase with subject age (R = +0.7183, P = 0.0448). Total hip BMD Z-scores were not significantly different among the three disorders (Ps > 0.05), and showed no age effect (Ps > 0.1). HR-pQCT available only for LRP6 HBM revealed indistinct corticomedullary boundaries, high distal forearm and tibial total volumetric BMD, and finite element analysis predicted marked fracture resistance. Hence, we have discovered mutations of LRP6 that cause a dento-osseous disorder indistinguishable without mutation analysis from LRP5 HBM. LRP6 HBM seems associated with generally good health, providing some reassurance for the development of anabolic treatments aimed to enhance LRP5/LRP6-mediated osteogenesis.
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Affiliation(s)
- Michael P Whyte
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - William H McAlister
- Mallinckrodt Institute of Radiology, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO 63110, USA.
| | - Fan Zhang
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Vinieth N Bijanki
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Angela Nenninger
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Gary S Gottesman
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Elizabeth L Lin
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - Margaret Huskey
- Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - Shenghui Duan
- Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - Kathryn Dahir
- Department of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Steven Mumm
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
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35
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Deciphering the Role of WNT Signaling in Metabolic Syndrome–Linked Alzheimer’s Disease. Mol Neurobiol 2019; 57:302-314. [DOI: 10.1007/s12035-019-01700-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 07/09/2019] [Indexed: 12/22/2022]
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Kang S, Pu JL. WITHDRAWN: Low Density Lipoprotein Receptor Related Protein 6-mediated Cardiovascular Diseases and associated signaling pathways. Can J Cardiol 2019. [DOI: 10.1016/j.cjca.2019.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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Montazeri-Najafabady N, Dabbaghmanesh MH, Mohammadian Amiri R. The association of LRP6 rs2302685 (V1062I) polymorphism with the risk of hyperlipidemia in Iranian children and adolescents. Ann Hum Genet 2018; 82:382-388. [PMID: 30039844 DOI: 10.1111/ahg.12254] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 03/04/2018] [Accepted: 03/23/2018] [Indexed: 01/01/2023]
Abstract
Wnt signaling/LRP6 plays a critical role in metabolic syndrome and atherosclerosis, and variation in this pathway may lead to hyperlipidemia, nonalcoholic fatty liver disease, and coronary artery disease. In the present study, we investigated the effect of LRP6 rs2302685 (V1062I) on hyperlipidemia in Iranian children and adolescents. The population in this study consisted of 200 children (101 boys, 99 girls) aged 9-18 years old. Total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), non-HDL cholesterol, and triglyceride levels were measured. Body composition was evaluated by the Hologic DXA system. PCR/restriction fragment length polymorphism was performed for LRP6 rs2302685 (V1062I) genotyping. Logistic regression analysis was done to find the association between LRP6 rs2302685 (V1062I) and categorized lipid parameters in the adjusted model for confounding factors (age, sex, and puberty). Individuals with the CC genotype showed significantly higher levels of cholesterol, triglycerides, LDL, and non-HDL compared to the CT and TT genotypes. In modeling analysis, for categorized lipid parameters, a significant association was found between CC versus CT, and CC versus TT in terms of cholesterol, LDL, and non-HDL. It seems that LRP6 rs2302685 (V1062I) variant carriers are associated with an increased risk of hyperlipidemia in Iranian children and adolescents.
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Affiliation(s)
- Nima Montazeri-Najafabady
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hossein Dabbaghmanesh
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Rajeeh Mohammadian Amiri
- Shiraz Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Oxidized phospholipids are ligands for LRP6. Bone Res 2018; 6:22. [PMID: 30038821 PMCID: PMC6050227 DOI: 10.1038/s41413-018-0023-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 05/10/2018] [Accepted: 05/30/2018] [Indexed: 02/07/2023] Open
Abstract
Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor for Wnt signaling and can be recruited by multiple growth factors/hormones to their receptors facilitating intracellular signaling activation. The ligands that bind directly to LRP6 have not been identified. Here, we report that bioactive oxidized phospholipids (oxPLs) are native ligands of LRP6, but not the closely related LRP5. oxPLs are products of lipid oxidation involving in pathological conditions such as hyperlipidemia, atherosclerosis, and inflammation. We found that cell surface LRP6 in bone marrow mesenchymal stromal cells (MSCs) decreased rapidly in response to increased oxPLs in marrow microenvironment. LRP6 directly bound and mediated the uptake of oxPLs by MSCs. oxPL-LRP6 binding induced LRP6 endocytosis through a clathrin-mediated pathway, decreasing responses of MSCs to osteogenic factors and diminishing osteoblast differentiation ability. Thus, LRP6 functions as a receptor and molecular target of oxPLs for their adverse effect on MSCs, revealing a potential mechanism underlying atherosclerosis-associated bone loss.
