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Azarboo A, Hosseinkhani S, Ghaseminejad-Raeini A, Aazami H, Mohammadi SM, Zeidi S, Razi F, Bandarian F. Association between ELMO1 gene polymorphisms and diabetic kidney disease: A systematic review and meta-analysis. PLoS One 2024; 19:e0295607. [PMID: 38277369 PMCID: PMC10817128 DOI: 10.1371/journal.pone.0295607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/25/2023] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Previous research has suggested that the ELMO1 gene may play a role in the development of diabetic kidney disease. Diabetic kidney disease (DKD) is a serious complication of diabetes and the leading cause of chronic kidney disease and end-stage renal disease (ESRD). OBJECTIVE AND RATIONALE This study aim was to systematically review and explore the association between ELMO1 gene polymorphisms and diabetic kidney disease. A comprehensive systematic review provides a clear conclusion and high-level evidence for the association between ELMO1 gene and DKD for future application in personalized medicine. METHODS A comprehensive search of electronic databases, per PRISMA instructions, was conducted in Scopus, EMBASE, Web of Science, and PubMed databases from 1980 to January 2023. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using appropriate models. Subgroup and sensitivity analyses were performed to explore potential sources of heterogeneity and assess the robustness of the findings. RESULTS A total of 5794 diabetes patients with DKD, 4886 diabetes patients without DKD, and 2023 healthy controls were included in the 17 studies that made up this systematic review. In the investigation of DM (Diabetes Mellitus) with DKD vs. DM without DKD, the susceptibility for DKD for the EMLO1 rs741301 polymorphism indicated a significant difference under the dominant, homozygote, and recessive genetic models. The susceptibility for DKD for the EMLO1 rs1345365, rs10255208, and rs7782979 polymorphisms demonstrated a significant difference under the allele genetic models in the analysis of DM with DKD vs. DM without DKD groups. There was a considerable increase in DKD risk in the Middle East when the population was stratified by the region. CONCLUSION The findings of the meta-analysis show that there are a significant connection between the EMLO1 rs741301 polymorphism and DKD susceptibility in overall analyses; as well as rs1345365, rs10255208, and rs7782979 polymorphisms; especially in the Middle East region.
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Affiliation(s)
- Alireza Azarboo
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Hosseinkhani
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Ghaseminejad-Raeini
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Aazami
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed Mohammad Mohammadi
- Evidence Based Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Zeidi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farideh Razi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Bandarian
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Balzer MS, Pavkovic M, Frederick J, Abedini A, Freyberger A, Vienenkötter J, Mathar I, Siudak K, Eitner F, Sandner P, Grundmann M, Susztak K. Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution. Cell Rep Med 2023; 4:100992. [PMID: 37023747 PMCID: PMC10140477 DOI: 10.1016/j.xcrm.2023.100992] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/29/2023] [Accepted: 03/14/2023] [Indexed: 04/08/2023]
Abstract
Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.
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Affiliation(s)
- Michael S Balzer
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, 10117 Berlin, Germany
| | - Mira Pavkovic
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Julia Frederick
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Amin Abedini
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alexius Freyberger
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Julia Vienenkötter
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Ilka Mathar
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Krystyna Siudak
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Frank Eitner
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany; Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany
| | - Peter Sandner
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany; Department of Pharmacology, Hannover Medical School, 30625 Hannover, Germany
| | - Manuel Grundmann
- Bayer AG, Research and Early Development, Pharma Research Center, 42096 Wuppertal, Germany
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Analyses of Long Noncoding RNA and mRNA Profiles in Subjects with the Phlegm-Dampness Constitution. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4896282. [PMID: 34926685 PMCID: PMC8683173 DOI: 10.1155/2021/4896282] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 11/02/2021] [Indexed: 12/18/2022]
Abstract
Background Constitution in traditional Chinese medicine (TCM) plays a key role in the genesis, development, and prognosis of diseases. Phlegm-dampness constitution (PDC) is one of the nine constitutions in TCM, susceptible to metabolic disorders, which is mainly manifested by profuse phlegm, loose abdomen, and greasy face. Epidemiologic, genomic, and epigenetic studies have been carried out in previous works, confirming that PDC represents a distinctive population with microcosmic changes related to metabolic disorders. However, whether long noncoding RNAs (lncRNAs) play a regulatory role in metabolic disease in subjects with PDC remains largely unknown. We aimed to investigate distinct lncRNA and mRNA expression signatures and lncRNA-mRNA regulatory networks in the phlegm-dampness constitution (PDC). Methods The peripheral blood mononuclear cells (PBMCs) were isolated from the subjects with PDC (n = 13) and balanced constitution (BC) (n = 9). The profiles of lncRNAs and mRNAs in PBMCs were analyzed using microarray and further validated with RT-qPCR. Subsequently, pathway analysis was performed to investigate the function of differentially expressed mRNAs by using Ingenuity Pathway Analysis (IPA). Results Results suggested that some mRNAs, which were regulated by the differentially expressed lncRNAs, were mainly enriched in lipid metabolism and immune inflammation-related pathways. This was consistent with the molecular characteristics of previous studies, indicating that the clinical characteristics of metabolic disorders in PDC might be regulated by lncRNAs. Furthermore, by making coexpression network construction as well as cis-regulated target gene analysis, several lncRNA-mRNA pairs with potential regulatory relationships were identified by bioinformatic analyses, including RP11-317J10.2-CA3, RP11-809C18.3-PIP4K2A, LINC0069-RFTN1, TTTY15-ARHGEF9, and AC135048.13-ORAI3. Conclusions This study first revealed that the expression characteristics of lncRNAs/mRNAs may be potential biomarkers, indicating that the distinctive physical and clinical characteristics of PDC might be partially attributed to the specific expression signatures of lncRNAs/mRNAs.
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Campbell-Thompson M, Butterworth EA, Boatwright JL, Nair MA, Nasif LH, Nasif K, Revell AY, Riva A, Mathews CE, Gerling IC, Schatz DA, Atkinson MA. Islet sympathetic innervation and islet neuropathology in patients with type 1 diabetes. Sci Rep 2021; 11:6562. [PMID: 33753784 PMCID: PMC7985489 DOI: 10.1038/s41598-021-85659-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac β-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.
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Affiliation(s)
- Martha Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA. .,Department of Biomedical Engineering, College of Engineering, University of Florida, Gainesville, FL, 32610, USA.
| | - Elizabeth A Butterworth
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - J Lucas Boatwright
- Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, 32610, USA
| | - Malavika A Nair
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Lith H Nasif
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Kamal Nasif
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Andy Y Revell
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Alberto Riva
- Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, 32610, USA
| | - Clayton E Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Ivan C Gerling
- Department of Medicine-Endocrinology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Desmond A Schatz
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.,Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
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Tziastoudi M, Stefanidis I, Zintzaras E. The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies. Clin Kidney J 2020; 13:768-781. [PMID: 33123356 PMCID: PMC7577775 DOI: 10.1093/ckj/sfaa077] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Indexed: 12/20/2022] Open
Abstract
Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.
