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Arthur TD, Nguyen JP, Henson BA, D'Antonio-Chronowska A, Jaureguy J, Silva N, Panopoulos AD, Izpisua Belmonte JC, D'Antonio M, McVicker G, Frazer KA. Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants. CELL GENOMICS 2025; 5:100775. [PMID: 39986281 PMCID: PMC11960542 DOI: 10.1016/j.xgen.2025.100775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 10/18/2024] [Accepted: 01/24/2025] [Indexed: 02/24/2025]
Abstract
Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.
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Affiliation(s)
- Timothy D Arthur
- Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093, USA; Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jennifer P Nguyen
- Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA
| | - Benjamin A Henson
- Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | | | - Jeffrey Jaureguy
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA; Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Nayara Silva
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Athanasia D Panopoulos
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | | | - Matteo D'Antonio
- Department of Biomedical Informatics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Graham McVicker
- Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Kelly A Frazer
- Institute of Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
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Al-Rawaf HA, Gabr SA, Alghadir T, Alghadir F, Iqbal A, Alghadir AH. Correlation between circulating microRNAs and vascular biomarkers in type 2 diabetes based upon physical activity: a biochemical analytic study. BMC Endocr Disord 2025; 25:55. [PMID: 40016689 PMCID: PMC11866858 DOI: 10.1186/s12902-025-01855-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 10/28/2024] [Accepted: 01/21/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND This research investigated how physical activity (PA) might impact the expression of several microRNAs, specifically miR-126, miR-146a, miR-34a, miR-124a, miR-155, and miR-221, in the blood of elderly individuals with type 2 diabetes (T2D). Additionally, the study examined the relationship between these microRNAs and markers of vascular endothelial dysfunction, including vascular endothelial growth factor (VEGF), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB), to assess their potential in the prevention, early detection, and treatment of diabetes. METHODS This correlational observational study involved 100 male participants, aged between 18 and 65 years, all of whom had been living with type 2 diabetes (T2D) for over six years. The participants were divided into three groups: inactive, moderate, and active, depending on their level of physical activity (PA). Real-time PCR and immunoassays were employed to measure the expression of selected miRNAs, as well as VEGF, apoA-I, apoB, and diabetic management indicators. PA levels were determined using ACTi graph GT1M accelerometer (model WAM 7164; Fort Walton Beach, FL) and energy expenditure was measured in the form of metabolic equivalent (MET) by indirect calorimetry method. RESULTS The expression levels of miR-146a, miR-34a, and miR-124a were significantly higher in patients with higher physical activity, while no such increase was observed for the other miRNAs in less active participants. Additionally, PA-active individuals showed a more pronounced decrease in fasting blood sugar (FBS), insulin resistance (IR), fasting insulin (FINS), HOMA-IR, HbA1c (%), and levels of VEGF, apoAI, apoB, and the apoB/apoA-I ratio. The alteration in miRNA expression was positively associated with physical activity, VEGF, apoAI, apoB, the apoB/apoA-I ratio, and diabetes-related metrics, while being inversely related to BMI. CONCLUSIONS In diabetic patients with higher physical activity levels, circulating miR-146a, miR-34a, and miR-124a showed elevated expression, accompanied by a notable decrease in vascular biomarkers, including apoAI, apoB, and the apoB/apoA-I ratio. The findings revealed a strong correlation between these vascular biomarkers and the physiological responses of miR-146a, miR-34a, and miR-124a, though larger studies are required to validate these results further. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Hadeel A Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Sami A Gabr
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Talal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Faisal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Amir Iqbal
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia.
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
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Rangraze IR, El-Tanani M, Arman Rabbani S, Babiker R, Matalka II, Rizzo M. Diabetes and its Silent Partner: A Critical Review of Hyperinsulinemia and its Complications. Curr Diabetes Rev 2025; 21:e15733998311738. [PMID: 39192649 DOI: 10.2174/0115733998311738240813110032] [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: 03/19/2024] [Revised: 06/09/2024] [Accepted: 06/21/2024] [Indexed: 08/29/2024]
Abstract
In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.
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Affiliation(s)
- Imran Rashid Rangraze
- Internal Medicine Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Rasal- Khaimah, United Arab Emirates
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Syed Arman Rabbani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Rasha Babiker
- Physiology Department, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras-al-Khaimah, United Arab Emirates
| | - Ismail I Matalka
- Department of Pathology, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Childcare, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, Palermo, Italy
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Jain U, Srivastava P, Sharma A, Sinha S, Johari S. Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus. Curr Diabetes Rev 2025; 21:e260424229342. [PMID: 38676505 DOI: 10.2174/0115733998265915231116043813] [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: 06/23/2023] [Revised: 09/06/2023] [Accepted: 09/20/2023] [Indexed: 04/29/2024]
Abstract
The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.
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Affiliation(s)
- Unnati Jain
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Ashwani Sharma
- Insight BioSolutions, Rue Joseph Colin, 35000 Rennes, France
| | - Subrata Sinha
- Centre of Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam 786004, India
| | - Surabhi Johari
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
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Kovac L, Gancheva S, Jähnert M, Sehgal R, Mastrototaro L, Schlensak M, Granderath FA, Rittig K, Roden M, Schürmann A, Kahl S, Ouni M. Different effects of bariatric surgery on epigenetic plasticity in skeletal muscle of individuals with and without type 2 diabetes. DIABETES & METABOLISM 2024; 50:101561. [PMID: 38977261 DOI: 10.1016/j.diabet.2024.101561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 07/10/2024]
Abstract
AIM Bariatric surgery is highly effective for the treatment of obesity in individuals without (OB1) and in those with type 2 diabetes (T2D2). However, whether bariatric surgery triggers similar or distinct molecular changes in OB and T2D remains unknown. Given that individuals with type 2 diabetes often exhibit more severe metabolic deterioration, we hypothesized that bariatric surgery induces distinct molecular adaptations in skeletal muscle, the major site of glucose uptake, of OB and T2D after surgery-induced weight loss. METHODS All participants (OB, n = 13; T2D, n = 13) underwent detailed anthropometry before and one year after the surgery. Skeletal muscle biopsies were isolated at both time points and subjected to transcriptome and methylome analyses using a comprehensive bioinformatic pipeline. RESULTS Before surgery, T2D had higher fasting glucose and insulin levels but lower whole-body insulin sensitivity, only glycemia remained higher in T2D than in OB after surgery. Surgery-mediated weight loss affected different subsets of genes with 2,013 differentially expressed in OB and 959 in T2D. In OB differentially expressed genes were involved in insulin, PPAR signaling and oxidative phosphorylation pathways, whereas ribosome and splicesome in T2D. LASSO regression analysis revealed distinct candidate genes correlated with improvement of phenotypic traits in OB and T2D. Compared to OB, DNA methylation was less affected in T2D in response to bariatric surgery. This may be due to increased global hydroxymethylation accompanied by decreased expression of one of the type 2 diabetes risk gene, TET2, encoding a demethylation enzyme in T2D. CONCLUSION OB and T2D exhibit differential skeletal muscle transcriptome responses to bariatric surgery, presumably resulting from perturbed epigenetic flexibility.
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Affiliation(s)
- Leona Kovac
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrueck, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany; Research Group Molecular and Clinical Life Science of Metabolic Diseases, Faculty of Health Sciences Brandenburg, University of Potsdam, Brandenburg, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Sofiya Gancheva
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Markus Jähnert
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrueck, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Ratika Sehgal
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrueck, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Lucia Mastrototaro
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | | | | | - Kilian Rittig
- Institute of Nutritional Science, University of Potsdam, Brandenburg, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrueck, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Institute of Nutritional Science, University of Potsdam, Brandenburg, Germany.
| | - Sabine Kahl
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Meriem Ouni
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrueck, Arthur-Scheunert-Allee 114-116, Nuthetal, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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Patel JN, Jiang C, Owzar K, Hertz DL, Wang J, Mulkey FA, Kelly WK, Halabi S, Furukawa Y, Lassiter C, Dorsey SG, Friedman PN, Small EJ, Carducci MA, Kelley MJ, Nakamura Y, Kubo M, Ratain MJ, Morris MJ, McLeod HL. Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance). THE PHARMACOGENOMICS JOURNAL 2024; 24:6. [PMID: 38438359 PMCID: PMC10912014 DOI: 10.1038/s41397-024-00328-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 03/06/2024]
Abstract
The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.
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Affiliation(s)
- Jai N Patel
- Department of Cancer Pharmacology & Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, NC, USA.
| | - Chen Jiang
- Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA
| | - Kouros Owzar
- Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Daniel L Hertz
- Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA
| | - Janey Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Flora A Mulkey
- Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA
| | - William K Kelly
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Susan Halabi
- Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Yoichi Furukawa
- Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Cameron Lassiter
- University of Maryland School of Nursing (Miltenyi Biotech at time of publication), Baltimore, MD, USA
| | - Susan G Dorsey
- University of Maryland School of Nursing (Miltenyi Biotech at time of publication), Baltimore, MD, USA
| | - Paula N Friedman
- Department of Pharmacology and Center for Pharmacogenomics, Northwestern University, Evanston, IL, USA
| | - Eric J Small
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Michael A Carducci
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Michael J Kelley
- Durham VA Medical Center/Duke University Medical Center, Durham, NC, USA
| | - Yusuke Nakamura
- Center for Personalized Therapeutics, University of Chicago (Japanese Foundation for Cancer Research, Ariake, Tokyo at time of publication), Chicago, IL, USA
| | - Michiaki Kubo
- Riken Center for Integrative Medical Sciences (Haradoi Hospital, Fukuoka, Japan at time of publication), Kanagawa, Japan
| | - Mark J Ratain
- Center for Personalized Therapeutics, University of Chicago (Japanese Foundation for Cancer Research, Ariake, Tokyo at time of publication), Chicago, IL, USA
| | - Michael J Morris
- Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Malick RAS, Munir S, Jami SI, Rauf S, Ferretti S, Cherifi H. DbKB a knowledge graph dataset for diabetes: A system biology approach. Data Brief 2024; 52:110003. [PMID: 38293574 PMCID: PMC10827411 DOI: 10.1016/j.dib.2023.110003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 02/01/2024] Open
Abstract
Diabetes has emerged as a prevalent disease, affecting millions of individuals annually according to statistics. Numerous studies have delved into identifying key genes implicated in the causal mechanisms of diabetes. This paper specifically concentrates on 20 functional genes identified in various studies contributing to the complexities associated with Type 2 diabetes (T2D), encompassing complications such as nephropathy, retinopathy, cardiovascular disorders, and foot ulcers. These functional genes serve as a foundation for identifying regulatory genes, their regulators, and protein-protein interactions. The current study introduces a multi-layer Knowledge Graph (DbKB based on MSNMD: Multi-Scale Network Model for Diabetes), encompassing biological networks such as gene regulatory networks and protein-protein interaction networks. This Knowledge Graph facilitates the visualization and querying of inherent relationships between biological networks associated with diabetes, enabling the retrieval of regulatory genes, functional genes, interacting proteins, and their relationships. Through the integration of biologically relevant genetic, molecular, and regulatory information, we can scrutinize interactions among T2D candidate genes [1] and ascertain diseased genes [2]. The first layer of regulators comprises direct regulators to the functional genes, sourced from the TRRUST database in the human transcription factors dataset, thereby forming a multi-layered directed graph. A comprehensive exploration of these direct regulators reveals a total of 875 regulatory transcription factors, constituting the initial layer of regulating transcription factors. Moving to the second layer, we identify 550 regulatory genes. These functional genes engage with other proteins to form complexes, exhibiting specific functions. Leveraging these layers, we construct a Knowledge Graph aimed at identifying interaction-driven sub-networks involving (i) regulating functional genes, (ii) functional genes, and (iii) protein-protein interactions.