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Abou Ziki MD, Mani A. The interplay of canonical and noncanonical Wnt signaling in metabolic syndrome. Nutr Res 2018; 70:18-25. [PMID: 30049588 DOI: 10.1016/j.nutres.2018.06.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/26/2018] [Accepted: 06/28/2018] [Indexed: 12/22/2022]
Abstract
Metabolic syndrome is a cluster of inherited metabolic traits, which centers around obesity and insulin resistance and is a major contributor to the growing prevalence of cardiovascular disease. The factors that underlie the association of metabolic traits in this syndrome are poorly understood due to disease heterogeneity and complexity. Genetic studies of kindreds with severe manifestation of metabolic syndrome have led to the identification of casual rare mutations in the LDL receptor-related protein 6, which serves as a co-receptor with frizzled protein receptors for Wnt signaling ligands. Extensive investigations have since unraveled the significance of the Wnt pathways in regulating body mass, glucose metabolism, de novo lipogenesis, low-density lipoprotein clearance, vascular smooth muscle plasticity, liver fat, and liver inflammation. The impaired canonical Wnt signaling observed in the R611C mutation carriers and the ensuing activation of noncanonical Wnt signaling constitute the underlying mechanism for these cardiometabolic abnormalities. Transcription factor 7-like 2 is a key transcription factor activated through LDL receptor-related protein 6 canonical Wnt and reciprocally inhibited by the noncanonical pathway. TC7L2 increases insulin receptor expression, decreases low-density lipoprotein and triglyceride synthesis, and inhibits vascular smooth muscle proliferation. Canonical Wnt also inhibits noncanonical protein kinase C, Ras homolog gene family member A, and Rho associated coiled-coil containing protein kinase 2 activation, thus inhibiting steatohepatitis and transforming growth factor β-mediated extracellular matrix deposition and hepatic fibrosis. Therefore, dysregulation of the highly conserved Wnt signaling pathway underlies the pleiotropy of metabolic traits of the metabolic syndrome and the subsequent end-organ complications.
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Affiliation(s)
- Maen D Abou Ziki
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510
| | - Arya Mani
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Deparetment of Genetics, Yale University School of Medicine, New Haven, CT, 06510.
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Wang ZM, Luo JQ, Xu LY, Zhou HH, Zhang W. Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases. THE PHARMACOGENOMICS JOURNAL 2018; 18:351-358. [PMID: 28696417 DOI: 10.1038/tpj.2017.28] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 04/27/2017] [Accepted: 05/10/2017] [Indexed: 12/12/2022]
Abstract
Wnt signaling regulates a broad variety of processes in both embryonic development and various diseases. Recent studies indicated that some genetic variants in Wnt signaling pathway may serve as predictors of diseases. Low-density lipoprotein receptor protein 6 (LRP6) is a Wnt co-receptor with essential functions in the Wnt/β-catenin pathway, and mutations in LRP6 gene are linked to many complex human diseases, including metabolic syndrome, cancer, Alzheimer's disease and osteoporosis. Therefore, we focus on the role of LRP6 genetic polymorphisms and Wnt signaling in complex diseases, and the mechanisms from mouse models and cell lines. It is also highly anticipated that LRP6 variants will be applied clinically in the future. The brief review provided here could be a useful resource for future research and may contribute to a more accurate diagnosis in complex diseases.
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Affiliation(s)
- Z-M Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - J-Q Luo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - L-Y Xu
- Department of Epidemiology and Statistics, School of Public Health, Central South University, Changsha, Hunan, China
| | - H-H Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - W Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
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41
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Sung YJ, Winkler TW, de las Fuentes L, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Li C, Feitosa MF, Kilpeläinen TO, Richard MA, Noordam R, Aslibekyan S, Aschard H, Bartz TM, Dorajoo R, Liu Y, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Warren HR, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, Horimoto ARVR, Hsu FC, Jackson AU, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, 'an Luan J, McKenzie CA, Meian H, Nelson CP, Rauramaa R, Schupf N, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cabrera CP, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, Chauhan G, Christensen K, Cocca M, Collins FS, Connell JM, et alSung YJ, Winkler TW, de las Fuentes L, Bentley AR, Brown MR, Kraja AT, Schwander K, Ntalla I, Guo X, Franceschini N, Lu Y, Cheng CY, Sim X, Vojinovic D, Marten J, Musani SK, Li C, Feitosa MF, Kilpeläinen TO, Richard MA, Noordam R, Aslibekyan S, Aschard H, Bartz TM, Dorajoo R, Liu Y, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Warren HR, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, Horimoto ARVR, Hsu FC, Jackson AU, Kähönen M, Kasturiratne A, Kühnel B, Leander K, Lee WJ, Lin KH, 'an Luan J, McKenzie CA, Meian H, Nelson CP, Rauramaa R, Schupf N, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking D, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cabrera CP, Cade B, Caizheng Y, Campbell A, Canouil M, Chakravarti A, Chauhan G, Christensen K, Cocca M, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Debette S, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Fisher VA, Forouhi NG, Franco OH, Friedlander Y, Gao H, Gigante B, Graff M, Gu CC, Gu D, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng CK, Hirata M, Hofman A, Howard BV, Hunt S, Irvin MR, Jia Y, Joehanes R, Justice AE, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh WP, Koistinen HA, Komulainen P, Kooperberg C, Krieger JE, Kubo M, Kuusisto J, Langefeld CD, Langenberg C, Launer LJ, Lehne B, Lewis CE, Li Y, Lim SH, Lin S, Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman KK, Long J, Louie T, Mägi R, Mahajan A, Meitinger T, Metspalu A, Milani L, Momozawa Y, Morris AP, Mosley TH, Munson P, Murray AD, Nalls MA, Nasri U, Norris JM, North K, Ogunniyi A, Padmanabhan S, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Seshadri S, Sever P, Sitlani CM, Smith JA, Snieder H, Starr JM, Strauch K, Tang H, Taylor KD, Teo YY, Tham YC, Uitterlinden AG, Waldenberger M, Wang L, Wang YX, Wei WB, Williams C, Wilson G, Wojczynski MK, Yao J, Yuan JM, Zonderman AB, Becker DM, Boehnke M, Bowden DW, Chambers JC, Chen YDI, de Faire U, Deary IJ, Esko T, Farrall M, Forrester T, Franks PW, Freedman BI, Froguel P, Gasparini P, Gieger C, Horta BL, Hung YJ, Jonas JB, Kato N, Kooner JS, Laakso M, Lehtimäki T, Liang KW, Magnusson PKE, Newman AB, Oldehinkel AJ, Pereira AC, Redline S, Rettig R, Samani NJ, Scott J, Shu XO, van der Harst P, Wagenknecht LE, Wareham NJ, Watkins H, Weir DR, Wickremasinghe AR, Wu T, Zheng W, Kamatani Y, Laurie CC, Bouchard C, Cooper RS, Evans MK, Gudnason V, Kardia SLR, Kritchevsky SB, Levy D, O'Connell JR, Psaty BM, van Dam RM, Sims M, Arnett DK, Mook-Kanamori DO, Kelly TN, Fox ER, Hayward C, Fornage M, Rotimi CN, Province MA, van Duijn CM, Tai ES, Wong TY, Loos RJF, Reiner AP, Rotter JI, Zhu X, Bierut LJ, Gauderman WJ, Caulfield MJ, Elliott P, Rice K, Munroe PB, Morrison AC, Cupples LA, Rao DC, Chasman DI. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet 2018; 102:375-400. [PMID: 29455858 PMCID: PMC5985266 DOI: 10.1016/j.ajhg.2018.01.015] [Show More Authors] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/18/2018] [Indexed: 12/18/2022] Open
Abstract
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
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Affiliation(s)
- Yun J Sung
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Thomas W Winkler
- Department of Genetic Epidemiology, University of Regensburg, Regensburg 93051, Germany
| | - Lisa de las Fuentes
- Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Amy R Bentley
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Michael R Brown
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX 77030, USA
| | - Aldi T Kraja
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Karen Schwander
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ioanna Ntalla
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK
| | - Xiuqing Guo
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27514, USA
| | - Yingchang Lu
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 117597, Singapore
| | - Xueling Sim
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore
| | - Dina Vojinovic
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jonathan Marten
- Medical Research Council Human Genetics Unit, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Solomon K Musani
- Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39213, USA
| | - Changwei Li
- Department of Epidemiology and Biostatistics, University of Giorgia at Athens College of Public Health, Athens, GA 30602, USA
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Tuomas O Kilpeläinen
- Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark; Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Melissa A Richard
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300RC, the Netherlands
| | - Stella Aslibekyan
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Hugues Aschard
- Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Centre de Bioinformatique Biostatistique et Biologie Integrative (C3BI), Institut Pasteur, Paris 75015, France
| | - Traci M Bartz
- Cardiovascular Health Research Unit, Biostatistics and Medicine, University of Washington, Seattle, WA 98101, USA
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore
| | - Yongmei Liu
- Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Alisa K Manning
- Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Tuomo Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Albert Vernon Smith
- Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Salman M Tajuddin
- Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Bamidele O Tayo
- Department of Public Health Sciences, Loyola University Chicago, Maywood, IL 60153, USA
| | - Helen R Warren
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Wei Zhao
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yanhua Zhou
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Nana Matoba
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan
| | - Tamar Sofer
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Maris Alver
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Marzyeh Amini
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands
| | - Mathilde Boissel
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille 59000, France
| | - Jin Fang Chai
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore
| | - Xu Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden
| | - Jasmin Divers
- Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Ilaria Gandin
- Department of Medical Sciences, University of Trieste, Trieste 34137, Italy
| | - Chuan Gao
- Department of Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Franco Giulianini
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - Anuj Goel
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Sarah E Harris
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Fernando Pires Hartwig
- Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS 96020220, Brazil
| | - Andrea R V R Horimoto
- Lab Genetics and Molecular Cardiology, Department of Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil
| | - Fang-Chi Hsu
- Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Anne U Jackson
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mika Kähönen
- Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
| | | | - Brigitte Kühnel
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Karin Leander
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden
| | - Wen-Jane Lee
- Department of Medical Research, Taichung Veterans General Hospital, Department of Social Work, Tunghai University, Taichung 40705, Taiwan
| | - Keng-Hung Lin
- Department of Opthalmology, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Jian 'an Luan
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Colin A McKenzie
- Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona JMAAW15, Jamaica
| | - He Meian
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Rainer Rauramaa
- Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio 70100, Finland
| | - Nicole Schupf
- Taub Institute for Research on Alzheimer disease and the Aging Brain, Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
| | - Robert A Scott
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Wayne H H Sheu
- Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; School of Medicine, National Yang-ming University, Taipei, Taiwan; School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Medical Technology, National Chung-Hsing University, Taichung 40705, Taiwan
| | - Alena Stančáková
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio 70210, Finland
| | - Fumihiko Takeuchi
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo 1628655, Japan
| | - Peter J van der Most
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands
| | - Tibor V Varga