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Affiliation(s)
- Maria Tziastoudi
- Department of Biomathematics, University of Thessaly, School of Medicine, Larissa, Greece
| | - Ioannis Stefanidis
- Department of Nephrology, University of Thessaly, School of Medicine, Larissa, Greece
| | - Elias Zintzaras
- Department of Biomathematics, University of Thessaly, School of Medicine, Larissa, Greece.,The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
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Kilis-Pstrusinska K. Carnosine and Kidney Diseases: What We Currently Know? Curr Med Chem 2020; 27:1764-1781. [PMID: 31362685 DOI: 10.2174/0929867326666190730130024] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/01/2019] [Accepted: 07/23/2019] [Indexed: 01/26/2023]
Abstract
Carnosine (beta-alanyl-L-histidine) is an endogenously synthesised dipeptide which is present in different human tissues e.g. in the kidney. Carnosine is degraded by enzyme serum carnosinase, encoding by CNDP1 gene. Carnosine is engaged in different metabolic pathways in the kidney. It reduces the level of proinflammatory and profibrotic cytokines, inhibits advanced glycation end products' formation, moreover, it also decreases the mesangial cell proliferation. Carnosine may also serve as a scavenger of peroxyl and hydroxyl radicals and a natural angiotensin-converting enzyme inhibitor. This review summarizes the results of experimental and human studies concerning the role of carnosine in kidney diseases, particularly in chronic kidney disease, ischemia/reperfusion-induced acute renal failure, diabetic nephropathy and also drug-induced nephrotoxicity. The interplay between serum carnosine concentration and serum carnosinase activity and polymorphism in the CNDP1 gene is discussed. Carnosine has renoprotective properties. It has a promising potential for the treatment and prevention of different kidney diseases, particularly chronic kidney disease which is a global public health issue. Further studies of the role of carnosine in the kidney may offer innovative and effective strategies for the management of kidney diseases.
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Early Diagnostics of Freemartinism in Polish Holstein-Friesian Female Calves. Animals (Basel) 2019; 9:ani9110971. [PMID: 31739521 PMCID: PMC6912765 DOI: 10.3390/ani9110971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/09/2019] [Accepted: 11/11/2019] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Freemartinism is the most common type of gender developmental disorder, resulting in infertility of heifers from multiple-sex twin pregnancies. The frequency of this syndrome is related to the frequency of multiple pregnancies, the number of which has significantly increased in dairy cattle populations (HF). Therefore, rapid diagnostics is necessary to enable early elimination of heifers with freemartinism from breeding. The aim of the study was to compare and identify the best method for early identification of freemartinism. The use of cytogenetic and molecular methods (PCR, short tandem repeats (STRs), real-time PCR) allowed us to conclude that molecular methods are more effective and guarantee fast and precise diagnosis. An additional advantage of molecular methods is the easy way to collect test material, which can be frozen, unlike blood samples for cytogenetic analysis, which must be fresh and delivered within 24 h to the laboratory, which generates further costs. Abstract Freemartinism in females born from heterosexual multiple pregnancies is characterized by the presence of XX/XY cell lines due to the formation of a shared blood system by anastomoses between fetal membranes of co–twins and leads to disturbed development of the reproductive system, including infertility. The aim of this study was to estimate the most precise and effective diagnostic method, especially useful for early identification of freemartinism in young female calves. The cytomolecular evaluation results of 24 Holstein-Friesian heifers from heterosexual twins was verified by molecular techniques: PCR, short tandem repeats (STRs), and relative quantitative PCR. The molecular analyses have been found to be a more efficient testing strategy, with a higher diagnostic success rate than karyotype evaluation. In 21 heifers, leucocyte chimerism determined by the 60, XX/60, XY karyotype was revealed—the proportion of the 60, XY male cell line in individual animals was in the range of 4–66%. In three cases, a normal karyotype 60, XX was identified, which indicates that anastomoses did not occur in 12.5% of studied twins and suggests that these potentially fertile heifers can be qualified for further breeding. The precise and early identification of freemartinism can be the basis for guidelines and selection recommendations concerning the reproductive performance of heifers born from heterosexual multiple pregnancies.
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Abstract
PURPOSE OF REVIEW To provide an updated summary of discoveries made to date resulting from genome-wide association study (GWAS) and sequencing studies, and to discuss the latest loci added to the growing repertoire of genetic signals predisposing to type 1 diabetes (T1D). RECENT FINDINGS Genetic studies have identified over 60 loci associated with T1D susceptibility. GWAS alone does not specifically inform on underlying mechanisms, but in combination with other sequencing and omics-data, advances are being made in our understanding of T1D genetic etiology and pathogenesis. Current knowledge indicates that genetic variation operating in both pancreatic β cells and in immune cells is central in mediating T1D risk. One of the main challenges is to determine how these recently discovered GWAS-implicated variants affect the expression and function of gene products. Once we understand the mechanism of action for disease-causing variants, we will be well placed to apply targeted genomic approaches to impede the premature activation of the immune system in an effort to ultimately prevent the onset of T1D.
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Affiliation(s)
- Marina Bakay
- The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Suite 1216B, Philadelphia, PA, 19104-4318, USA
| | - Rahul Pandey
- The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Suite 1216B, Philadelphia, PA, 19104-4318, USA
| | - Struan F A Grant
- The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Suite 1216B, Philadelphia, PA, 19104-4318, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Hakon Hakonarson
- The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center, Suite 1216B, Philadelphia, PA, 19104-4318, USA.
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Kakoki M, Bahnson EM, Hagaman JR, Siletzky RM, Grant R, Kayashima Y, Li F, Lee EY, Sun MT, Taylor JM, Rice JC, Almeida MF, Bahr BA, Jennette JC, Smithies O, Maeda-Smithies N. Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production. JCI Insight 2019; 4:127660. [PMID: 31217360 DOI: 10.1172/jci.insight.127660] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/08/2019] [Indexed: 01/31/2023] Open
Abstract
Engulfment and cell motility protein 1 (ELMO1) is part of a guanine nucleotide exchange factor for Ras-related C3 botulinum toxin substrate (Rac), and ELMO1 polymorphisms were identified to be associated with diabetic nephropathy in genome-wide association studies. We generated a set of Akita Ins2C96Y diabetic mice having 5 graded cardiac mRNA levels of ELMO1 from 30% to 200% of normal and found that severe dilated cardiomyopathy develops in ELMO1-hypermorphic mice independent of renal function at age 16 weeks, whereas ELMO1-hypomorphic mice were completely protected. As ELMO1 expression increased, reactive oxygen species indicators, dissociation of the intercalated disc, mitochondrial fragmentation/dysfunction, cleaved caspase-3 levels, and actin polymerization increased in hearts from Akita mice. Cardiomyocyte-specific overexpression in otherwise ELMO1-hypomorphic Akita mice was sufficient to promote cardiomyopathy. Cardiac Rac1 activity was positively correlated with the ELMO1 levels, and oral administration of a pan-Rac inhibitor, EHT1864, partially mitigated cardiomyopathy of the ELMO1 hypermorphs. Disrupting Nox4, a Rac-independent NADPH oxidase, also partially mitigated it. In contrast, a pan-NADPH oxidase inhibitor, VAS3947, markedly prevented cardiomyopathy. Our data demonstrate that in diabetes mellitus ELMO1 is the "rate-limiting" factor of reactive oxygen species production via both Rac-dependent and Rac-independent NADPH oxidases, which in turn trigger cellular signaling cascades toward cardiomyopathy.