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Affiliation(s)
- Rauf Ahmed Shams Malick
- Department of Computer Science, National University of Computer and Emerging Sciences, Karachi, Pakistan
| | - Siraj Munir
- Department of Applied and Pure Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Syed Imran Jami
- Department of Computer Science, Mohammad Ali Jinnah University, Karachi, Pakistan
| | - Shoaib Rauf
- Department of Computer Science, National University of Computer and Emerging Sciences, Karachi, Pakistan
| | - Stefano Ferretti
- Department of Applied and Pure Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Hocine Cherifi
- ICB UMR 6303 CNRS, University of Burgundy, Dijon, France
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Mendhe HG, Borkar SK, Shaikh MK, Choudhari SG. Assessment of Obesity and Associated Risk Factors of Diabesity in an Urban Population in Central India. Cureus 2023; 15:e39776. [PMID: 37398701 PMCID: PMC10312357 DOI: 10.7759/cureus.39776] [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: 11/17/2022] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Background Over the past 20 years, the prevalence of adult obesity has doubled. International awareness of the body mass index (BMI) as a benchmark for identifying and categorizing overweight and obesity has grown. This study was conducted to assess the socio-demographic factors of the study participants, assess the prevalence of obesity amongst the study subjects, find an association between risk factors and diabesity, and assess obesity using the percentage body fat and waist-hip ratio of study participants. Methods This study was undertaken among diabetes patients residing in the field practice area of the Urban Health and Training Centre (UHTC), Wadi, affiliated with the Datta Meghe Medical College, Nagpur, from July 2022 to September 2022. Two hundred and seventy-eight diabetic people were included as study participants. Systematic random sampling was used to identify study subjects visiting UHTC, Wadi. The World Health Organization's step-by-step approach to the surveillance of risk factors for chronic diseases served as the model for the questionnaire. Results Among the 278 diabetic study participants, the prevalence of generalized obesity was 76.61%. Obesity was more prevalent in subjects with a family history of diabetes. All hypertensive subjects were obese. Obesity was more prevalent among tobacco chewers. In obesity assessment using body fat percentage when compared with standard BMI, the sensitivity was found to be 84% and specificity was 48%. Conclusion Body fat percentage is a simple estimation that can identify obesity among diabetic individuals who are non-obese by BMI. We can change the behavior amongst non-obese diabetic individuals by giving health education, thereby reducing insulin resistance and improving compliance and adherence to the treatment.
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Affiliation(s)
- Harshal G Mendhe
- Community Medicine, Datta Meghe Medical College, Datta Meghe Institute of Medical Sciences, Nagpur, IND
| | - Sonali K Borkar
- Community Medicine, Datta Meghe Medical College, Datta Meghe Institute of Medical Sciences, Nagpur, IND
| | - Mohammed Kamran Shaikh
- Community Medicine, Datta Meghe Medical College, Datta Meghe Institute of Medical Sciences, Nagpur, IND
| | - Sonali G Choudhari
- School of Epidemiology & Public Health, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, IND
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Elfaki I, Mir R, J Tayeb F, Barnawi J, Alalawy AI, Mirghani H, Alshammari SE, Dabla PK. Pharmacogenetics of CYP2C19*17: Functional and Clinical Implications of CYP2C19*17 - rs12248560 (c.-806C>T) in the Development of Type 2 Diabetes. BIOMEDICAL AND PHARMACOLOGY JOURNAL 2022; 15:1897-1904. [DOI: 10.13005/bpj/2528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
The prevalence of diabetes mellitus (DM) is increasing worldwide including Saudi Arabia. DM increases mortality rate, morbidity and vascular complications, accompanied by poor general health status and low quality of life. CYP2C19*17 polymorphism in CYP2C19 gene is associated with the clinical outcome of drugs that are substrates of CYP2C19. CYP2C19*17 confers reduced susceptibility to certain illnesses. This research was conducted to develop a robust method to genotype the rs12248560 single nucleotide variation (SNV). We enrolled 206 subjects: 100 subjects were clinically confirmed cases of type 2 diabetes (T2D), and 106 subjects were healthy controls in this study. Samples from all subjects were screened for the CYP2C19 rs12248560 (c.-806C>T) by the amplification-refractory mutation system PCR (ARMS-PCR). The frequencies of CYP2C19*17 TT, CT, CC genotypes in T2D cases were 12%, 21%, and 67%, respectively whereas those in healthy controls were 70.75%, 26.41%, and 2.83%, respectively. The difference was significant (p < 0.035). T allele (fT) prevalence was found to be substantially greater in T2D cases compared to healthy controls (0.22 vs. 0.16). Results indicated that the CYP2C19*17 - TT genotype is associated with increased susceptibility to T2D with OR = 4.47, RR = 2.64, (p < 0.024). Moreover, the ARMS-based assay proved to be an easy method for the determination of CYP2C19*17 genotypes with reduced cost and good accuracy. In addition, this result helps in the detection and stratification of the individuals who are at risk for the development of T2D. Nevertheless, this finding needs to be validated in molecular genetic studies with increased specimen size and in different ethnicities.
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Affiliation(s)
- Imadeldin Elfaki
- 1Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Rashid Mir
- 2Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Faris J Tayeb
- 2Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Jameel Barnawi
- 2Prince and Fahd Bin Sultan Research Chair, Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Adel Ibrahim Alalawy
- 1Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Hyder Mirghani
- 3Internal Medicine and Endocrine, Medical Department, Faculty of Medicine, University of Tabuk, Tabuk 71491, Kingdom of Saudi Arabia
| | - Sanad E Alshammari
- 4Department of Pharmacology and Toxicology, College of Pharmacy, Hail University, Hail, Saudi Arabia
| | - Pradeep Kumar Dabla
- 5 Department of Biochemistry, G.B.Pant Institute of Postgraduate Medical Education & Research (GIPMER),Associated Maulana Azad Medical College, Delhi, India
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10
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Ebrahim N, Shakirova K, Dashinimaev E. PDX1 is the cornerstone of pancreatic β-cell functions and identity. Front Mol Biosci 2022; 9:1091757. [PMID: 36589234 PMCID: PMC9798421 DOI: 10.3389/fmolb.2022.1091757] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Diabetes has been a worldwide healthcare problem for many years. Current methods of treating diabetes are still largely directed at symptoms, aiming to control the manifestations of the pathology. This creates an overall need to find alternative measures that can impact on the causes of the disease, reverse diabetes, or make it more manageable. Understanding the role of key players in the pathogenesis of diabetes and the related β-cell functions is of great importance in combating diabetes. PDX1 is a master regulator in pancreas organogenesis, the maturation and identity preservation of β-cells, and of their role in normal insulin function. Mutations in the PDX1 gene are correlated with many pancreatic dysfunctions, including pancreatic agenesis (homozygous mutation) and MODY4 (heterozygous mutation), while in other types of diabetes, PDX1 expression is reduced. Therefore, alternative approaches to treat diabetes largely depend on knowledge of PDX1 regulation, its interaction with other transcription factors, and its role in obtaining β-cells through differentiation and transdifferentiation protocols. In this article, we review the basic functions of PDX1 and its regulation by genetic and epigenetic factors. Lastly, we summarize different variations of the differentiation protocols used to obtain β-cells from alternative cell sources, using PDX1 alone or in combination with various transcription factors and modified culture conditions. This review shows the unique position of PDX1 as a potential target in the genetic and cellular treatment of diabetes.
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Affiliation(s)
- Nour Ebrahim
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia,Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
| | - Ksenia Shakirova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Erdem Dashinimaev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia,Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia,*Correspondence: Erdem Dashinimaev,
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11
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New Insights on the Regulation of the Insulin-Degrading Enzyme: Role of microRNAs and RBPs. Cells 2022; 11:cells11162538. [PMID: 36010613 PMCID: PMC9406717 DOI: 10.3390/cells11162538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
The evident implication of the insulin-degrading enzyme (IDE) in Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM), among its capacity to degrade insulin and amyloid-β peptide (Aβ), suggests that IDE could be an essential link in the relation between hyperinsulinemia, insulin resistance and AD. However, little is known about the cellular and molecular regulation of IDE expression, and even less has been explored regarding the post-transcriptional regulation of IDE, although it represents a great molecular target of interest for therapeutic treatments. We recently described that miR-7, a novel candidate for linking AD and T2DM at the molecular level, regulates IDE and other key genes in both pathologies, including some key genes involved in the insulin signaling pathway. Here, we explored whether other miRNAs as well as other post-transcriptional regulators, such as RNA binding proteins (RBP), could potentially participate in the regulation of IDE expression in vitro. Our data showed that in addition to miR-7, miR-125, miR-490 and miR-199 regulate IDE expression at the post-transcriptional level. Moreover, we also found that IDE contains multiple potential binding sites for several RBPs, and a narrow-down prediction analysis led us to speculate on a novel regulation of IDE by RALY and HuD. Taken together, these results demonstrate the novel players controlling IDE expression that could represent potential therapeutical targets to treat several metabolic diseases with a high impact on human health, including AD and T2DM.