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden
| | - Heming Wang
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Yajuan Wang
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Erin B Ware
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA; Institute for Social Research, Research Center for Group Dynamics, University of Michigan, Ann Arbor, MI 48104, USA
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz Arndt University Greifswald, Greifswald 17487, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Lisa R Yanek
- General Internal Medicine, GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Weihua Zhang
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK
| | - Jing Hua Zhao
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Saima Afaq
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK
| | - Tamuno Alfred
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA
| | - Najaf Amin
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Dan Arking
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Tin Aung
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 117597, Singapore
| | - R Graham Barr
- Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY 10032, USA
| | - Lawrence F Bielak
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eric Boerwinkle
- Human Genetics Center, The University of Texas School of Public Health, Houston, TX 77030, USA; Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA
| | - Erwin P Bottinger
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA
| | - Peter S Braund
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA 98101, USA
| | - Ulrich Broeckel
- Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Claudia P Cabrera
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Brian Cade
- Sleep Medicine and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Yu Caizheng
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Archie Campbell
- Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Mickaël Canouil
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille 59000, France
| | - Aravinda Chakravarti
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ganesh Chauhan
- Centre for Brain Research, Indian Institute of Schience, Bangalore 560012, India
| | - Kaare Christensen
- The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | - Massimiliano Cocca
- Department of Medical Sciences, University of Trieste, Trieste 34137, Italy
| | - Francis S Collins
- Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - John M Connell
- Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK
| | - Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300RC, the Netherlands
| | | | - Stephanie Debette
- Inserm U1219 Neuroepidemiology, University of Bordeaux, Bordeaux, France; Department of Neurology, University Hospital, Bordeaux, France; Boston University School of Medicine, Boston, MA 02118, USA
| | - Marcus Dörr
- DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Department of Internal Medicine B, University Medicine Greifswald, Greifswald 17475, Germany
| | - Qing Duan
- Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA
| | - Charles B Eaton
- Department of Family Medicine and Epidemiology, Alpert Medical School of Brown University, Providence, RI 02860, USA
| | - Georg Ehret
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Cardiology, Department of Specialties of Medicine, Geneva University Hospital, Geneva 1211, Switzerland
| | - Evangelos Evangelou
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece
| | - Jessica D Faul
- Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI 48104, USA
| | - Virginia A Fisher
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Nita G Forouhi
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Oscar H Franco
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Yechiel Friedlander
- Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel
| | - He Gao
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Bruna Gigante
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden
| | - Misa Graff
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27514, USA
| | - C Charles Gu
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Dongfeng Gu
- Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Preeti Gupta
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore
| | - Saskia P Hagenaars
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, The University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Tamara B Harris
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sami Heikkinen
- University of Eastern Finland, Institute of Biomedicine, Kuopio 70211, Finland
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore
| | - Makoto Hirata
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku 108-8639, Japan
| | - Albert Hofman
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Barbara V Howard
- MedStar Health Research Institute, Hyattsville, MD 20782, USA; Center for Clinical and Translational Sciences and Department of Medicine, Georgetown-Howard Universities, Washington, DC 20057, USA
| | - Steven Hunt
- Cardiovascular Genetics, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84108, USA; Weill Cornell Medicine in Qatar, Doha, Qatar
| | - Marguerite R Irvin
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yucheng Jia
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Roby Joehanes
- Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA; Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA
| | - Anne E Justice
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27514, USA
| | - Tomohiro Katsuya
- Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita 5650871, Japan; Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita 5650871, Japan
| | - Joel Kaufman
- Epidemiology, Department of Occupational and Environmental Medicine Program, University of Washington, Seattle, WA 98105, USA
| | - Nicola D Kerrison
- MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore
| | - Heikki A Koistinen
- Department of Health, National Institute for Health and Welfare, Helsinki 00271, Finland; Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029, Finland
| | - Pirjo Komulainen
- Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio 70100, Finland
| | - Charles Kooperberg
- Fred Hutchinson Cancer Research Center, University of Washington School of Public Health, Seattle, WA 98109, USA
| | - Jose E Krieger
- Lab Genetics and Molecular Cardiology, Department of Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil
| | - Michiaki Kubo
- Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan
| | - Johanna Kuusisto
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland
| | - Carl D Langefeld
- Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | | | - Lenore J Launer
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA