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Affiliation(s)
- Masao Kakoki
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Edward M Bahnson
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Surgery, Division of Vascular Surgery, and Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - John R Hagaman
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Robin M Siletzky
- Department of Surgery, Division of Vascular Surgery, and Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ruriko Grant
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yukako Kayashima
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Feng Li
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Esther Y Lee
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Michelle T Sun
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joan M Taylor
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jessica C Rice
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - Michael F Almeida
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - Ben A Bahr
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - J Charles Jennette
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Oliver Smithies
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nobuyo Maeda-Smithies
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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10
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Gu HF. Genetic and Epigenetic Studies in Diabetic Kidney Disease. Front Genet 2019; 10:507. [PMID: 31231424 PMCID: PMC6566106 DOI: 10.3389/fgene.2019.00507] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 05/08/2019] [Indexed: 01/19/2023] Open
Abstract
Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD). DKD is a microvascular complication and occurs in 30–40% of diabetes patients. Epidemiological investigations and clinical observations on the familial clustering and heritability in DKD have highlighted an underlying genetic susceptibility. Furthermore, DKD is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual’s genetic background. In recent years, researchers have undertaken genetic and epigenetic studies of DKD in order to better understand its molecular mechanisms. In this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of DKD are described. Current information from genetic and epigenetic studies of DKD and ESRD in patients with diabetes, including the approaches of genome-wide association study (GWAS) or epigenome-wide association study (EWAS) and candidate gene association analyses, are summarized. Further investigation of molecular defects in DKD with new approaches such as next generation sequencing analysis and phenome-wide association study (PheWAS) is also discussed.
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Affiliation(s)
- Harvest F Gu
- Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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11
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Jeong KH, Kim JS, Woo JT, Rhee SY, Lee YH, Kim YG, Moon JY, Kim SK, Kang SW, Lee SH, Kim YH. Genome-wide association study identifies new susceptibility loci for diabetic nephropathy in Korean patients with type 2 diabetes mellitus. Clin Genet 2019; 96:35-42. [PMID: 30883692 DOI: 10.1111/cge.13538] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/26/2019] [Accepted: 03/14/2019] [Indexed: 12/11/2022]
Abstract
Genetic factors are considered to be important in the pathogenesis of diabetic nephropathy (DN). Despite several genome-wide association studies (GWASs) demonstrating that specific polymorphisms of candidate genes were associated with DN, there were some limitations in previous studies. We conducted a GWAS using customized DNA chips to identify novel susceptibility loci for DN in Korean. We analyzed a total of 414 DN cases and 474 normoalbuminuric diabetic hyper-controls across two stages using customized DNA chips containing 98 667 single nucleotide polymorphisms (SNPs). We explored the associations between SNPs and DN in samples from 87 DN cases, mostly confirmed by renal biopsy, and 104 diabetic hyper-controls, and replicated these associations in independent cohort samples with 327 DN cases and 370 diabetic hyper-controls. The top significant SNPs from the discovery samples were selected for replication in the independent cohort. rs3765156 in PIK3C2B was significantly associated with DN in the replication cohort after multiple test. The SNPs identified in our study provide new insights into the pathogenesis of DN in the Korean population. Additional studies are needed to determine biological effects and clinical utility of our findings.
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Affiliation(s)
- Kyung H Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Jin S Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Jeong-Taek Woo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Sang Y Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Yu H Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Yang G Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Su K Kim
- Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung, Republic of Korea
| | - Sun W Kang
- Division of Nephrology, School of Medicine, Inje University, Busan, Republic of Korea
| | - Sang H Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Yeong H Kim
- Division of Nephrology, School of Medicine, Inje University, Busan, Republic of Korea
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12
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Rodriguez-Niño A, Hauske SJ, Herold A, Qiu J, van den Born J, Bakker SJL, Krämer BK, Yard BA. Serum Carnosinase-1 and Albuminuria Rather than the CNDP1 Genotype Correlate with Urinary Carnosinase-1 in Diabetic and Nondiabetic Patients with Chronic Kidney Disease. J Diabetes Res 2019; 2019:6850628. [PMID: 31950064 PMCID: PMC6948305 DOI: 10.1155/2019/6850628] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/24/2019] [Accepted: 11/27/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Carnosinase-1 (CN-1) can be detected in 24 h urine of healthy individuals and patients with type 2 diabetes (T2DM). We aimed to assess whether urinary CN-1 is also reliably measured in spot urine and investigated its association with renal function and the albumin/creatinine ratio (ACR). We also assessed associations between the CNDP1 (CTG) n genotype and CN-1 concentrations in serum and urine. METHODS Patients with T2DM (n = 85) and nondiabetic patients with chronic kidney disease (CKD) (n = 26) stratified by albuminuria (ACR ≤ 300 mg/g or ACR > 300 mg/g) recruited from the nephrology clinic and healthy subjects (n = 24) were studied. RESULTS Urinary CN-1 was more frequently detected and displayed higher concentrations in patients with ACR > 300 mg/g as compared to those with ACR ≤ 300 mg/g irrespective of the baseline disease (T2DM: 554 ng/ml [IQR 212-934 ng/ml] vs. 31 ng/ml [IQR 31-63 ng/ml] (p < 0.0001) and nondiabetic CKD: 197 ng/ml [IQR 112-739] vs. 31 ng/ml [IQR 31-226 ng/ml] (p = 0.015)). A positive correlation between urinary CN-1 and ACR was found (r = 0.68, p < 0.0001). Multivariate linear regression analysis revealed that ACR and serum CN-1 concentrations but not eGFR or the CNDP1 genotype are independent predictors of urinary CN-1, explaining 47% of variation of urinary CN-1 concentrations (R 2 = 0.47, p < 0.0001). CONCLUSION These results confirm and extend previous findings on urinary CN-1 concentrations, suggesting that assessment of CN-1 in spot urine is as reliable as in 24 h urine and may indicate that urinary CN-1 in macroalbuminuric patients is primarily serum-derived and not locally produced.