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12
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McDonald S, Ray P, Bunn RC, Fowlkes JL, Thrailkill KM, Popescu I. Heterogeneity and altered β-cell identity in the TallyHo model of early-onset type 2 diabetes. Acta Histochem 2022; 124:151940. [PMID: 35969910 DOI: 10.1016/j.acthis.2022.151940] [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: 04/10/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/01/2022]
Abstract
A primary underlying defect makes β-cells "susceptible" to no longer compensate for the peripheral insulin resistance and to trigger the onset of type 2 diabetes (T2D). New evidence suggests that in T2D, β-cells are not destroyed but experience a loss of identity, reverting to a progenitor-like state and largely losing the ability to sense glucose and produce insulin. We assessed (using fluorescence microscopy and histomorphometry correlated with the glycaemic status) the main β-cell identity modifications as diabetes progresses in the TallyHo/JngJ (TH) male mice, a polygenic model of spontaneous T2D, akin to the human phenotype. We found that: 1) conversion to overt diabetes is paralleled by a progressive reduction of insulin-expressing cells and expansion of a glucagon-positive population, together with alteration of islet size and shape; 2) the β-cell population is highly heterogeneous in terms of insulin content and specific transcription factors like PDX1 and NKX6.1, that are gradually lost during diabetes progression; 3) GLUT2 expression is altered early and strongly reduced at late stages of diabetes; 4) an endocrine developmental program dependent on NGN3-expressing progenitors is revived when hyperglycaemia becomes severe; and 5) the re-expression of the EMT-associated factor vimentin occurs as diabetes worsens, representing a possible regenerative response to β-cell loss. Based on these results, we formulated additional hypotheses for the β-cell identity alteration in the TH model, together with several limitations of the study, that constitute future research directions.
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Affiliation(s)
- Sarah McDonald
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA
| | - Phil Ray
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA; Department of Pediatric Endocrinology, University of Kentucky, College of Medicine, 2195 Harrodsburg Rd., Lexington, KY 40504, USA
| | - Robert C Bunn
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA; Department of Pediatric Endocrinology, University of Kentucky, College of Medicine, 2195 Harrodsburg Rd., Lexington, KY 40504, USA
| | - John L Fowlkes
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA; Department of Pediatric Endocrinology, University of Kentucky, College of Medicine, 2195 Harrodsburg Rd., Lexington, KY 40504, USA
| | - Kathryn M Thrailkill
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA; Department of Pediatric Endocrinology, University of Kentucky, College of Medicine, 2195 Harrodsburg Rd., Lexington, KY 40504, USA
| | - Iuliana Popescu
- Barnstable Brown Diabetes Center, University of Kentucky, College of Medicine, 900S. Limestone, CTW 469, Lexington, KY 40536, USA.
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13
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Abstract
There are many nonmodifiable and modifiable risk factors for type 2 diabetes. Nonmodifiable risk factors include age, genetics, epigenetics, and social determinants of health (including education level, socioeconomic status, and noise and arsenic exposure). Modifiable risk factors include obesity, the microbiome, diet, cigarette smoking, sleep duration, sleep quality, and sedentary behavior. Major lifestyle interventions to prevent and treat diabetes relate to these risk factors. Weight loss is the lifestyle intervention with the largest benefit for both preventing and treating diabetes. Exercise, even without weight loss, significantly reduces the incidence of type 2 diabetes.
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14
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Hussain S, Yadav SS, Dwivedi P, Banerjee M, Usman K, Nath R, Khattri S. SNPs of FOXO1 and Their Interactions Contributes to the Enhanced Risk of Diabetes Among Elderly Individuals. DNA Cell Biol 2022; 41:381-389. [PMID: 35325578 DOI: 10.1089/dna.2021.1139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We have assessed the impact of three single nucleotide polymorphisms (SNPs) of Forkhead Box O1 (FOXO1) and their interaction on susceptibility of type 2 diabetes mellitus in geriatric population from northern India. We genotyped three SNPs (rs2721068, rs17446614, and rs4581585) of FOXO1 gene in 190 elderly individuals with diabetes and 182 unrelated healthy controls of similar ethnicity by using TaqMan SNP assays. SNP-SNP and SNP-environment interactions among polymorphic loci were studied by the multifactor dimensionality reduction (MDR) method. The AA genotype carriers of rs17446614 was associated with the increased susceptibility of diabetes in both adjusted and unadjusted model, whereas rs4581585 was associated with the risk in unadjusted model only. Genotype and minor allele interaction with quantitative parameters revealed that AA genotype of rs17446614 had significantly higher fasting plasma glucose (FPG) in diabetic subjects, also minor allele (A) in patients was positively associated with FPG and glycated hemoglobin. Haplotype Trs2721068Grs17446614Trs4581585 increases the risk of diabetes, whereas carrier of haplotypes Crs2721068Grs17446614Crs4581585 and Crs2721068 Grs17446614Trs4581585 were protective. The MDR analysis revealed that interaction of rs17446614 with body mass index (BMI) increased the susceptibility of diabetes. Therefore presence of rs17446614 variant and its interaction with BMI and haplotype Trs2721068Grs17446614Trs4581585 modulates the risk of diabetes and can be used as a promising tool for identifying high-risk individuals.
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Affiliation(s)
- Sartaj Hussain
- Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India.,ICMR-RMRC, Gorakhpur, Uttar Pradesh, India
| | - Suraj Singh Yadav
- Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Pradeep Dwivedi
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Monisha Banerjee
- Department of Zoology, Lucknow University, Lucknow, Uttar Pradesh, India
| | - Kauser Usman
- Department of Medicine, King George's Medical University Lucknow, Lucknow, Uttar Pradesh, India
| | - Rajendra Nath
- Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sanjay Khattri
- Department of Pharmacology and Therapeutics, King George's Medical University, Lucknow, Uttar Pradesh, India
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15
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Abdullah AS, Ali SK. Assessment of the relationship of transcription factor 7-like 2 rs4506565 (T/A) variant with type 2 diabetes in Iraqi Arab patients. Meta Gene 2022. [DOI: 10.1016/j.mgene.2021.101008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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16
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Park M, Jeong HB, Lee JH, Park T. Spatial rank-based multifactor dimensionality reduction to detect gene-gene interactions for multivariate phenotypes. BMC Bioinformatics 2021; 22:480. [PMID: 34607566 PMCID: PMC8489107 DOI: 10.1186/s12859-021-04395-y] [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: 11/19/2020] [Accepted: 09/17/2021] [Indexed: 01/11/2023] Open
Abstract
Background Identifying interaction effects between genes is one of the main tasks of genome-wide association studies aiming to shed light on the biological mechanisms underlying complex diseases. Multifactor dimensionality reduction (MDR) is a popular approach for detecting gene–gene interactions that has been extended in various forms to handle binary and continuous phenotypes. However, only few multivariate MDR methods are available for multiple related phenotypes. Current approaches use Hotelling’s T2 statistic to evaluate interaction models, but it is well known that Hotelling’s T2 statistic is highly sensitive to heavily skewed distributions and outliers. Results We propose a robust approach based on nonparametric statistics such as spatial signs and ranks. The new multivariate rank-based MDR (MR-MDR) is mainly suitable for analyzing multiple continuous phenotypes and is less sensitive to skewed distributions and outliers. MR-MDR utilizes fuzzy k-means clustering and classifies multi-locus genotypes into two groups. Then, MR-MDR calculates a spatial rank-sum statistic as an evaluation measure and selects the best interaction model with the largest statistic. Our novel idea lies in adopting nonparametric statistics as an evaluation measure for robust inference. We adopt tenfold cross-validation to avoid overfitting. Intensive simulation studies were conducted to compare the performance of MR-MDR with current methods. Application of MR-MDR to a real dataset from a Korean genome-wide association study demonstrated that it successfully identified genetic interactions associated with four phenotypes related to kidney function. The R code for conducting MR-MDR is available at https://github.com/statpark/MR-MDR. Conclusions Intensive simulation studies comparing MR-MDR with several current methods showed that the performance of MR-MDR was outstanding for skewed distributions. Additionally, for symmetric distributions, MR-MDR showed comparable power. Therefore, we conclude that MR-MDR is a useful multivariate non-parametric approach that can be used regardless of the phenotype distribution, the correlations between phenotypes, and sample size.
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Affiliation(s)
- Mira Park
- Department of Preventive Medicine, Eulji University, Daejeon, 34824, Republic of Korea
| | - Hoe-Bin Jeong
- Department of Statistics, Korea University, Seoul, 02841, Republic of Korea
| | - Jong-Hyun Lee
- Department of Statistics, Korea University, Seoul, 02841, Republic of Korea
| | - Taesung Park
- Department of Statistics, Seoul National University, Seoul, 08826, Republic of Korea.
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17
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Kivrane A, Igumnova V, Kimsis J, Freimane L, Sadovska D, Viksna A, Pole I, Ranka R. Implementation of a next-generation sequencing-based targeted approach for full-length CYP3A4 gene sequencing. Pharmacogenomics 2021; 22:519-527. [PMID: 34003019 DOI: 10.2217/pgs-2020-0128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To evaluate the application of next-generation sequencing-based targeted protocol for full-length CYP3A4 gene sequencing analysis. Materials & methods: The developed sequencing protocol was applied to analyze human DNA samples (n = 7) obtained from tuberculosis patients admitted to the Riga East University Hospital, Center of Tuberculosis and Lung diseases. Results: The sequencing data quality was sufficient for the detection of already known genetic variants, as well as for identifying rare and novel variants dispersed throughout the CYP3A4 gene with a high degree of confidence. Conclusion: Developed protocol can be applied in subpopulation level association studies to determine whether specific genetic variants or variant combinations from multiple regions of the CYP3A4 gene are of clinical significance.
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Affiliation(s)
- Agnija Kivrane
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia.,Riga Stradins University, Dzirciema Street 16, Riga, LV1007, Latvia
| | - Viktorija Igumnova
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia.,Riga Stradins University, Dzirciema Street 16, Riga, LV1007, Latvia
| | - Janis Kimsis
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia
| | - Lauma Freimane
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia
| | - Darja Sadovska
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia.,Riga Stradins University, Dzirciema Street 16, Riga, LV1007, Latvia
| | - Anda Viksna
- Riga Stradins University, Dzirciema Street 16, Riga, LV1007, Latvia.,Riga East University Hospital, Centre of Tuberculosis and Lung Diseases, Stopini region, Upeslejas, LV2118, Latvia
| | - Ilva Pole
- Riga East University Hospital, Centre of Tuberculosis and Lung Diseases, Stopini region, Upeslejas, LV2118, Latvia
| | - Renate Ranka
- Latvian Biomedical Research and Study Centre, Ratsupites Street 1, k-1, Riga, LV1067, Latvia.,Riga Stradins University, Dzirciema Street 16, Riga, LV1007, Latvia
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18
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Cho SB, Jang JH, Chung MG, Kim SC. Exome Chip Analysis of 14,026 Koreans Reveals Known and Newly Discovered Genetic Loci Associated with Type 2 Diabetes Mellitus. Diabetes Metab J 2021; 45:231-240. [PMID: 32794382 PMCID: PMC8024163 DOI: 10.4093/dmj.2019.0163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 02/10/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Most loci associated with type 2 diabetes mellitus (T2DM) discovered to date are within noncoding regions of unknown functional significance. By contrast, exonic regions have advantages for biological interpretation. METHODS We analyzed the association of exome array data from 14,026 Koreans to identify susceptible exonic loci for T2DM. We used genotype information of 50,543 variants using the Illumina exome array platform. RESULTS In total, 7 loci were significant with a Bonferroni adjusted P=1.03×10-6. rs2233580 in paired box gene 4 (PAX4) showed the highest odds ratio of 1.48 (P=1.60×10-10). rs11960799 in membrane associated ring-CH-type finger 3 (MARCH3) and rs75680863 in transcobalamin 2 (TCN2) were newly identified loci. When we built a model to predict the incidence of diabetes with the 7 loci and clinical variables, area under the curve (AUC) of the model improved significantly (AUC=0.72, P<0.05), but marginally in its magnitude, compared with the model using clinical variables (AUC=0.71, P<0.05). When we divided the entire population into three groups-normal body mass index (BMI; <25 kg/m2), overweight (25≤ BMI <30 kg/m2), and obese (BMI ≥30 kg/m2) individuals-the predictive performance of the 7 loci was greatest in the group of obese individuals, where the net reclassification improvement was highly significant (0.51; P=8.00×10-5). CONCLUSION We found exonic loci having a susceptibility for T2DM. We found that such genetic information is advantageous for predicting T2DM in a subgroup of obese individuals.