| | - Benjamin Lehne
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK
| | - Cora E Lewis
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USA
| | - Yize Li
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Sing Hui Lim
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore
| | - Shiow Lin
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Ching-Ti Liu
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Jianjun Liu
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore
| | - Jingmin Liu
- WHI CCC, Fred Hutchinson Cancer Research Center, Seattle, WA 98115, USA
| | - Kiang Liu
- Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Yeheng Liu
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Marie Loh
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research 138648, Singapore
| | - Kurt K Lohman
- Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Tin Louie
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Reedik Mägi
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute of Human Genetics, Technische Universität München, Munich 80333, Germany
| | - Andres Metspalu
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Lili Milani
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan
| | - Andrew P Morris
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK
| | - Thomas H Mosley
- Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Peter Munson
- Mathematical and Statistical Computing Laboratory, Center for Information Technology, NIH, Bethesda, MD 20892, USA
| | - Alison D Murray
- The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen AB25 2ZD, UK
| | - Mike A Nalls
- Data Tecnica International, Glen Echo, MD 20812, USA; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
| | - Ubaydah Nasri
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA
| | - Kari North
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27514, USA
| | | | - Sandosh Padmanabhan
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK
| | - Walter R Palmas
- Internal Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Nicholette D Palmer
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - James S Pankow
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55454, USA
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden
| | - Annette Peters
- Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Neuherberg 85764, Germany
| | - Patricia A Peyser
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ozren Polasek
- Faculty of Medicine, University of Split, Split, Croatia
| | - Olli T Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland
| | - Frida Renström
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden; Department of Biobank Research, Umeå University, Umeå, Västerbotten 901 87, Sweden
| | - Treva K Rice
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Paul M Ridker
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
| | | | - Jennifer G Robinson
- Department of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Lynda M Rose
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - Igor Rudan
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, UK
| | - Charumathi Sabanayagam
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore
| | | | - Kevin Sandow
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Carsten O Schmidt
- DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany
| | - Pamela J Schreiner
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55454, USA
| | - William R Scott
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; National Heart and Lung Institute, Imperial College London, London W12 0NN, UK
| | - Sudha Seshadri
- Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Peter Sever
- International Centre for Circulatory Health, Imperial College London, London W2 1PG, UK
| | - Colleen M Sitlani
- Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA 98101, USA
| | - Jennifer A Smith
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands
| | - John M Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich 81377, Germany
| | - Hua Tang
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Kent D Taylor
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Yik Ying Teo
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore 117456, Singapore; NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117456, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore
| | - Yih Chung Tham
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore
| | - André G Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Lihua Wang
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Ya X Wang
- Beijing Institute of Ophthalmology, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Capital Medical University, Beijing, China 100730, China
| | - Wen Bin Wei
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Christine Williams
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Gregory Wilson
- Jackson Heart Study, Department of Public Health, Jackson State University, Jackson, MS 39213, USA
| | - Mary K Wojczynski
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Jie Yao
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA
| | - Alan B Zonderman
- Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Diane M Becker
- General Internal Medicine, GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Donald W Bowden
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - John C Chambers
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK
| | - Yii-Der Ida Chen
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Ulf de Faire
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden
| | - Ian J Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, The University of Edinburgh, Edinburgh EH8 9JZ, UK
| | - Tõnu Esko
- Estonian Genome Center, University of Tartu, Tartu 51010, Estonia; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA
| | - Martin Farrall
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Terrence Forrester
- Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona JMAAW15, Jamaica
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA 02115, USA; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Västerbotten 901 85, Sweden
| | - Barry I Freedman
- Division of Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Philippe Froguel
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille 59000, France; Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK
| | - Paolo Gasparini
- Department of Medical Sciences, University of Trieste, Trieste 34137, Italy; Division Experimental Genetics, Sidra, Doha 26999, Qatar
| | - Christian Gieger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany
| | - Bernardo Lessa Horta
- Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS 96020220, Brazil
| | - Yi-Jen Hung
- Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taipei 11490, Taiwan