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Affiliation(s)
- Angelica Rodriguez-Niño
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
| | - Sibylle J. Hauske
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
| | - Anna Herold
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
| | - Jiedong Qiu
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
| | - Jacob van den Born
- Department of Nephrology, University Medical Centre Groningen, University of Groningen, Groningen 9700RB, Netherlands
| | - Stephan J. L. Bakker
- Department of Nephrology, University Medical Centre Groningen, University of Groningen, Groningen 9700RB, Netherlands
| | - Bernhard K. Krämer
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
| | - Benito A. Yard
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim 68167, Germany
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13
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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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14
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Peters V, Zschocke J, Schmitt CP. Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency. J Inherit Metab Dis 2018; 41:39-47. [PMID: 29027595 DOI: 10.1007/s10545-017-0099-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 09/20/2017] [Accepted: 09/26/2017] [Indexed: 12/15/2022]
Abstract
Carnosinase (CN1) is a dipeptidase, encoded by the CNDP1 gene, that degrades histidine-containing dipeptides, such as carnosine, anserine and homocarnosine. Loss of CN1 function (also called carnosinase deficiency or aminoacyl-histidine dipeptidase deficiency) has been reported in a small number of patients with highly elevated blood carnosine concentrations, denoted carnosinaemia; it is unclear whether the variety of clinical symptoms in these individuals is causally related to carnosinase deficiency. Reduced CN1 function should increase serum carnosine concentrations but the genetic basis of carnosinaemia has not been formally confirmed to be due to CNDP1 mutations. A CNDP1 polymorphism associated with low CN1 activity correlates with significantly reduced risk for diabetic nephropathy, especially in women with type 2 diabetes, and may slow progression of chronic kidney disease in children with glomerulonephritis. Studies in rodents demonstrate antiproteinuric and vasculoprotective effects of carnosine, the precise molecular mechanisms, however, are still incompletely understood. Thus, carnosinemia due to CN1 deficiency may be a non-disease; in contrast, carnosine may potentially protect against long-term sequelae of reactive metabolites accumulating, e.g. in diabetes and chronic renal failure.
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MESH Headings
- Amino Acid Metabolism, Inborn Errors/diagnosis
- Amino Acid Metabolism, Inborn Errors/enzymology
- Amino Acid Metabolism, Inborn Errors/epidemiology
- Amino Acid Metabolism, Inborn Errors/genetics
- Animals
- Brain Diseases, Metabolic, Inborn/diagnosis
- Brain Diseases, Metabolic, Inborn/enzymology
- Brain Diseases, Metabolic, Inborn/epidemiology
- Brain Diseases, Metabolic, Inborn/genetics
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/enzymology
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/genetics
- Diabetic Nephropathies/diagnosis
- Diabetic Nephropathies/enzymology
- Diabetic Nephropathies/epidemiology
- Diabetic Nephropathies/genetics
- Dipeptidases/deficiency
- Dipeptidases/genetics
- Humans
- Mutation
- Polymorphism, Genetic
- Prognosis
- Protective Factors
- Risk Factors
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Affiliation(s)
- Verena Peters
- Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
| | - Johannes Zschocke
- Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
| | - Claus P Schmitt
- Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany
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15
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Jin L, Wang T, Jiang S, Chen M, Zhang R, Hu C, Jia W, Liu Z. The Association of a Genetic Variant in SCAF8-CNKSR3 with Diabetic Kidney Disease and Diabetic Retinopathy in a Chinese Population. J Diabetes Res 2017; 2017:6542689. [PMID: 28401168 PMCID: PMC5376416 DOI: 10.1155/2017/6542689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/23/2017] [Indexed: 12/19/2022] Open
Abstract
Background. Genome-wide association studies found rs955333 located in 6q25.2 was associated with diabetic kidney disease in multiple ethnic populations, including European Americans, African Americans, and Mexican Americans. We aimed to investigate the association between the variant rs955333 in SCAF8-CNKSR3 and DKD susceptibility in Chinese type 2 diabetes patients. Methods. The variant rs955333 was genotyped in 1884 Chinese type 2 diabetes patients. Associations of the variant rs955333 with DKD and DR susceptibility and related quantitative traits were evaluated. Results. The variant rs955333 was not associated with DKD in our samples, while subjects with genotype GG were associated with DR (P = 0.047, OR = 0.5525 [0.308,0.9911]), and it also showed association with microalbuminuria (P = 0.024, beta = -0.1812 [-0.339, -0.024]). Conclusion. Our data suggests the variant rs955333 was not associated with DKD but showed association with diabetic retinopathy in Chinese type 2 diabetes patients.
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Affiliation(s)
- Li Jin
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210016, China
| | - Tao Wang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Song Jiang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210016, China
| | - Miao Chen
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- *Weiping Jia: and
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210016, China
- *Zhihong Liu:
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16
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Sandholm N, Van Zuydam N, Ahlqvist E, Juliusdottir T, Deshmukh HA, Rayner NW, Di Camillo B, Forsblom C, Fadista J, Ziemek D, Salem RM, Hiraki LT, Pezzolesi M, Trégouët D, Dahlström E, Valo E, Oskolkov N, Ladenvall C, Marcovecchio ML, Cooper J, Sambo F, Malovini A, Manfrini M, McKnight AJ, Lajer M, Harjutsalo V, Gordin D, Parkkonen M, Tuomilehto J, Lyssenko V, McKeigue PM, Rich SS, Brosnan MJ, Fauman E, Bellazzi R, Rossing P, Hadjadj S, Krolewski A, Paterson AD, Florez JC, Hirschhorn JN, Maxwell AP, Dunger D, Cobelli C, Colhoun HM, Groop L, McCarthy MI, Groop PH. The Genetic Landscape of Renal Complications in Type 1 Diabetes. J Am Soc Nephrol 2016; 28:557-574. [PMID: 27647854 DOI: 10.1681/asn.2016020231] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/17/2016] [Indexed: 12/14/2022] Open
Abstract
Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
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Affiliation(s)
- Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Natalie Van Zuydam
- Wellcome Trust Centre for Human Genetics,Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.,Medical Research Institute
| | - Emma Ahlqvist
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
| | | | - Harshal A Deshmukh
- Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom
| | - N William Rayner
- Wellcome Trust Centre for Human Genetics,Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.,Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
| | - Barbara Di Camillo
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Joao Fadista
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Daniel Ziemek
- Computational Sciences, Pfizer Worldwide Research and Development, Berlin, Germany
| | - Rany M Salem
- Departments of Genetics,Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.,Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts
| | - Linda T Hiraki
- Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Marcus Pezzolesi
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
| | - David Trégouët
- Sorbonne Universities, Pierre et Marie Curie University (UPMC) and National Institute for Health and Medical Research, Mixed Research Unit in Health (UMR_S) 1166, Paris, France.,Institute for Cardiometabolism and Nutrition, Genomics and pathophysiology of Cardiovascular diseases, Paris, France
| | - Emma Dahlström
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Erkka Valo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Nikolay Oskolkov
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Claes Ladenvall
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
| | | | - Jason Cooper
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
| | - Francesco Sambo
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Alberto Malovini
- Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.,Laboratory of Informatics and Systems Engineering for Clinical Research, Scientific Institute for Research, Hospitalization and Health Care, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico); Salvatore Maugeri Foundation, Pavia, Italy
| | - Marco Manfrini
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Amy Jayne McKnight
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom
| | - Maria Lajer
- Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.,The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Daniel Gordin