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Affiliation(s)
- Seong Beom Cho
- Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju, Korea
| | - Jin Hwa Jang
- Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju, Korea
| | - Myung Guen Chung
- Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju, Korea
| | - Sang Cheol Kim
- Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, Korea Center for Disease Control and Prevention, Cheongju, Korea
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19
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Denyer AL, Catchpole B, Davison LJ. Genetics of canine diabetes mellitus part 2: Current understanding and future directions. Vet J 2021; 270:105612. [PMID: 33641811 DOI: 10.1016/j.tvjl.2021.105612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 02/08/2023]
Abstract
Part 1 of this 2-part review outlined the importance of disease classification in diabetes genetic studies, as well as the ways in which genetic variants may contribute to risk of a complex disease within an individual, or within a particular group of individuals. Part 2, presented here, describes in more detail our current understanding of the genetics of canine diabetes mellitus compared to our knowledge of the human disease. Ongoing work to improve our knowledge, using new technologies, is also introduced.
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Affiliation(s)
- Alice L Denyer
- Department of Pathology and Pathogen Biology, Royal Veterinary College, Hatfield, UK
| | - Brian Catchpole
- Department of Pathology and Pathogen Biology, Royal Veterinary College, Hatfield, UK
| | - Lucy J Davison
- Department of Clinical Sciences and Services, Royal Veterinary College, Hatfield, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
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20
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Al-Awaida WJ, Hameed WS, Al Hassany HJ, Al-Dabet MM, Al-Bawareed O, Hadi NR. Evaluation of the Genetic Association and Expressions of Notch-2 /Jagged-1 in Patients with Type 2 Diabetes Mellitus. Med Arch 2021; 75:101-108. [PMID: 34219868 PMCID: PMC8228649 DOI: 10.5455/medarh.2021.75.101-108] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Background Diabetes mellitus (DM) is the world's most common cause of chronic kidney diseases (CKD), with approximately 1 in 4 adults with DM having CKD and 1 out of 10 to 20% of DM patients die from CKD. Objective The current study aims to investigate the correlation between Notch-2 and Jag-1expressions and specific inflammation biomarkers IL-1β and IL-6 with different stages of diabetic nephropathy. Methods From August 2018 to January 2019, three hundred subjects were recruited for this study. One hundred and fifty subjects were healthy and age-matched to the diabetic group and selected as a control group. Another 150 patients with an established diagnosis of type 2 diabetes (T2DM) according to the criteria of the American Diabetes Association (ADA) were also recruited. Blood specimens were eventually used to identify the expressions Notch-2 and Jagged-1 and the levels of inflammatory biomarkers IL-1β and IL-6. Result The current study shows a significant increase in gene expression and inflammatory biomarkers in patients with moderate and severe diabetic nephropathy compared to the control group. However, there was no significant difference between healthy control and mild diabetic nephropathy patients. This study shows a close association between the increase in the levels of inflammatory biomarkers IL-1β and IL-6 as well as the gene expressions levels of both Notch-2 and Jag-1 with human diabetic nephropathy. Conclusion According to our findings, we emphasize the use of Notch-2 and Jag-1 expressions and IL-1β and IL-6 levels as potential biomarkers for different stages of diabetic nephropathy.
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Affiliation(s)
- Wajdy J Al-Awaida
- Department of Biology and Biotechnology, American University of Madaba, Madaba, Jordan
| | - Wasan S Hameed
- Department of Microbiology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Haider J Al Hassany
- Department of Microbiology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | | | - Omar Al-Bawareed
- Department of normal physiology, RUDN University, Moscow, Russia
| | - Najah R Hadi
- Department of Pharmacology and Therapeutics,Faculty of Medicine, University of Kufa, Kufa, Iraq
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21
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Aga H, Hallahan N, Gottmann P, Jaehnert M, Osburg S, Schulze G, Kamitz A, Arends D, Brockmann G, Schallschmidt T, Lebek S, Chadt A, Al-Hasani H, Joost HG, Schürmann A, Vogel H. Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning. Front Genet 2020; 11:567191. [PMID: 33133152 PMCID: PMC7561370 DOI: 10.3389/fgene.2020.567191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/28/2020] [Indexed: 12/27/2022] Open
Abstract
Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL), Nidd/DBA on chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of β-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12, Osbpl9, Ttc39a, and Calr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTL Nidd/DBA. Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.
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Affiliation(s)
- Heja Aga
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Nicole Hallahan
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Pascal Gottmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Markus Jaehnert
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Sophie Osburg
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Gunnar Schulze
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Anne Kamitz
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Danny Arends
- Animal Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute for Agricultural and Horticultural Sciences, Humboldt University of Berlin, Berlin, Germany
| | - Gudrun Brockmann
- Animal Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute for Agricultural and Horticultural Sciences, Humboldt University of Berlin, Berlin, Germany
| | - Tanja Schallschmidt
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sandra Lebek
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Alexandra Chadt
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,German Diabetes Center (DDZ), Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Hans-Georg Joost
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Heike Vogel
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Potsdam, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Molecular and Clinical Life Science of Metabolic Diseases, University of Potsdam, Potsdam, Germany
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22
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Sirdah MM, Reading NS. Genetic predisposition in type 2 diabetes: A promising approach toward a personalized management of diabetes. Clin Genet 2020; 98:525-547. [PMID: 32385895 DOI: 10.1111/cge.13772] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 05/04/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus, also known simply as diabetes, has been described as a chronic and complex endocrine metabolic disorder that is a leading cause of death across the globe. It is considered a key public health problem worldwide and one of four important non-communicable diseases prioritized for intervention through world health campaigns by various international foundations. Among its four categories, Type 2 diabetes (T2D) is the commonest form of diabetes accounting for over 90% of worldwide cases. Unlike monogenic inherited disorders that are passed on in a simple pattern, T2D is a multifactorial disease with a complex etiology, where a mixture of genetic and environmental factors are strong candidates for the development of the clinical condition and pathology. The genetic factors are believed to be key predisposing determinants in individual susceptibility to T2D. Therefore, identifying the predisposing genetic variants could be a crucial step in T2D management as it may ameliorate the clinical condition and preclude complications. Through an understanding the unique genetic and environmental factors that influence the development of this chronic disease individuals can benefit from personalized approaches to treatment. We searched the literature published in three electronic databases: PubMed, Scopus and ISI Web of Science for the current status of T2D and its associated genetic risk variants and discus promising approaches toward a personalized management of this chronic, non-communicable disorder.
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Affiliation(s)
- Mahmoud M Sirdah
- Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.,Biology Department, Al Azhar University-Gaza, Gaza, Palestine
| | - N Scott Reading
- Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA.,Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
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23
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Mambiya M, Shang M, Wang Y, Li Q, Liu S, Yang L, Zhang Q, Zhang K, Liu M, Nie F, Zeng F, Liu W. The Play of Genes and Non-genetic Factors on Type 2 Diabetes. Front Public Health 2019; 7:349. [PMID: 31803711 PMCID: PMC6877736 DOI: 10.3389/fpubh.2019.00349] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022] Open
Abstract
Diabetes has been a disease of public health concern for a number of decades. It was in the 1930s when scientists made an interesting discovery that the disease is actually divided into two types as some patients were insensitive to insulin treatment then. Type 2 Diabetes which happens to be the non-insulin dependent one is the most common form of the disease and is caused by the interaction between genetic and non-genetic factors. Despite conflicting results, numerous studies have identified genetic and non-genetic factors associated with this common type of diabetes. This review has summarized literature on some genes and non-genetic factors which have been identified to be associated with Type 2 diabetes. It has sourced literature from PubMed, Web of Science and Medline without any limitation to regions, publication types, or languages. The paper has started with the introduction, the play of non-genetic factors, the impact of genes in general, and ended with the interaction between some genes and environmental factors.
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Affiliation(s)
- Michael Mambiya
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Mengke Shang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Yue Wang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Qian Li
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Shan Liu
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Luping Yang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Qian Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Kaili Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Mengwei Liu
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Fangfang Nie
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Fanxin Zeng
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
| | - Wanyang Liu
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, China
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24
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Moir HJ, Kemp R, Folkerts D, Spendiff O, Pavlidis C, Opara E. Genes and Elite Marathon Running Performance: A Systematic Review. J Sports Sci Med 2019; 18:559-568. [PMID: 31427879 PMCID: PMC6683622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/06/2019] [Indexed: 06/10/2023]
Abstract
Genetics has long been considered to associate with many exercise-related traits and sport performance phenotypes. A genetic basis for elite international marathon running performance exists due to the heritability of endurance-related traits. This has prompted a generation of genomic study to identify marathon success. The aim of this study was to systematically review the evidence of genes, and their polymorphisms, that may play a role in marathon running performance. A search strategy was implemented on systematic databases following PRISMA guidelines. Studies were case-control, cohort or genome-wide association designs and provided data on the genotypes associated with elite marathon athlete status and/or marathon running performance. The search identified 241 studies, from which, 14 studies were deemed suitable for inclusion. A total of 160 different polymorphisms in 27 genes were identified in 10,442 participants, of which 2,984 were marathon distance runners. The review identified a possible 16 single nucleotide polymorphisms (SNPs) in 14 genes associated with marathon running performance. While multiple genes and their polymorphisms have been associated with marathon running performance, predicting future marathon success based on genomic data is premature due to the lack of replicated studies. There is limited replication of genotype-phenotype associations and there is possible publication bias, thus, further studies are required to strengthen our understanding of the genes involved in marathon running. Future research utilising genome-wide technologies in large cohorts is required to elucidate the multiple genetic factors that govern complex endurance-related traits and the impact of epigenetics should be considered.