| | - Jost B Jonas
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, Mannheim 68167, Germany
| | - Norihiro Kato
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo 1628655, Japan
| | - Jaspal S Kooner
- Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK; National Heart and Lung Institute, Imperial College London, London W12 0NN, UK
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Lifes Sciences, University of Tampere, Tampere 33014, Finland
| | - Kae-Woei Liang
- School of Medicine, National Yang-ming University, Taipei, Taiwan; Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan; Department of Medicine, China Medical University, Taichung 40705, Taiwan
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden
| | - Anne B Newman
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Albertine J Oldehinkel
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands
| | - Alexandre C Pereira
- Lab Genetics and Molecular Cardiology, Department of Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil; Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Susan Redline
- Sleep Medicine and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Rainer Rettig
- DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Institute of Physiology, University Medicine Greifswald, Greifswald 17495, Germany
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
| | - James Scott
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Pim van der Harst
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands
| | - Lynne E Wagenknecht
- Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | | | - Hugh Watkins
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - David R Weir
- Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI 48104, USA
| | | | - Tangchun Wu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Yoichiro Kamatani
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan
| | - Cathy C Laurie
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Claude Bouchard
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Richard S Cooper
- Department of Public Health Sciences, Loyola University Chicago, Maywood, IL 60153, USA
| | - Michele K Evans
- Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
| | - Sharon L R Kardia
- School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Stephen B Kritchevsky
- Sticht Center for Health Aging and Alzheimer's Prevention, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Daniel Levy
- Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA
| | - Jeff R O'Connell
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington, Health Research Institute, Seattle, WA 98101, USA
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Mario Sims
- Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39213, USA
| | - Donna K Arnett
- Dean's Office, University of Kentucky College of Public Health, Lexington, KY 40536, USA
| | - Dennis O Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300RC, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2300RC, the Netherlands
| | - Tanika N Kelly
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
| | - Ervin R Fox
- Cardiology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Charles N Rotimi
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Michael A Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - E Shyong Tai
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 117597, Singapore
| | - Ruth J F Loos
- Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA; Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, New York, NY 10029, USA
| | - Alex P Reiner
- Fred Hutchinson Cancer Research Center, University of Washington School of Public Health, Seattle, WA 98109, USA
| | - Jerome I Rotter
- Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Genomic Outcomes, Department of Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Xiaofeng Zhu
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Laura J Bierut
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - W James Gauderman
- Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA
| | - Mark J Caulfield
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Kenneth Rice
- Department of Biostatistics, University of Washington, Seattle, WA 98105, USA
| | - Patricia B Munroe
- William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK
| | - Alanna C Morrison
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX 77030, USA
| | - L Adrienne Cupples
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA
| | - Dabeeru C Rao
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Daniel I Chasman
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
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Abstract
Accumulating epidemiological evidence indicates a strong clinical association between obesity and an increased risk of cancer. The global pandemic of obesity indicates a public health trend towards a substantial increase in cancer incidence and mortality. However, the mechanisms that link obesity to cancer remain incompletely understood. The fruit fly Drosophila melanogaster has been increasingly used to model an expanding spectrum of human diseases. Fly models provide a genetically simpler system that is ideal for use as a first step towards dissecting disease interactions. Recently, the combining of fly models of diet-induced obesity with models of cancer has provided a novel model system in which to study the biological mechanisms that underlie the connections between obesity and cancer. In this Review, I summarize recent advances, made using Drosophila, in our understanding of the interplay between diet, obesity, insulin resistance and cancer. I also discuss how the biological mechanisms and therapeutic targets that have been identified in fly studies could be utilized to develop preventative interventions and treatment strategies for obesity-associated cancers. Summary: This Review highlights a Drosophila model of diet-induced obesity and cancer, and how these two models are combined to study the interplay between obesity and cancer.
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Affiliation(s)
- Susumu Hirabayashi
- Metabolism and Cell Growth Group, MRC Clinical Sciences Centre (CSC), Du Cane Road, London W12 0NN, UK Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK
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Masoudkabir F, Sarrafzadegan N, Gotay C, Ignaszewski A, Krahn AD, Davis MK, Franco C, Mani A. Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. Atherosclerosis 2017; 263:343-351. [PMID: 28624099 PMCID: PMC6207942 DOI: 10.1016/j.atherosclerosis.2017.06.001] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/08/2017] [Accepted: 06/01/2017] [Indexed: 12/21/2022]
Abstract
Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention.