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Maija Parkkonen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | | | - Jaakko Tuomilehto
- The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.,Centre for Vascular Prevention, Danube University Krems, Krems, Austria
| | - Valeriya Lyssenko
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.,Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark
| | - Paul M McKeigue
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | | | - Eric Fauman
- Computational Sciences, Pfizer Worldwide Research and Development, Cambridge, Massachusetts
| | - Riccardo Bellazzi
- Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy
| | - Peter Rossing
- Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark.,Department of Health, Aarhus University, Aarhus, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Samy Hadjadj
- Functional Research Unit of Medicine and Pharmacy, University of Poitiers, Poitiers, France.,Department of Endocrinology-Diabetology and Center of Clinical Investigation, Poitiers University Hospital, Poitiers, France.,Institute National pour la Santé et la Recherche Médicale, National Institute for Health and Medical Research, Center of Clinical Investigation 1402 and Unit 1082, Poitiers, France
| | - Andrzej Krolewski
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
| | - Andrew D Paterson
- Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | | | - Jose C Florez
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.,Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
| | - Joel N Hirschhorn
- Departments of Genetics,Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.,Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts
| | - Alexander P Maxwell
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom.,Regional Nephrology Unit, Belfast City Hospital, Belfast, United Kingdom; and
| | | | - David Dunger
- Department of Paediatrics, Institute of Metabolic Science, and
| | - Claudio Cobelli
- Department of Information Engineering, University of Padova, Padova, Italy
| | - Helen M Colhoun
- Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom
| | - Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
| | - Mark I McCarthy
- Wellcome Trust Centre for Human Genetics,Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.,Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.,Baker IDI (International Diabetes Institute) Heart and Diabetes Institute, Melbourne, Victoria, Australia
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17
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Lin CH, Chang YC, Chuang LM. Early detection of diabetic kidney disease: Present limitations and future perspectives. World J Diabetes 2016; 7:290-301. [PMID: 27525056 PMCID: PMC4958689 DOI: 10.4239/wjd.v7.i14.290] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called “non-albuminuric renal impairment” is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eGFR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
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18
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Methyl-Arginine Profile of Brain from Aged PINK1-KO+A53T-SNCA Mice Suggests Altered Mitochondrial Biogenesis. PARKINSONS DISEASE 2016; 2016:4686185. [PMID: 27034888 PMCID: PMC4791501 DOI: 10.1155/2016/4686185] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 01/13/2016] [Accepted: 01/14/2016] [Indexed: 11/29/2022]
Abstract
Hereditary Parkinson's disease can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) or the autosomal recessive deficiency of PINK1. We recently showed that the combination of PINK1-knockout with overexpression of A53T-SNCA in double mutant (DM) mice potentiates phenotypes and reduces survival. Now we studied brain hemispheres of DM mice at age of 18 months in a hypothesis-free approach, employing a quantitative label-free global proteomic mass spectrometry scan of posttranslational modifications focusing on methyl-arginine. The strongest effects were documented for the adhesion modulator CMAS, the mRNA decapping/deadenylation factor PATL1, and the synaptic plasticity mediator CRTC1/TORC1. In addition, an intriguing effect was observed for the splicing factor PSF/SFPQ, known to interact with the dopaminergic differentiation factor NURR1 as well as with DJ-1, the protein responsible for the autosomal recessive PARK7 variant of PD. CRTC1, PSF, and DJ-1 are modulators of PGC1alpha and of mitochondrial biogenesis. This pathway was further stressed by dysregulations of oxygen sensor EGLN3 and of nuclear TMPO. PSF and TMPO cooperate with dopaminergic differentiation factors LMX1B and NURR1. Further dysregulations concerned PRR18, TRIO, HNRNPA1, DMWD, WAVE1, ILDR2, DBNDD1, and NFM. Thus, we report selective novel endogenous stress responses in brain, which highlight early dysregulations of mitochondrial homeostasis and midbrain vulnerability.
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High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy. Proc Natl Acad Sci U S A 2016; 113:2218-22. [PMID: 26858454 DOI: 10.1073/pnas.1600511113] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2(Akita) gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.
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Harder JL, Hodgin JB, Kretzler M. Integrative Biology of Diabetic Kidney Disease. KIDNEY DISEASES 2015; 1:194-203. [PMID: 26929927 DOI: 10.1159/000439196] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND The leading cause of ESRD in the U.S. is diabetic kidney disease (DKD). Despite significant efforts to improve outcomes in DKD, the impact on disease progression has been disappointing. This has prompted clinicians and researchers to search for alternative approaches to identify persons at risk, and to search for more effective therapies to halt progression of DKD. Identification of novel therapies is critically dependent on a more comprehensive understanding of the pathophysiology of DKD, specifically at the molecular level. A more expansive and exploratory view of DKD is needed to complement more traditional research approaches that have focused on single molecules. SUMMARY In recent years, sophisticated research methodologies have emerged within systems biology that should allow for a more comprehensive disease definition of DKD. Systems biology provides an inter-disciplinary approach to describe complex interactions within biological systems including how these interactions influence systems' functions and behaviors. Computational modeling of large, system-wide, quantitative data sets is used to generate molecular interaction pathways, such as metabolic and cell signaling networks. KEY MESSAGES Importantly, interpretation of data generated by systems biology tools requires integration with enhanced clinical research data and validation using model systems. Such an integrative biological approach has already generated novel insights into pathways and molecules involved in DKD. In this review, we highlight recent examples of how combining systems biology with traditional clinical and model research efforts results in an integrative biology approach that has significantly added to the understanding of the complex pathophysiology of DKD.
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Affiliation(s)
- Jennifer L Harder
- Department of Internal Medicine, the Division of Nephrology, University of Michigan, Ann Arbor, Michigan
| | - Jeffrey B Hodgin
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Matthias Kretzler
- Department of Internal Medicine, the Division of Nephrology, University of Michigan, Ann Arbor, Michigan ; Department of Bioinformatics and Computational Medicine, University of Michigan, Ann Arbor, Michigan
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Banerji J. Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis). Int J Mol Med 2015; 36:607-26. [PMID: 26178806 PMCID: PMC4533780 DOI: 10.3892/ijmm.2015.2285] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 07/15/2015] [Indexed: 12/14/2022] Open
Abstract
The present treatment of childhood T-cell leukemias involves the systemic administration of prokary-otic L-asparaginase (ASNase), which depletes plasma Asparagine (Asn) and inhibits protein synthesis. The mechanism of therapeutic action of ASNase is poorly understood, as are the etiologies of the side-effects incurred by treatment. Protein expression from genes bearing Asn homopolymeric coding regions (N-hCR) may be particularly susceptible to Asn level fluctuation. In mammals, N-hCR are rare, short and conserved. In humans, misfunctions of genes encoding N-hCR are associated with a cluster of disorders that mimic ASNase therapy side-effects which include impaired glycemic control, dislipidemia, pancreatitis, compromised vascular integrity, and neurological dysfunction. This paper proposes that dysregulation of Asn homeostasis, potentially even by ASNase produced by the microbiome, may contribute to several clinically important syndromes by altering expression of N-hCR bearing genes. By altering amino acid abundance and modulating ribosome translocation rates at codon repeats, the microbiomic environment may contribute to genome decoding and to shaping the proteome. We suggest that impaired translation at poly Asn codons elevates diabetes risk and severity.