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Affiliation(s)
- Hannah J Moir
- School of Life Sciences, Pharmacy & Chemistry, Faculty of Science, Engineering and Computing, Kingston University, London, UK
| | - Rachael Kemp
- School of Life Sciences, Pharmacy & Chemistry, Faculty of Science, Engineering and Computing, Kingston University, London, UK
- School of Sport, Health and Exercise Sciences, Bangor University, UK
| | - Dirk Folkerts
- School of Life Sciences, Pharmacy & Chemistry, Faculty of Science, Engineering and Computing, Kingston University, London, UK
- Department of Sport Psychology, Faculty of Sport and Exercise Sciences, University of Muenster, Germany
| | - Owen Spendiff
- School of Life Sciences, Pharmacy & Chemistry, Faculty of Science, Engineering and Computing, Kingston University, London, UK
| | | | - Elizabeth Opara
- School of Life Sciences, Pharmacy & Chemistry, Faculty of Science, Engineering and Computing, Kingston University, London, UK
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25
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Huang YC, Chen CC, Wang TY, Nguyen HTT, Chen YH, Wu CM, Chang YW, Liao WL, Tsai FJ. C-Reactive Protein Gene Variants and Their Serum Levels in Early Adult-onset Type 2 Diabetes Mellitus. In Vivo 2019; 33:1685-1690. [PMID: 31471424 DOI: 10.21873/invivo.11656] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/09/2019] [Accepted: 07/12/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND/AIM C-Reactive protein (CRP) is a common marker of inflammation. Elevated CRP levels have been associated with increased risk of development of type 2 diabetes mellitus (T2DM). This study aimed to evaluate the association of CRP gene polymorphisms with early-onset T2DM and the effect of genetic variants on CRP level. MATERIALS AND METHODS In total, 948 individuals with early-onset (n=271) or late-onset (n=677) T2DM were enrolled in the study. Five single-nucleotide polymorphisms (SNPs) in the CRP gene, namely rs3093077, rs2808630, rs1800947, rs11265263, and rs11265265, were selected for genotyping, and CRP levels were measured. RESULTS Genotypic, allelic, and haplotype frequencies of these five SNPs were not significantly different between patients with early- and those with late-onset. T2DM Higher serum CRP levels were independently associated with the C-allele of rs3093077 and T-allele of rs11265265 (p<0.001). Furthermore, the C-allele of rs3093077 was associated with higher CRP level in both early- (p=0.016) and late-onset (p<0.001) T2DM. CONCLUSION CRP gene variants may contribute to the risk of early-onset T2DM by affecting the serum CRP level.
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Affiliation(s)
- Yu-Chuen Huang
- School of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C.,Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Ching-Chu Chen
- School of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C.,Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Tzu-Yuan Wang
- Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Hung Tran The Nguyen
- International Master's Program of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
| | - Yung-Hsiang Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan, R.O.C
| | - Chia-Ming Wu
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Ya-Wen Chang
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Wen-Ling Liao
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan, R.O.C. .,Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Fuu-Jen Tsai
- Department of Medical Research, Medical Genetics and Pediatrics, China Medical University Hospital, Taichung, Taiwan, R.O.C. .,Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan, R.O.C
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26
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Batarfi AA, Filimban N, Bajouh OS, Dallol A, Chaudhary AG, Bakhashab S. MC4R variants rs12970134 and rs17782313 are associated with obese polycystic ovary syndrome patients in the Western region of Saudi Arabia. BMC MEDICAL GENETICS 2019; 20:144. [PMID: 31429705 PMCID: PMC6701028 DOI: 10.1186/s12881-019-0876-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 08/12/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder causing infertility in reproductive-age women. The cause of PCOS is not fully understood but it is thought to be influenced by environmental and genetic factors. Obesity is greatly related to PCOS and its reduction is one of the major aims in treating PCOS. Melanocortin 4 receptor (MC4R) gene polymorphisms were detected to be associated with different levels of obesity. Therefore, we aimed to determine the genotype and allele frequency of MC4R variants rs12970134 (A/G) and rs17782313 (C/T) in PCOS and investigate their association with PCOS and its clinical variables. METHODS A case-control study was conducted on 189 women, consisting of 95 PCOS cases and 94 controls. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan™ Genotyping assays. Quantitative data were presented as (median ± interquartile range (IQR) whereas qualitative data were presented as frequencies. The chi-squared test was used to observe the difference between SNPs within the study groups (PCOS and control subjects). Multinomial logistic regression was used to test the risk of obesity and development of PCOS considering p < 0.05 is statistically significant. RESULTS Rs12970134 and rs17782313 are significantly associated with body mass index (BMI, kg/m2, p < 0.0001) in PCOS women but not associated with PCOS itself. Risk alleles in our population are A in rs12970134 and C in rs17782313 that are associated with high BMI (> 30 kg/m2) in obese women with PCOS (OR = 1.348, p = 0.002 and OR = 1.364, p = 0.002 respectively) in the homozygous state. In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS. CONCLUSIONS These findings demonstrate that MC4R single nucleotide polymorphisms, rs12970134 and rs17782313, are correlated with elevated BMI in PCOS but are not causative factors for PCOS among women in the western region of Saudi Arabia. Moreover, the reverse genotypes are associated with major clinical variants in non-obese (< 30 kg/m2) PCOS patients may demonstrate a poor prognosis for this group.
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Affiliation(s)
- Asma A Batarfi
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Abdullah Sulayman St., Jeddah, 21589, Saudi Arabia
| | - Najlaa Filimban
- Centre of Innovation in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia
| | - Osama S Bajouh
- Centre of Innovation in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia.,Department of Obstetrics and Gynaecology, Faculty of Medicine, King Abdulaziz University, P.O. Box 80205, Jeddah, Saudi Arabia
| | - Ashraf Dallol
- Centre of Innovation in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia
| | - Adeel G Chaudhary
- Centre of Innovation in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia
| | - Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Abdullah Sulayman St., Jeddah, 21589, Saudi Arabia. .,Centre of Innovation in Personalized Medicine, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia.
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27
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Ion Transporters, Channelopathies, and Glucose Disorders. Int J Mol Sci 2019; 20:ijms20102590. [PMID: 31137773 PMCID: PMC6566632 DOI: 10.3390/ijms20102590] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 01/19/2023] Open
Abstract
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.
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28
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Witka BZ, Oktaviani DJ, Marcellino M, Barliana MI, Abdulah R. Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors. Diabetes Metab Syndr Obes 2019; 12:2689-2706. [PMID: 31908510 PMCID: PMC6927489 DOI: 10.2147/dmso.s230061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a major cause of mortality worldwide. There are several types of diabetes, with type 2 diabetes mellitus (T2DM) being the most common. Many factors, including environmental and genetic factors, are involved in the etiology of the disease. Numerous studies have reported the role of genetic polymorphisms in the initiation and development of T2DM. While genome-wide association studies have identified around more than 200 susceptibility loci, it remains unclear whether these loci are correlated with the pathophysiology of the disease. The present review aimed to elucidate the potential genetic mechanisms underlying T2DM. We found that some genetic polymorphisms were related to T2DM, either in the form of single-nucleotide polymorphisms or direct amino acid changes in proteins. These polymorphisms are potential predictors for the management of T2DM.
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Affiliation(s)
- Beska Z Witka
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Dede J Oktaviani
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Marcellino Marcellino
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Melisa I Barliana
- Departement of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
- Correspondence: Melisa I Barliana Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM. 21, Jatinangor45363, Indonesia Email
| | - Rizky Abdulah
- Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
- Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Jatinangor, Indonesia
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Jaghutriz BA, Heni M, Lutz SZ, Fritsche L, Machicao F, Staiger H, Peter A, Häring HU, Fritsche A, Wagner R. Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion. Front Endocrinol (Lausanne) 2019; 10:72. [PMID: 30846969 PMCID: PMC6393347 DOI: 10.3389/fendo.2019.00072] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/24/2019] [Indexed: 12/18/2022] Open
Abstract
Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP's showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.
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Affiliation(s)
- Benjamin Assad Jaghutriz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Martin Heni
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- *Correspondence: Martin Heni
| | - Stefan Zoltán Lutz
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
| | - Fausto Machicao
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Róbert Wagner
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
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30
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Balakrishnan P, Vaidya D, Voruganti VS, Haack K, Kent JW, North KE, Laston S, Howard BV, Umans JG, Lee ET, Best LG, MacCluer JW, Cole SA, Navas-Acien A, Franceschini N. Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study. Front Genet 2018; 9:466. [PMID: 30369944 PMCID: PMC6194194 DOI: 10.3389/fgene.2018.00466] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/24/2018] [Indexed: 01/03/2023] Open
Abstract
Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10−7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10−9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.
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Affiliation(s)
- Poojitha Balakrishnan
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, United States
| | - Dhananjay Vaidya
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States.,Clinical and Translational Research, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - V Saroja Voruganti
- Department of Nutrition, UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, United States
| | - Karin Haack
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Jack W Kent
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Kari E North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Sandra Laston
- South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, United States
| | - Barbara V Howard
- MedStar Health Research Institute, Hyattsville, MD, United States
| | - Jason G Umans
- MedStar Health Research Institute, Hyattsville, MD, United States.,Georgetown and Howard Universities Center for Clinical and Translational Science, Washington, DC, United States
| | - Elisa T Lee
- Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Lyle G Best
- Missouri Breaks Industries Research, Inc., Eagle Butte, SD, United States
| | - Jean W MacCluer
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Shelley A Cole
- Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Ana Navas-Acien
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, United States
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Fawad Ali Shah S, Iqbal T, Naveed N, Akram S, Arshad Rafiq M, Hussain S. ARG1 single nucleotide polymorphisms rs2781666 and rs2781665 confer risk of Type 2 diabetes mellitus. EXCLI JOURNAL 2018; 17:847-855. [PMID: 30233283 PMCID: PMC6141821 DOI: 10.17179/excli2018-1178] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/20/2018] [Indexed: 11/25/2022]
Abstract
Genetic polymorphisms mapped in the ARG1 locus (chr6:131894344-131905472) and their functional effects on type 2 diabetes mellitus (T2DM) have not been thoroughly elucidated to date. The present study aimed to investigate an association between variant alleles at ARG1 locus and T2DM in patients. Two ARG1 single nucleotide polymorphisms (SNPs) were characterized in a representative sample of 500 patients with T2DM and 500 healthy volunteers. Serum lipid profile was studied by spectrophotometric analysis, while serum arginase-1 concentrations were determined by an enzyme-linked immunosorbent assay. The regions, encompassing target SNPs (rs2781665 and rs2781666), were amplified by polymerase chain reaction and genotypes were assigned by restriction digestions. A statistically significant increase was observed in the serum hs-CRP and arginase-1 levels in the subjects with T2DM than in controls (P <0.0001; for each). The variant genotypes of rs2781666 and rs2781665 were significantly associated with T2DM when compared with controls (P< 0.0001). Moreover, type 2 diabetic patients showed higher frequencies of T allele at rs2781666 and rs2781665 compared to the controls (OR = 1.7; 95 % CI=1.31-2.13; P <0.0001, and OR = 1.9; 95 % CI=1.45-2.38; P <0.0001, respectively). Haplotype T-T (chr6: 131893247-131893559) mapped at rs2781665-A/T and rs2781666-G/T displays higher frequency in the subjects when compared to the healthy ethnically-matched control samples (P <0.0001). We wish to propose, the first ever observation to our knowledge that concluding high levels of arginase-1 and the ARG1 polymorphisms are possible causes to confer/augment the risk of T2DM in subjects originates in Pakistan.