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Affiliation(s)
- Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Carolyn Gotay
- School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada; Cancer Control Research Program, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Andrew Ignaszewski
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot K Davis
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christopher Franco
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Abou Ziki MD, Mani A. Wnt signaling, a novel pathway regulating blood pressure? State of the art review. Atherosclerosis 2017; 262:171-178. [PMID: 28522145 PMCID: PMC5508596 DOI: 10.1016/j.atherosclerosis.2017.05.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 04/06/2017] [Accepted: 05/03/2017] [Indexed: 12/18/2022]
Abstract
Recent antihypertensive trials show conflicting results on blood pressure (BP) targets in patient populations with different metabolic profiles, with lowest benefit from tight BP control observed in patients with type 2 diabetes mellitus. This paradox could arise from the heterogeneity of study populations and underscores the importance of precision medicine initiatives towards understanding and treating hypertension. Wnt signaling pathways and genetic variations in its signaling peptides have been recently associated with metabolic syndrome, hypertension and diabetes, generating a breakthrough for advancement of precision medicine in the field of hypertension. We performed a review of PubMed for publications addressing the contributions of Wnt to BP regulation and hypertension. In addition, we performed a manual search of the reference lists for relevant articles, and included unpublished observations from our laboratory. There is emerging evidence for Wnt's role in BP regulation and its involvement in the pathogenesis of hypertension. Wnt signaling has pleiotropic effects on distinct pathways that involve vascular smooth muscle plasticity, and cardiac, renal, and neural physiology. Hypertension is a heterogeneous disease with unique molecular pathways regulating its response to therapy. Recognition of these pathways is a prerequisite to identify novel targets for drug development and personalizing medicine. A review of Wnt signaling reveals its emerging role in BP regulation and as a target for novel drug development that has the potential to transform the therapy of hypertension in specific populations.
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Affiliation(s)
- Maen D Abou Ziki
- Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Arya Mani
- Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
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Alowolodu O, Johnson G, Alashwal L, Addou I, Zhdanova IV, Uversky VN. Intrinsic disorder in spondins and some of their interacting partners. INTRINSICALLY DISORDERED PROTEINS 2016; 4:e1255295. [PMID: 28232900 DOI: 10.1080/21690707.2016.1255295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 10/22/2016] [Accepted: 10/27/2016] [Indexed: 12/28/2022]
Abstract
Spondins, which are proteins that inhibit and promote adherence of embryonic cells so as to aid axonal growth are part of the thrombospondin-1 family. Spondins function in several important biological processes, such as apoptosis, angiogenesis, etc. Spondins constitute a thrombospondin subfamily that includes F-spondin, a protein that interacts with Aβ precursor protein and inhibits its proteolytic processing; R-spondin, a 4-membered group of proteins that regulates Wnt pathway and have other functions, such as regulation of kidney proliferation, induction of epithelial proliferation, the tumor suppressant action; M-spondin that mediates mechanical linkage between the muscles and apodemes; and the SCO-spondin, a protein important for neuronal development. In this study, we investigated intrinsic disorder status of human spondins and their interacting partners, such as members of the LRP family, LGR family, Frizzled family, and several other binding partners in order to establish the existence and importance of disordered regions in spondins and their interacting partners by conducting a detailed analysis of their sequences, finding disordered regions, and establishing a correlation between their structure and biological functions.
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Affiliation(s)
- Oluwole Alowolodu
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida , Tampa, FL, USA
| | - Gbemisola Johnson
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida , Tampa, FL, USA
| | - Lamis Alashwal
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida , Tampa, FL, USA
| | - Iqbal Addou
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida , Tampa, FL, USA
| | - Irina V Zhdanova
- Department of Anatomy & Neurobiology, Boston University School of Medicine , Boston, MA, USA
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; USF Health Byrd Alzheimer Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
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Guo J, Li Y, Ren YH, Sun Z, Dong J, Yan H, Xu Y, Wang DW, Zheng GY, Du J, Tian XL. Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease. Int J Mol Sci 2016; 17:E1173. [PMID: 27455246 PMCID: PMC4964544 DOI: 10.3390/ijms17071173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 07/13/2016] [Accepted: 07/14/2016] [Indexed: 11/16/2022] Open
Abstract
Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway.
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Affiliation(s)
- Jian Guo
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Yang Li
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Yi-Hong Ren
- Department of Cardiovascular, PLA General Hospital, Beijing 100853, China.
| | - Zhijun Sun
- Department of Cardiovascular, PLA General Hospital, Beijing 100853, China.
| | - Jie Dong
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Han Yan
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Yujun Xu
- The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China.
| | - Dao Wen Wang
- The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China.
| | - Gu-Yan Zheng
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Jie Du
- Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China.
| | - Xiao-Li Tian
- Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
- Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, Nanchang 330031, China.
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47
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Jin T. Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis. Endocr Rev 2016; 37:254-77. [PMID: 27159876 DOI: 10.1210/er.2015-1146] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The role of the Wnt signaling pathway in metabolic homeostasis has drawn our intensive attention, especially after the genome-wide association study discovery that certain polymorphisms of its key effector TCF7L2 are strongly associated with the susceptibility to type 2 diabetes. For a decade, great efforts have been made in determining the function of TCF7L2 in various metabolic organs, which have generated both considerable achievements and disputes. In this review, I will briefly introduce the canonical Wnt signaling pathway, focusing on its effector β-catenin/TCF, including emphasizing the bidirectional feature of TCFs and β-catenin post-translational modifications. I will then summarize the observations on the association between TCF7L2 polymorphisms and type 2 diabetes risk. The main content, however, is on the intensive functional exploration of the metabolic role of TCF7L2, including the disputes generated on determining its role in the pancreas and liver with various transgenic mouse lines. Finally, I will discuss those achievements and disputes and present my future perspectives.