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Affiliation(s)
- Julian Banerji
- Center for Computational and Integrative Biology, MGH, Simches Research Center, Boston, MA 02114, USA
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Abstract
The global prevalence of diabetic nephropathy is rising in parallel with the increasing incidence of diabetes in most countries. Unfortunately, up to 40 % of persons diagnosed with diabetes may develop kidney complications. Diabetic nephropathy is associated with substantially increased risks of cardiovascular disease and premature mortality. An inherited susceptibility to diabetic nephropathy exists, and progress is being made unravelling the genetic basis for nephropathy thanks to international research collaborations, shared biological resources and new analytical approaches. Multiple epidemiological studies have highlighted the clinical heterogeneity of nephropathy and the need for better phenotyping to help define important subgroups for analysis and increase the power of genetic studies. Collaborative genome-wide association studies for nephropathy have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms, but progress towards clinically relevant risk prediction models for diabetic nephropathy has been slow. This review summarises the current status, recent developments and ongoing challenges elucidating the genetics of diabetic nephropathy.
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Affiliation(s)
- Amy Jayne McKnight
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, c/o Regional Genetics Centre, Level A, Tower Block, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK,
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Kwak SH, Park KS. Genetic Studies on Diabetic Microvascular Complications: Focusing on Genome-Wide Association Studies. Endocrinol Metab (Seoul) 2015; 30:147-58. [PMID: 26194074 PMCID: PMC4508258 DOI: 10.3803/enm.2015.30.2.147] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 05/26/2015] [Accepted: 05/26/2015] [Indexed: 01/13/2023] Open
Abstract
Diabetes is a common metabolic disorder with a worldwide prevalence of 8.3% and is the leading cause of visual loss, end-stage renal disease and amputation. Recently, genome-wide association studies (GWASs) have identified genetic risk factors for diabetic microvascular complications of retinopathy, nephropathy, and neuropathy. We summarized the recent findings of GWASs on diabetic microvascular complications and highlighted the challenges and our opinion on future directives. Five GWASs were conducted on diabetic retinopathy, nine on nephropathy, and one on neuropathic pain. The majority of recent GWASs were underpowered and heterogeneous in terms of study design, inclusion criteria and phenotype definition. Therefore, few reached the genome-wide significance threshold and the findings were inconsistent across the studies. Recent GWASs provided novel information on genetic risk factors and the possible pathophysiology of diabetic microvascular complications. However, further collaborative efforts to standardize phenotype definition and increase sample size are necessary for successful genetic studies on diabetic microvascular complications.
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Affiliation(s)
- Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital; Depatment of Internal Medicine, Seoul National University College of Medicine; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
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Liu R, Lee K, He JC. Genetics and Epigenetics of Diabetic Nephropathy. KIDNEY DISEASES (BASEL, SWITZERLAND) 2015; 1:42-51. [PMID: 27536664 PMCID: PMC4934801 DOI: 10.1159/000381796] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 03/20/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in the USA and worldwide, contributing to significant morbidity and mortality in diabetic patients. A genetic factor for the development of DN is strongly implicated, as only one third of diabetic patients eventually develop kidney disease. Growing evidence also supports an important role of epigenetic modifications in DN. SUMMARY Multiple studies have been performed to identify risk genes and loci associated with DN. So far, only several genes and loci have been identified, none of which showed a strong association with DN. Therefore, a better study design with a larger sample size to identify rare variants and a clinically defined patient population to identify genes and loci associated with progressive DN are still needed. In addition to genetic factors, epigenetic modifications, such as DNA methylation, histone modifications and microRNAs, also play a major role in the pathogenesis of DN through a second layer of gene regulation. Although a major progress has been made in this field, epigenetic studies in DN are still in the early phase and have been limited mostly due to the heterogeneity of kidney tissue samples with multiple cells. However, rapid development of high-throughput genome-wide techniques will help us to better identify genetic variants and epigenetic changes in DN. KEY MESSAGE Understanding of genetic and epigenetic changes in DN is needed for the development of new biomarkers and better drug targets against DN. Summarized in this review are important recent findings on genetic and epigenetic studies in the field of DN.
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Affiliation(s)
- Ruijie Liu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
- Renal Section, James J. Peters VAMC, New York, N.Y., USA
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
- Renal Section, James J. Peters VAMC, New York, N.Y., USA
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Abstract
The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of morbidity and mortality that is attributable to the complications of chronic hyperglycaemia. These complications include blindness, renal failure and cardiovascular disease. Current therapeutic options for chronic hyperglycaemia reduce, but do not eradicate, the risk of these complications. Success in defining new preventative and therapeutic strategies hinges on an improved understanding of the molecular processes involved in the development of these complications. This Review explores the role of human genetics in delivering such insights, and describes progress in characterizing the sequence variants that influence individual predisposition to diabetic kidney disease, retinopathy, neuropathy and accelerated cardiovascular disease. Numerous risk variants for microvascular complications of diabetes have been reported, but very few have shown robust replication. Furthermore, only limited evidence exists of a difference in the repertoire of risk variants influencing macrovascular disease between those with and those without diabetes. Here, we outline the challenges associated with the genetic analysis of diabetic complications and highlight ongoing efforts to deliver biological insights that can drive translational benefits.
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Sortica DA, Buffon MP, Souza BM, Nicoletto BB, Santer A, Assmann TS, Crispim D, Canani LH. Association between the ENPP1 K121Q polymorphism and risk of diabetic kidney disease: a systematic review and meta-analysis. PLoS One 2015; 10:e0118416. [PMID: 25794151 PMCID: PMC4368055 DOI: 10.1371/journal.pone.0118416] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 01/16/2015] [Indexed: 01/05/2023] Open
Abstract
The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.
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Affiliation(s)
- Denise Alves Sortica
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Marjorie Piucco Buffon
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Bianca Marmontel Souza
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Bruna Bellicanta Nicoletto
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Andressa Santer
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Tais Silveira Assmann
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daisy Crispim
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Luis Henrique Canani
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- Postgraduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- * E-mail:
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Sambo F, Malovini A, Sandholm N, Stavarachi M, Forsblom C, Mäkinen VP, Harjutsalo V, Lithovius R, Gordin D, Parkkonen M, Saraheimo M, Thorn LM, Tolonen N, Wadén J, He B, Osterholm AM, Tuomilehto J, Lajer M, Salem RM, McKnight AJ, Tarnow L, Panduru NM, Barbarini N, Di Camillo B, Toffolo GM, Tryggvason K, Bellazzi R, Cobelli C, Groop PH. Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification. Diabetologia 2014; 57:1611-22. [PMID: 24871321 DOI: 10.1007/s00125-014-3256-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 04/11/2014] [Indexed: 10/25/2022]
Abstract
AIMS/HYPOTHESIS Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. METHODS We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). RESULTS Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. CONCLUSIONS/INTERPRETATION This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.
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Affiliation(s)
- Francesco Sambo
- Department of Information Engineering, University of Padova, Padova, Italy
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Gangadhariah MH, Luther JM, Garcia V, Paueksakon P, Zhang MZ, Hayward SW, Love HD, Falck JR, Manthati VL, Imig JD, Schwartzman ML, Zent R, Capdevila JH, Pozzi A. Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. J Am Soc Nephrol 2014; 26:597-610. [PMID: 25071086 DOI: 10.1681/asn.2013090980] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.