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Affiliation(s)
- Syed Fawad Ali Shah
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shehzad, Islamabad 45550, Pakistan
| | - Tahir Iqbal
- Department of Internal Medicine, Shifa College of Medicine, Shifa International Hospital, H-8/4, Islamabad 44000, Pakistan
| | - Nasreen Naveed
- The Diabetic Centre, Phulgran Stop Near Toll Plaza, Murree Express Way, Islamabad 635, Pakistan
| | - Sumaira Akram
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shehzad, Islamabad 45550, Pakistan
| | - Muhammad Arshad Rafiq
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shehzad, Islamabad 45550, Pakistan
| | - Sabir Hussain
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shehzad, Islamabad 45550, Pakistan
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32
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Design of Arab Diabetes Gene-Centric Array (ADGCA) in population with an epidemic of Type 2 Diabetes: A population specific SNP evaluation. Gene 2018; 663:157-164. [DOI: 10.1016/j.gene.2018.04.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 04/05/2018] [Accepted: 04/09/2018] [Indexed: 12/18/2022]
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Zou LS, Erdos MR, Taylor DL, Chines PS, Varshney A, Parker SCJ, Collins FS, Didion JP. BoostMe accurately predicts DNA methylation values in whole-genome bisulfite sequencing of multiple human tissues. BMC Genomics 2018; 19:390. [PMID: 29792182 PMCID: PMC5966887 DOI: 10.1186/s12864-018-4766-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 05/08/2018] [Indexed: 01/14/2023] Open
Abstract
Background Bisulfite sequencing is widely employed to study the role of DNA methylation in disease; however, the data suffer from biases due to coverage depth variability. Imputation of methylation values at low-coverage sites may mitigate these biases while also identifying important genomic features associated with predictive power. Results Here we describe BoostMe, a method for imputing low-quality DNA methylation estimates within whole-genome bisulfite sequencing (WGBS) data. BoostMe uses a gradient boosting algorithm, XGBoost, and leverages information from multiple samples for prediction. We find that BoostMe outperforms existing algorithms in speed and accuracy when applied to WGBS of human tissues. Furthermore, we show that imputation improves concordance between WGBS and the MethylationEPIC array at low WGBS depth, suggesting improved WGBS accuracy after imputation. Conclusions Our findings support the use of BoostMe as a preprocessing step for WGBS analysis. Electronic supplementary material The online version of this article (10.1186/s12864-018-4766-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luli S Zou
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Michael R Erdos
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - D Leland Taylor
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.,European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK
| | - Peter S Chines
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Arushi Varshney
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
| | | | - Stephen C J Parker
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Francis S Collins
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - John P Didion
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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Brandão KO, Tabel VA, Atsma DE, Mummery CL, Davis RP. Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. Dis Model Mech 2018; 10:1039-1059. [PMID: 28883014 PMCID: PMC5611968 DOI: 10.1242/dmm.030320] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.
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Affiliation(s)
- Karina O Brandão
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Viola A Tabel
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Douwe E Atsma
- Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Richard P Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Lee S, Kim Y, Choi S, Hwang H, Park T. Pathway-based approach using hierarchical components of rare variants to analyze multiple phenotypes. BMC Bioinformatics 2018; 19:79. [PMID: 29745849 PMCID: PMC5998880 DOI: 10.1186/s12859-018-2066-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND As one possible solution to the "missing heritability" problem, many methods have been proposed that apply pathway-based analyses, using rare variants that are detected by next generation sequencing technology. However, while a number of methods for pathway-based rare-variant analysis of multiple phenotypes have been proposed, no method considers a unified model that incorporate multiple pathways. RESULTS Simulation studies successfully demonstrated advantages of multivariate analysis, compared to univariate analysis, and comparison studies showed the proposed approach to outperform existing methods. Moreover, real data analysis of six type 2 diabetes-related traits, using large-scale whole exome sequencing data, identified significant pathways that were not found by univariate analysis. Furthermore, strong relationships between the identified pathways, and their associated metabolic disorder risk factors, were found via literature search, and one of the identified pathway, was successfully replicated by an analysis with an independent dataset. CONCLUSIONS Herein, we present a powerful, pathway-based approach to investigate associations between multiple pathways and multiple phenotypes. By reflecting the natural hierarchy of biological behavior, and considering correlation between pathways and phenotypes, the proposed method is capable of analyzing multiple phenotypes and multiple pathways simultaneously.
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Affiliation(s)
- Sungyoung Lee
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea
| | - Yongkang Kim
- Department of Statistics, Seoul National University, 1 Gwanak-ro Gwanak-gu, Seoul, 08826, Korea
| | - Sungkyoung Choi
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea
| | - Heungsun Hwang
- Department of Psychology, McGill University, Montreal, Canada
| | - Taesung Park
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea.
- Department of Statistics, Seoul National University, 1 Gwanak-ro Gwanak-gu, Seoul, 08826, Korea.
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36
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Turki A, Mzoughi S, Mtitaoui N, Khairallah M, Marmouch H, Hammami S, Mahjoub T, Almawi WY. Gender differences in the association of ELMO1 genetic variants with type 2 diabetes in Tunisian Arabs. J Endocrinol Invest 2018; 41:285-291. [PMID: 28752301 DOI: 10.1007/s40618-017-0734-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE Polymorphisms of the engulfment and cell motility 1 (ELMO1) gene were recently associated with type 2 diabetes (T2DM) and its complications. We investigated the association of rs10255208, rs7782979, and rs2041801 ELMO1 gene variants with T2DM in Tunisian Arabs. METHODS Subjects comprised 900 T2DM patients and 600 normoglycemic controls. ELMO1 genotyping was done by PCR-RFLP; the contribution of ELMO1 variants to T2DM was analyzed by Haploview and regression analysis. RESULTS Minor allele frequencies of rs7782979 and rs10255208 ELMO1 variants were significantly higher among unselected T2DM cases than controls, and significant differences in the distribution of rs7782979 genotypes were seen between T2DM cases and control subjects, which was seen in male but not female subjects. Three-locus ELMO1 haplotype analysis identified haplotype GAA to be positively associated, and haplotypes GCA, AAA, and GCG to be negatively associated with T2DM. The distribution of these haplotypes was gender-dependent for some (GCA, GCG, AAG), and gender-independent for others (GAA, AAA). This translated into altered risk of T2DM in male or female subjects, which persisted after adjusting for BMI, systolic and diastolic blood pressure, and serum lipid profile. CONCLUSION These results confirm role for ELMO1 as T2DM susceptibility locus, which appears to be gender-dependent.
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Affiliation(s)
- A Turki
- Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - S Mzoughi
- Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - N Mtitaoui
- Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, Monastir, Tunisia
| | - M Khairallah
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - H Marmouch
- Department of Endocrinology and Internal Medicine, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - S Hammami
- Department of Endocrinology and Internal Medicine, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - T Mahjoub
- Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - W Y Almawi
- Faculty of Sciences, El Manar University, Tunis, Tunisia.
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Wang X, Sterr M, Burtscher I, Chen S, Hieronimus A, Machicao F, Staiger H, Häring HU, Lederer G, Meitinger T, Cernilogar FM, Schotta G, Irmler M, Beckers J, Hrabě de Angelis M, Ray M, Wright CVE, Bakhti M, Lickert H. Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. Mol Metab 2018; 9:57-68. [PMID: 29396371 PMCID: PMC5870105 DOI: 10.1016/j.molmet.2018.01.011] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/05/2018] [Accepted: 01/16/2018] [Indexed: 12/14/2022] Open
Abstract
Objective Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. Methods In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. Results ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes. Conclusions Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
PDX1 ChIP-seq analysis revealed 5664 target genes in human pancreatic progenitors, including unreported target genes. Comparison of PDX1 profiles from PPs and adult human islets identified stage-specific PDX1 target gene sets. T2DM-associated SNPs are enriched in active chromatin regions from iPSC-derived PPs. Three SNPs fall into PDX1 occupied sites, located in intronic regions of the developmental regulatory TFs TCF7L2 and HNF1B.
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Affiliation(s)
- Xianming Wang
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of ß-Cell Biology, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of ß-Cell Biology, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany
| | - Ingo Burtscher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Shen Chen
- iPS and Cancer Research Unit, Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Anja Hieronimus
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Fausto Machicao
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Harald Staiger
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Gabriele Lederer
- Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Filippo M Cernilogar
- Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
| | - Gunnar Schotta
- Biomedical Center and Center for Integrated Protein Science Munich, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences Weihenstephan, Technische Universität München, 85354 Freising, Germany
| | - Michael Ray
- Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Christopher V E Wright
- Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Mostafa Bakhti
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of ß-Cell Biology, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
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Kido T, Sikora-Wohlfeld W, Kawashima M, Kikuchi S, Kamatani N, Patwardhan A, Chen R, Sirota M, Kodama K, Hadley D, Butte AJ. Are minor alleles more likely to be risk alleles? BMC Med Genomics 2018; 11:3. [PMID: 29351777 PMCID: PMC5775585 DOI: 10.1186/s12920-018-0322-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 01/08/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. METHODS Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. RESULTS Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS's power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. CONCLUSIONS Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS's power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.