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Affiliation(s)
- Tianru Jin
- Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
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Abstract
PURPOSE OF REVIEW Metabolic syndrome (MetS) is a cluster of interrelated and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic cause. RECENT FINDINGS Genome-wide association studies have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome. SUMMARY Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge toward understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology.
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Affiliation(s)
- Maen D Abou Ziki
- Department of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
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Ockeloen CW, Khandelwal KD, Dreesen K, Ludwig KU, Sullivan R, van Rooij IALM, Thonissen M, Swinnen S, Phan M, Conte F, Ishorst N, Gilissen C, RoaFuentes L, van de Vorst M, Henkes A, Steehouwer M, van Beusekom E, Bloemen M, Vankeirsbilck B, Bergé S, Hens G, Schoenaers J, Poorten VV, Roosenboom J, Verdonck A, Devriendt K, Roeleveldt N, Jhangiani SN, Vissers LELM, Lupski JR, de Ligt J, Von den Hoff JW, Pfundt R, Brunner HG, Zhou H, Dixon J, Mangold E, van Bokhoven H, Dixon MJ, Kleefstra T, Hoischen A, Carels CEL. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genet Med 2016; 18:1158-1162. [PMID: 26963285 PMCID: PMC5018235 DOI: 10.1038/gim.2016.10] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/09/2016] [Indexed: 12/15/2022] Open
Abstract
Purpose Here we aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole exome sequencing (WES) and targeted re-sequencing in a large cohort of TA and OFC patients. Methods WES was performed in two unrelated patients, one with severe TA and OFC and another with severe TA only. After identifying deleterious mutations in a gene encoding the low density lipoprotein receptor-related protein 6 (LRP6), all its exons were re-sequenced with molecular inversion probes, in 67 patients with TA, 1,072 patients with OFC and in 706 controls. Results We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice site mutation (c.3398-2A>C, p.?) in LRP6 respectively in the patient with TA and OFC, and in the patient with severe TA only. The targeted re-sequencing showed significant enrichment of unique LRP6 variants in TA patients, but not in nonsyndromic OFC. From the 5 variants in patients with TA, 2 affect the canonical splice site and 3 were missense variants; all variants segregated with the dominant phenotype and in 1 case the missense mutation occurred de novo. Conclusion Mutations in LRP6 cause tooth agenesis in man.
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Affiliation(s)
- Charlotte W Ockeloen
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Kriti D Khandelwal
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Karoline Dreesen
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Kerstin U Ludwig
- Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany
| | - Robert Sullivan
- Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom
| | - Iris A L M van Rooij
- Department for Health Evidence, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Michelle Thonissen
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Steven Swinnen
- Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Milien Phan
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Federica Conte
- Radboud University, Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands
| | - Nina Ishorst
- Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany
| | - Christian Gilissen
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Laury RoaFuentes
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Maartje van de Vorst
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Arjen Henkes
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Marloes Steehouwer
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Ellen van Beusekom
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Marjon Bloemen
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Bruno Vankeirsbilck
- DNA facility, Center for Human Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Stefaan Bergé
- Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Greet Hens
- Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Joseph Schoenaers
- Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Vincent Vander Poorten
- Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Jasmien Roosenboom
- Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - An Verdonck
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Koen Devriendt
- Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium.,Center for Human Genetics, Department of Clinical Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium
| | - Nel Roeleveldt
- Department for Health Evidence, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Shalini N Jhangiani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, Texas, USA
| | - Lisenka E L M Vissers
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.,Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, Texas, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.,Texas Children's Hospital, Houston, TX 77030, Texas, USA
| | - Joep de Ligt
- Hubrecht Institute, KNAW and University Medical Center Utrecht, 3508 AD, Utrecht, The Netherlands
| | - Johannes W Von den Hoff
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Rolph Pfundt
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Han G Brunner
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Huiqing Zhou
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Radboud University, Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands
| | - Jill Dixon
- Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom
| | - Elisabeth Mangold
- Institute of Human Genetics, Biomedical Center, University of Bonn, D-53127, Bonn, Germany
| | - Hans van Bokhoven
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Michael J Dixon
- Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom
| | - Tjitske Kleefstra
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Alexander Hoischen
- Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands
| | - Carine E L Carels
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.,Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium
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50
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Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8:1-23. [PMID: 26839654 PMCID: PMC4728103 DOI: 10.4330/wjc.v8.i1.1] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 10/18/2015] [Accepted: 11/10/2015] [Indexed: 02/06/2023] Open
Abstract
Atherosclerotic coronary artery disease (CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction (MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MI-associated genetic variants identified using candidate gene approaches and genome-wide association studies (GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI.
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Affiliation(s)
- Xuming Dai
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Szymon Wiernek
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - James P Evans
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Marschall S Runge
- Xuming Dai, Szymon Wiernek, Marschall S Runge, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
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