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Affiliation(s)
| | - James M Luther
- Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, New York
| | | | | | - Simon W Hayward
- Urologic Surgery; Vanderbilt University, Nashville, Tennessee
| | - Harold D Love
- Urologic Surgery; Vanderbilt University, Nashville, Tennessee
| | - John R Falck
- Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Vijaya L Manthati
- Division of Chemistry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and
| | | | - Roy Zent
- Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee
| | | | - Ambra Pozzi
- Divisions of Nephrology and Department of Medicine, Veterans Affairs Hospitals, Nashville, Tennessee
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Shi M, Umbach DM, Weinberg CR. Disentangling pooled triad genotypes for association studies. Ann Hum Genet 2014; 78:345-56. [PMID: 24962618 DOI: 10.1111/ahg.12073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 05/05/2014] [Indexed: 11/30/2022]
Abstract
Association studies that genotype affected offspring and their parents (triads) offer robustness to genetic population structure while enabling assessments of maternal effects, parent-of-origin effects, and gene-by-environment interaction. We propose case-parents designs that use pooled DNA specimens to make economical use of limited available specimens. One can markedly reduce the number of genotyping assays required by randomly partitioning the case-parent triads into pooling sets of h triads each and creating three pools from every pooling set, one pool each for mothers, fathers, and offspring. Maximum-likelihood estimation of relative risk parameters proceeds via log-linear modeling using the expectation-maximization algorithm. The approach can assess offspring and maternal genetic effects and accommodate genotyping errors and missing genotypes. We compare the power of our proposed analysis for testing offspring and maternal genetic effects to that based on a difference approach and that of the gold standard based on individual genotypes, under a range of allele frequencies, missing parent proportions, and genotyping error rates. Power calculations show that the pooling strategies cause only modest reductions in power if genotyping errors are low, while reducing genotyping costs and conserving limited specimens.
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Affiliation(s)
- Min Shi
- Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, NC, USA
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McKnight AJ, McKay GJ, Maxwell AP. Genetic and epigenetic risk factors for diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21:287-96. [PMID: 24780457 DOI: 10.1053/j.ackd.2014.03.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 03/10/2014] [Indexed: 12/22/2022]
Abstract
Diabetes is increasing at daunting rates worldwide, and approximately 40% of affected individuals will develop kidney complications. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and there are significant healthcare costs providing appropriate renal replacement therapies to affected individuals. For several decades, investigators have sought to discover inherited risk factors and biomarkers for DKD. In recent years, advances in high-throughput laboratory techniques and computational analyses, coupled with the establishment of multicenter consortia, have helped to identify genetic loci that are replicated across multiple populations. Several genome-wide association studies (GWAS) have been conducted for DKD with further meta-analysis of GWAS and comprehensive "single gene" meta-analyses now published. Despite these efforts, much of the inherited predisposition to DKD remains unexplained. Meta-analyses and integrated-omics pathway studies are being used to help elucidate underlying genetic risks. Epigenetic phenomena are increasingly recognized as important drivers of disease risk, and several epigenome-wide association studies have now been completed. This review describes key findings and ongoing genetic and epigenetic initiatives for DKD.
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Affiliation(s)
- Amy Jayne McKnight
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
| | - Gareth J McKay
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom
| | - Alexander P Maxwell
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom
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Kuricová K, Tanhäuserová V, Pácal L, Bartáková V, Brožová L, Jarkovský J, Kaňková K. NOS3 894G>T polymorphism is associated with progression of kidney disease and cardiovascular morbidity in type 2 diabetic patients: NOS3 as a modifier gene for diabetic nephropathy? Kidney Blood Press Res 2014; 38:92-8. [PMID: 24603156 DOI: 10.1159/000355757] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS We have previously associated SNP 894G>T in the NOS3 gene with diabetic nephropathy (DN) using multi-locus analysis. Variant 894G>T has been widely studied as a DN susceptibility factor with contradictory results. In the present study we genotyped 894G>T in the cohort of prospectively followed type 2 diabetics with the aim to investigate its possible role in the progression of DN and development of morbidity and mortality associated with diabetes. METHODS 311 subjects with defined stage of DN were enrolled in the study and followed up for a median of 38 months. We considered three end-points: progression of DN, major cardiovascular event and all-cause mortality. RESULTS Considering baseline GFR, age at enrolment and diabetes duration as confounders, Cox regression analysis identified 894GT genotype as a risk factor for DN progression (HR = 1.843 [95% CI 1.088 - 3.119], P = 0.023) and 894TT genotype as a risk factor for major cardiovascular event (HR = 2.515 [95% CI 1.060 - 5.965], P = 0.036). CONCLUSION We ascertained the significant effect of the NOS3 894G>T variant on DN progression and occurrence of major cardiovascular event in T2DM subjects. Based on these results NOS3 can be considered a modifier gene for DN.
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Affiliation(s)
- Katarína Kuricová
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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DiStefano JK, Taila M, Alvarez ML. Emerging roles for miRNAs in the development, diagnosis, and treatment of diabetic nephropathy. Curr Diab Rep 2013; 13:582-91. [PMID: 23666892 DOI: 10.1007/s11892-013-0386-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Although the causes of diabetic nephropathy are not yet fully known, emerging evidence suggests a role for epigenetic factors in the development of the disease. In particular, microRNAs (miRNAs) are becoming recognized as important mediators of biological processes relevant to diabetic nephropathy. Until recently, investigations of miRNAs in the development of diabetic nephropathy have remained relatively limited; however, the number of reports identifying potential new candidates and mechanisms of impact is presently expanding at a rapid pace. This review seeks to summarize these recent findings, focusing on new candidates and/or novel mechanisms, including the intersection between genetic variation and miRNA function in modulating disease expression, emerging in the field. We also review the latest advances in the diagnostic and therapeutic potential of miRNAs in the treatment of diabetic nephropathy.
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Affiliation(s)
- Johanna K DiStefano
- Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
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Wu HY, Wang Y, Chen M, Zhang X, Wang D, Pan Y, Li L, Liu D, Dai XM. Association of ELMO1 gene polymorphisms with diabetic nephropathy in Chinese population. J Endocrinol Invest 2013; 36:298-302. [PMID: 22842811 DOI: 10.3275/8525] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Genetic variations in the engulfment and cell motility 1 (ELMO1) gene have recently been identified to be associated with nephropathy attributed to Type 2 diabetes mellitus (T2DM). Since T2DM-associated complications are proved to be more common among Asians than Western individuals, and Chinese people have a high incidence of diabetic nephropathy (DN), this study sought to analyze the association of ELMO1 gene polymorphisms with DN to probe into the effects of ELMO1 gene on susceptibility of DN in Chinese population. METHODS We genotyped 6 polymorphism sites of ELMO1 gene in 200 unrelated Chinese subjects (123 T2DM with DN case subjects and 77 T2DM without DN control subjects). Genotyping was detected by a Sequenom MassARRAY genotyping system. RESULTS The strongest associations in ELMO1 gene with DN occurred at rs741301 [odds ratio (OR) 1.89; p=0.004] and rs10951509 (OR 1.76; p=0.02). Unconditional logistic regression analysis identified that the rs741301 polymorphism (presence of A allele, adjusted OR 3.27; p=0.03) and duration of T2DM (adjusted OR 1.15; p=0.04) were independent predictors for DN. The marker rs741301 located in intron 18 of ELMO1 gene was in strong linkage disequilibrium (LD) with rs11769038 (D'=0.91). Furthermore, haplotype analysis identified that haplotype 1 [CAAAGA] (OR 1.95; p=0.01), haplotype 2 [CAAAGG] (OR 0.50; p=0.01), and haplotype 9 [TGCGGG] (OR 0.17; p=0.007) of ELMO1 were significantly associated with DN. CONCLUSIONS This study first investigated the association of ELMO1 gene polymorphisms with DN in a Chinese population, supporting its key role as a candidate gene in the susceptibility of DN.