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Affiliation(s)
- Takashi Kido
- Rikengenesis Co., Ltd., 1-2-2 Ohsaki, Shinagawa-ku, Tokyo, 141-0032, Japan. .,Preferred Networks, Inc., Otemachi Bldg. 2F, Chiyoda-ku, Tokyo, 100-0004, Japan.
| | - Weronika Sikora-Wohlfeld
- Division of Systems Medicine, Department of Pediatrics, Stanford University, Stanford, CA, 94305-5208, USA
| | - Minae Kawashima
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Hongo, 7-3-1, Tokyo, 113-0033, Japan
| | - Shinichi Kikuchi
- AI System Department, DeNA, Inc., Shibuya 2-21-1, Tokyo, 150-8510, Japan
| | | | - Anil Patwardhan
- Personalis, Inc., 1330 O'Brien Dr, Menlo Park, CA, 94025, USA
| | - Richard Chen
- Personalis, Inc., 1330 O'Brien Dr, Menlo Park, CA, 94025, USA
| | - Marina Sirota
- Institute for Computational Health Sciences, University of California, 550 16th Street, San Francisco, CA, 94158, USA.,Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Keiichi Kodama
- Institute for Computational Health Sciences, University of California, 550 16th Street, San Francisco, CA, 94158, USA
| | - Dexter Hadley
- Institute for Computational Health Sciences, University of California, 550 16th Street, San Francisco, CA, 94158, USA.,Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Atul J Butte
- Institute for Computational Health Sciences, University of California, 550 16th Street, San Francisco, CA, 94158, USA.,Department of Pediatrics, University of California, San Francisco, CA, USA
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Bowman P, Flanagan SE, Hattersley AT. Future Roadmaps for Precision Medicine Applied to Diabetes: Rising to the Challenge of Heterogeneity. J Diabetes Res 2018; 2018:3061620. [PMID: 30599002 PMCID: PMC6288579 DOI: 10.1155/2018/3061620] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 10/11/2018] [Indexed: 12/17/2022] Open
Abstract
Precision medicine, the concept that specific treatments can be targeted to groups of individuals with specific genetic, cellular, or molecular features, is a key aspect of modern healthcare, and its use is rapidly expanding. In diabetes, the application of precision medicine has been demonstrated in monogenic disease, where sulphonylureas are used to treat patients with neonatal diabetes due to mutations in ATP-dependent potassium (KATP) channel genes. However, diabetes is highly heterogeneous, both between and within polygenic and monogenic subtypes. Making the correct diagnosis and using the correct treatment from diagnosis can be challenging for clinicians, but it is crucial to prevent long-term morbidity and mortality. To facilitate precision medicine in diabetes, research is needed to develop a better understanding of disease heterogeneity and its impact on potential treatments for specific subtypes. Animal models have been used in diabetes research, but they are not translatable to humans in the majority of cases. Advances in molecular genetics and functional laboratory techniques and availability and sharing of large population data provide exciting opportunities for human studies. This review will map the key elements of future diabetes research in humans and its potential for clinical translation to promote precision medicine in all diabetes subtypes.
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Affiliation(s)
- P. Bowman
- University of Exeter Medical School, Exeter, UK
- Exeter NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | | | - A. T. Hattersley
- University of Exeter Medical School, Exeter, UK
- Exeter NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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40
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de Jesús Ascencio-Montiel I, Pinto D, Parra EJ, Valladares-Salgado A, Cruz M, Scherer SW. Characterization of Large Copy Number Variation in Mexican Type 2 Diabetes subjects. Sci Rep 2017; 7:17105. [PMID: 29213072 PMCID: PMC5719030 DOI: 10.1038/s41598-017-17361-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 11/20/2017] [Indexed: 01/26/2023] Open
Abstract
The effect of Copy Number Variants (CNVs) on Type 2 Diabetes (T2D) remains little explored. The present study characterized large rare CNVs in 686 T2D and 194 non-T2D subjects of Mexican ancestry genotyped using the Affymetrix Genome-Wide Human SNP array 5.0. Rare CNVs with ≥ 100 kb length were identified using a stringent strategy based on merging CNVs calls generated using Birdsuit, iPattern and PennCNV algorithms. We applied three different strategies to evaluate the distribution of CNVs in the T2D and non-T2D samples: 1) Burden analysis, 2) Identification of CNVs in loci previously associated to T2D, and 3) Identification of CNVs observed only in the T2D group. In the CNV burden analysis, the T2D group showed a higher proportion of CNVs, and also a higher proportion of CNVs overlapping at least one gene than the non T2D group. Five of the six loci previously associated with T2D had duplications or deletions in the T2D sample, but not the non-T2D sample. A gene-set analysis including genes with CNVs observed only in the T2D group highlighted gene-sets related with sensory perception (olfactory receptors, OR) and phenylpyruvate tautomerase/dopachrome isomerase activity (MIF and DDT genes).
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Affiliation(s)
- Iván de Jesús Ascencio-Montiel
- Instituto Mexicano del Seguro Social, Coordinación de Vigilancia Epidemiológica, Mier y Pesado 120, Col. del Valle, Benito Juárez, 03100, Mexico City, Mexico.
| | - Dalila Pinto
- Departments of Psychiatry, Genetics and Genomic Sciences, The Mindich Child Health & Development Institute, Seaver Autism Center, Institute for Genomics and Multiscale Biology, at the Icahn School of Medicine at Mount Sinai, New York, 1470 Madison Avenue, S8-115, New York, NY, 10029, USA
| | - Esteban J Parra
- Department of Anthropology, University of Toronto at Mississauga, 3359 Mississauga Road, room 352, Health Sciences Complex, Mississauga, ON L5L 1C6, Canada
| | - Adán Valladares-Salgado
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. del Doctores, 06720, Mexico City, Mexico
| | - Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. del Doctores, 06720, Mexico City, Mexico
| | - Stephen W Scherer
- The Centre for Applied Genomics. The Hospital for Sick Children. Peter Gilgan Centre for Research and Learning, 686 Bay Street, Room 139800, Toronto, Ontario, M5G 0A4, Canada.,McLaughlin Centre and Department of Molecular Genetics, University of Toronto, 686 Bay Street, 13th Floor, Toronto, Ontario, M5G 0A4, Canada
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Identification of genetic variants of Brucella spp. through genome-wide association studies. INFECTION GENETICS AND EVOLUTION 2017; 56:92-98. [PMID: 29154929 DOI: 10.1016/j.meegid.2017.11.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 11/08/2017] [Accepted: 11/14/2017] [Indexed: 12/25/2022]
Abstract
Brucellosis is an important zoonotic disease caused by Brucella spp. We present a phylogeny of 552 strains based on genome-wide single nucleotide polymorphisms (SNPs) determined by an alignment-free k-mer approach. A total of 138,029 SNPs were identified from 552 Brucella genomes. Of these, 31,152 and 106,877 were core and non-core SNPs, respectively. Based on pan-genome analysis 11,937 and 972 genes were identified as pan and core genome, respectively. The pan-genome-wide analysis studies (Pan-GWAS) could not identify the group-specific variants in Brucella spp. Therefore, we focused on SNP based genome-wide association studies (SNP-GWAS) to identify the species-specific genetic determinants in Brucella spp. Phylogenetic tree representing eleven recognized Brucella spp. showed 16 major lineages. We identified 143 species-specific SNPs in Brucella abortus that are conserved in 311 B. abortus genomes. Of these, 141 species-specific SNPs were confined in the positively significant SNPs of B. abortus using SNP-GWAS. Since conserved in all the B. abortus genomes studied, these SNPs might have originated very early during the evolution of B. abortus and might be responsible for the evolution of B. abortus with cattle as the preferred host. Similarly, we identified 383 species-specific SNPs conserved in 132 Brucella melitensis genomes. Of these 379 species-specific SNPs were identified as positively associated using GWAS. Interestingly, >98% of the SNPs that are significantly, positively associated with the traits showed 100% sensitivity and 100% specificity. These identified species-specific core-SNPs identified in Brucella genomes could be responsible for the speciation and their respective host adaptation.
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Rathjen T, Yan X, Kononenko NL, Ku MC, Song K, Ferrarese L, Tarallo V, Puchkov D, Kochlamazashvili G, Brachs S, Varela L, Szigeti-Buck K, Yi CX, Schriever SC, Tattikota SG, Carlo AS, Moroni M, Siemens J, Heuser A, van der Weyden L, Birkenfeld AL, Niendorf T, Poulet JFA, Horvath TL, Tschöp MH, Heinig M, Trajkovski M, Haucke V, Poy MN. Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1. Nat Neurosci 2017. [PMID: 28628102 PMCID: PMC5533218 DOI: 10.1038/nn.4590] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic β-cell function, and energy homeostasis. Genome-wide association studies identified an association between body mass index and two loci near Cell Adhesion Molecule1 (CADM1) and Cell Adhesion Molecule2 (CADM2), genes encoding membrane proteins mediating synaptic assembly. We show these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes is elevated in obese mice and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.
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Affiliation(s)
- Thomas Rathjen
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Xin Yan
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Natalia L Kononenko
- Leibniz Institute for Molecular Pharmacology, Berlin, Germany.,CECAD Research Center, University of Cologne, Cologne, Germany.,Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Min-Chi Ku
- Max Delbrück Center for Molecular Medicine, Berlin, Germany.,Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Kun Song
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Leiron Ferrarese
- Max Delbrück Center for Molecular Medicine, Berlin, Germany.,Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Valentina Tarallo
- University of Geneva, Medical Faculty, Department of Cell Physiology and Metabolism, Centre Médical Universitaire (CMU), Geneva, Switzerland
| | - Dmytro Puchkov
- Leibniz Institute for Molecular Pharmacology, Berlin, Germany
| | | | - Sebastian Brachs
- Charité - Universitätsmedizin Berlin, Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Berlin, Germany
| | - Luis Varela
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Klara Szigeti-Buck
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Chun-Xia Yi
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Division of Metabolic Diseases, Technical University Munich, Munich, Germany
| | - Sonja C Schriever
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Division of Metabolic Diseases, Technical University Munich, Munich, Germany
| | | | | | - Mirko Moroni
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Jan Siemens
- Department of Pharmacology, University of Heidelberg, Heidelberg, Germany
| | - Arnd Heuser
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Louise van der Weyden
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | - Andreas L Birkenfeld
- Section of Metabolic Vascular Medicine and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Medical Clinic III, University Clinic Dresden, Dresden, Germany.,Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Thoralf Niendorf
- Max Delbrück Center for Molecular Medicine, Berlin, Germany.,Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany.,Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - James F A Poulet
- Max Delbrück Center for Molecular Medicine, Berlin, Germany.,Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Tamas L Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Department of Anatomy and Histology, University of Veterinary Sciences, Budapest, Hungary
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Division of Metabolic Diseases, Technical University Munich, Munich, Germany
| | - Matthias Heinig
- Helmholtz Zentrum München, Institute of Computational Biology, Neuherberg, Germany
| | - Mirko Trajkovski
- University of Geneva, Medical Faculty, Department of Cell Physiology and Metabolism, Centre Médical Universitaire (CMU), Geneva, Switzerland
| | - Volker Haucke
- Leibniz Institute for Molecular Pharmacology, Berlin, Germany.,Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Matthew N Poy
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
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Maguire JM, Bevan S, Stanne TM, Lorenzen E, Fernandez-Cadenas I, Hankey GJ, Jimenez-Conde J, Jood K, Lee JM, Lemmens R, Levi C, Norrving B, Rannikmae K, Rost N, Rosand J, Rothwell PM, Scott R, Strbian D, Sturm J, Sudlow C, Traylor M, Thijs V, Tatlisumak T, Wieloch T, Woo D, Worrall BB, Jern C, Lindgren A. GISCOME - Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study. Eur Stroke J 2017; 2:229-237. [PMID: 31008316 DOI: 10.1177/2396987317704547] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 03/17/2017] [Indexed: 01/12/2023] Open
Abstract
Introduction Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60-190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.
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Affiliation(s)
- Jane M Maguire
- Faculty of Health, University of Technology, Australia.,Hunter Medical Research Institute, University of Newcastle, Australia.,Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Australia
| | - Steve Bevan
- School of Life Sciences, University of Lincoln, UK
| | - Tara M Stanne
- Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden
| | - Erik Lorenzen
- Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden
| | - Israel Fernandez-Cadenas
- Stroke Pharmacogenomics and Genetics, Fundació Docència I Recerca Mutuaterrassa, Mutua de Terrassa Hospital, Spain.,Neurovascular Research Laboratory and Neurovascular Unit, Neurology and Medicine Departments - Universitat Autònoma de Barcelona, Vall d'Hebrón Hospital, Spain
| | - Graeme J Hankey
- School of Medicine and Pharmacology, The University of Western Australia, Australia
| | - Jordi Jimenez-Conde
- Department of Neurology, Institut Hospital del Mar d'Investigació Mèdica (IMIM), Spain.,Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques); Universitat Autònoma de Barcelona/DCEXS
| | - Katarina Jood
- Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden
| | - Jin-Moo Lee
- Department of Neurology, Washington University School of Medicine, USA
| | - Robin Lemmens
- Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, Belgium.,Laboratory of Neurobiology, VIB, Vesalius Research Center, Belgium.,Department of Neurology, University Hospitals Leuven, Belgium
| | - Christopher Levi
- Hunter Medical Research Institute, University of Newcastle, Australia.,Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Australia.,Faculty of Health and Medicine, University of Newcastle, Australia
| | - Bo Norrving
- Department of Clinical Sciences Lund, Neurology, Lund University, Sweden.,Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Sweden
| | | | - Natalia Rost
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, USA
| | - Jonathan Rosand
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, USA.,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA.,Center for Human Genetic Research, Massachusetts General Hospital, USA
| | - Peter M Rothwell
- Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, UK
| | - Rodney Scott
- Faculty of Health, University of Technology, Australia.,Hunter Medical Research Institute, University of Newcastle, Australia
| | - Daniel Strbian
- Department of Neurology, Helsinki University Hospital, Finland
| | - Jonathan Sturm
- Faculty of Health and Medicine, University of Newcastle, Australia
| | - Cathie Sudlow
- Centre for Clinical Brain Sciences, University of Edinburgh, UK
| | - Matthew Traylor
- Department of Clinical Neurosciences, University of Cambridge, UK
| | - Vincent Thijs
- Department of Neurology, Austin Health, Heidelberg, Australia.,Florey Institute for Neuroscience and Mental Health, University of Melbourne, Australia
| | - Turgut Tatlisumak
- Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden.,Department of Neurology, Helsinki University Hospital, Finland
| | - Tadeusz Wieloch
- Department of Clinical Sciences Lund, Neurology, Lund University, Sweden
| | - Daniel Woo
- Department of Neurology and Rehabilitation, University of Cincinnati, College of Medicine, USA
| | - Bradford B Worrall
- Department of Neurology, University of Virginia, USA.,Department of Health Evaluation Sciences, University of Virginia, USA
| | - Christina Jern
- Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Sweden
| | - Arne Lindgren
- Department of Clinical Sciences Lund, Neurology, Lund University, Sweden.,Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Sweden
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Owusu D, Pan Y, Xie C, Harirforoosh S, Wang KS. Polymorphisms in PDLIM5 gene are associated with alcohol dependence, type 2 diabetes, and hypertension. J Psychiatr Res 2017; 84:27-34. [PMID: 27693979 DOI: 10.1016/j.jpsychires.2016.09.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/29/2016] [Accepted: 09/15/2016] [Indexed: 12/15/2022]
Abstract
The PDZ and LIM domain 5 (PDLIM5) gene may play a role in alcohol dependence (AD), bipolar disorder, and major depressive disorder; however, no study has identified shared genetic variants within PDLIM5 gene among AD, type 2 diabetes (T2D), and hypertension. This study investigated the association of 72 single nucleotide polymorphism (SNPs) with AD (1066 AD cases and 1278 controls) in the Study of Addiction - Genetics and Environment (SAGE) sample and 47 SNPs with T2D (878 cases and 2686 non-diabetic) and hypertension (825 cases and 2739 non-hypertensive) in the Marshfield sample. Multiple logistic regression models in PLINK software were used to examine the associations of genetic variants with AD, T2D, and hypertension and SNP x alcohol consumption interactions for T2D and hypertension. Twenty-five SNPs were associated with AD in the SAGE sample (p < 0.05); rs1048627 showed the strongest association with AD (p = 5.53 × 10-4). Of the 25 SNPs, 5 SNPs showed associations with both AD in the SAGE sample and T2D in the Marshfield sample (top SNP rs11097432 with p = 0.00107 for T2D and p = 0.0483 for AD) while 6 SNPs showed associations with both AD in the SAGE sample and hypertension in the Marshfield sample (top SNP rs12500426 with p = 0.0119 for hypertension and p = 1.51 × 10-3 for AD). SNP (rs6532496) showed significant interaction with alcohol consumption for hypertension. Our results showed that several genetic variants in PDLIM5 gene influence AD, T2D and hypertension. These findings offer the potential for new insights into the pathogenesis of AD, T2D, and hypertension.
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Affiliation(s)
- Daniel Owusu
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN 37614, USA
| | - Yue Pan
- Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Changchun Xie
- Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Sam Harirforoosh
- Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, USA
| | - Ke-Sheng Wang
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN 37614, USA.
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Hizel C, Tremblay J, Bartlett G, Hamet P. Introduction. PROGRESS AND CHALLENGES IN PRECISION MEDICINE 2017:1-34. [DOI: 10.1016/b978-0-12-809411-2.00001-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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46
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White MG, Shaw JAM, Taylor R. Type 2 Diabetes: The Pathologic Basis of Reversible β-Cell Dysfunction. Diabetes Care 2016; 39:2080-2088. [PMID: 27926891 DOI: 10.2337/dc16-0619] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 08/23/2016] [Indexed: 02/03/2023]
Abstract
The reversible nature of early type 2 diabetes has been demonstrated in in vivo human studies. Recent in vivo and in vitro studies of β-cell biology have established that the β-cell loses differentiated characteristics, including glucose-mediated insulin secretion, under metabolic stress. Critically, the β-cell dedifferentiation produced by long-term excess nutrient supply is reversible. Weight loss in humans permits restoration of first-phase insulin secretion associated with the return to normal of the elevated intrapancreatic triglyceride content. However, in type 2 diabetes of duration greater than 10 years, the cellular changes appear to pass a point of no return. This review summarizes the evidence that early type 2 diabetes can be regarded as a reversible β-cell response to chronic positive calorie balance.
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Affiliation(s)
- Michael G White
- Regenerative Medicine for Diabetes Group and Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K
| | - James A M Shaw
- Regenerative Medicine for Diabetes Group and Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K
| | - Roy Taylor
- Regenerative Medicine for Diabetes Group and Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
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47
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Watve M, Diwekar-Joshi M. What to expect from an evolutionary hypothesis for a human disease: The case of type 2 diabetes. HOMO-JOURNAL OF COMPARATIVE HUMAN BIOLOGY 2016; 67:349-368. [DOI: 10.1016/j.jchb.2016.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 07/28/2016] [Indexed: 12/29/2022]
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Hamann L, Bustami J, Iakoubov L, Szwed M, Mossakowska M, Schumann RR, Puzianowska-Kuznicka M. TLR-6 SNP P249S is associated with healthy aging in nonsmoking Eastern European Caucasians - A cohort study. IMMUNITY & AGEING 2016; 13:7. [PMID: 26997964 PMCID: PMC4797164 DOI: 10.1186/s12979-016-0062-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/11/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND To investigate mechanisms that determine healthy aging is of major interest in the modern world marked by longer life expectancies. In addition to lifestyle and environmental factors genetic factors also play an important role in aging phenotypes. The aged immune system is characterized by a chronic micro-inflammation, known as inflamm-aging, that is suspected to trigger the onset of age-related diseases such as cardiovascular disease, Alzheimer's disease, cancer, and Diabetes Mellitus Type 2 (DMT2). We have recently shown that a Toll-like receptor 6 variant (P249S) is associated with susceptibility to cardiovascular disease and speculated that this variant may also be associated with healthy aging in general by decreasing the process of inflamm-aging. RESULTS Analyzing the PolSenior cohort we show here that nonsmoking S allele carriers are significantly protected from age-related diseases (P = 0.008, OR: 0.654). This association depends not only on the association with cardiovascular diseases (P = 0.018, OR: 0.483) for homozygous S allele carriers, but is also driven by a protection from Diabetes Mellitus type 2 (P = 0.010, OR: 0.486) for S allele carriers. In addition we detect a trend but no significant association of this allele with inflamm-aging in terms of baseline IL-6 levels. CONCLUSION We confirm our previous finding of the TLR-6 249S variant to be protective regarding cardiovascular diseases. Furthermore, we present first evidence of TLR-6 249S being involved in DMT2 susceptibility and may be in general associated with healthy aging possibly by reducing the process of inflamm-aging.
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Affiliation(s)
- Lutz Hamann
- Institute for Microbiology and Hygiene, Charité University Medical Center Berlin, Rahel-Hirsch-Weg 3, 10117 Berlin, Germany
| | - Jasmin Bustami
- Institute for Microbiology and Hygiene, Charité University Medical Center Berlin, Rahel-Hirsch-Weg 3, 10117 Berlin, Germany
| | | | - Malgorzata Szwed
- Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Malgorzata Mossakowska
- Polsenior Project, International Institute of Molecular and Cell Biology, Warsaw, Poland
| | - Ralf R Schumann
- Institute for Microbiology and Hygiene, Charité University Medical Center Berlin, Rahel-Hirsch-Weg 3, 10117 Berlin, Germany
| | - Monika Puzianowska-Kuznicka
- Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland ; Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, Warsaw, Poland
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Malodobra-Mazur M, Bednarska-Chabowska D, Olewinski R, Chmielecki Z, Adamiec R, Dobosz T. Single nucleotide polymorphisms in 5′-UTR of the SLC2A4 gene regulate solute carrier family 2 member 4 gene expression in visceral adipose tissue. Gene 2016; 576:499-504. [DOI: 10.1016/j.gene.2015.10.067] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 10/15/2015] [Accepted: 10/28/2015] [Indexed: 11/25/2022]
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50
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Xu P, Zhou D, Ouyang J, Chen B. STAT5gene polymorphisms are associated with the response of acute myeloid leukemia patients to Ara-C-based chemotherapy. Leuk Lymphoma 2015; 57:921-6. [DOI: 10.3109/10428194.2015.1087521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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