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Affiliation(s)
- H Y Wu
- Department of Endocrinology, Jingzhou First People's Hospital, Yangtze University, 8 Hang-kong street, Jingzhou, Hubei 434000, People's Republic of China.
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Zhu JM, Wang B, Li J, Chen GM, Fan YG, Feng CC, Pan HF, Ye DQ. D18S880 microsatellite polymorphism of carnosinase gene and diabetic nephropathy: a meta-analysis. Genet Test Mol Biomarkers 2013; 17:289-94. [PMID: 23402577 DOI: 10.1089/gtmb.2012.0341] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The aim of this study was to determine whether the CNDP1 (carnosinase gene) D18S880 microsatellite polymorphism confers susceptibility to diabetic nephropathy (DN). METHODS The authors conducted meta-analysis on association between the CNDP1 D18S880 microsatellite polymorphism and DN susceptibility, using fixed and random effects models. RESULTS A total of nine comparative studies were included in this meta-analysis, which included 4546 DN, 7994 diabetes mellitus (DM), and 1826 healthy (Heal) subjects. Overall, the analysis revealed that the D18S880 microsatellite polymorphism was significantly associated with DN for the five trinucleotide repeat (5L) allele and five leucines repeat (5L-5L) homozygous in the comparisons of DN versus DM (5L: odds ratio [OR] 0.90, 95% confidence interval [CI] 0.84-0.97, p=0.008; 5L-5L: OR 0.88, 95% CI 0.81-0.97, p=0.006) and DN versus non-DN (DM+Heal) (5L: OR 0.92, 95% CI 0.86-0.98, p=0.009; 5L-5L: OR 0.89, 95% CI 0.82-0.96, p=0.004). The protective effects of the D18S880 polymorphism were similar to those observed in the subgroups of the type 2 DM and the Caucasian population. However, significant association was not found in the type 1 DM population. CONCLUSIONS This meta-analysis confirms that the carnosinase D18S880 microsatellite polymorphism is associated with DN susceptibility, especially in the type 2 DM and the Caucasian population.
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Affiliation(s)
- Ji-Min Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People's Republic of China
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Lee T, Wadehra D. Genetic causation of neointimal hyperplasia in hemodialysis vascular access dysfunction. Semin Dial 2011; 25:65-73. [PMID: 21917012 DOI: 10.1111/j.1525-139x.2011.00967.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The major cause of hemodialysis vascular access failure is venous stenosis resulting from neointimal hyperplasia. Genetic factors have been shown to be associated with cardiovascular disease and peripheral vascular disease (PVD) in the general population. Genetic factors may also play an important role in vascular access stenosis and development of neointimal hyperplasia by affecting pathways that lead to inflammation, endothelial function, oxidative stress, and vascular smooth muscle proliferation. This review will discuss the role of genetics in understanding neointimal hyperplasia development in hemodialysis vascular access dysfunction and other disease processes with similar neointimal hyperplasia development such as coronary artery disease and PVD.
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Affiliation(s)
- Timmy Lee
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Cincinnati, Cincinnati, Ohio 45267-0585, USA.
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Ahluwalia TS, Lindholm E, Groop LC. Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes. Diabetologia 2011; 54:2295-302. [PMID: 21573905 DOI: 10.1007/s00125-011-2178-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Accepted: 04/13/2011] [Indexed: 10/18/2022]
Abstract
AIMS/HYPOTHESIS Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-L-histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. METHODS We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case-control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). RESULTS Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2, were associated with an increased risk of diabetic nephropathy (rs2346061 p = 5.07 × 10(-4); rs7577 p = 0.021). The latter was also associated with estimated GFR (β = -0.037, p = 0.014), particularly in women. A haplotype including these SNPs (C-C-G) was associated with a threefold increased risk of diabetic nephropathy (OR 2.98, 95% CI 2.43-3.67, p < 0.0001). CONCLUSIONS/INTERPRETATION These data suggest that common variants in CNDP1 and CNDP2 play a role in susceptibility to kidney disease in patients with type 2 diabetes.
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Affiliation(s)
- T S Ahluwalia
- Department of Clinical Sciences-Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, University Hospital Skane, UMAS, 20502 Malmo, Sweden.
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Böger CA, Heid IM. Chronic kidney disease: novel insights from genome-wide association studies. Kidney Blood Press Res 2011; 34:225-34. [PMID: 21691125 DOI: 10.1159/000326901] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA(2)R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low-frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes.
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Affiliation(s)
- Carsten A Böger
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
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Chakkera HA, Hanson RL, Kobes S, Millis MP, Nelson RG, Knowler WC, Distefano JK. Association of variants in the carnosine peptidase 1 gene (CNDP1) with diabetic nephropathy in American Indians. Mol Genet Metab 2011; 103:185-90. [PMID: 21393041 PMCID: PMC3101283 DOI: 10.1016/j.ymgme.2011.02.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 02/15/2011] [Indexed: 01/11/2023]
Abstract
CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several populations, including Pima Indians. However, evidence for association between CNDP1 alleles and diabetic nephropathy is equivocal and population-dependent. This study investigated CNDP1 as a candidate for diabetic kidney disease in Pima Indians. Nineteen tag single nucleotide polymorphisms spanning the CNDP1 locus were selected using genotype data from Chinese individuals in the HapMap resource along with 2 variants previously associated with diabetic nephropathy. All variants were genotyped in 3 different samples including a diabetic end-stage renal disease (ESRD) case-control study, a family-based study of diabetic individuals who participated in the linkage study for nephropathy, and a cohort of diabetic individuals in whom longitudinal measures of glomerular filtration rates (GFR) were performed. There was no statistically significant evidence for association with diabetic ESRD. However, nominal evidence for association was found in the family study, where markers rs12957330 (Odds ratio [OR]=0.29 per copy of G allele; p=0.04) and rs17817077 (OR=0.46 per copy of G allele; p=0.05) were associated with diabetic nephropathy. In addition, markers rs12964454, rs7244647, and rs7229005 were associated with changes in GFR (-8.5ml/min per copy of the G allele; p=0.04; 18.8ml/min per copy of the C allele; p=0.03; and -13.4ml/min per copy of the C allele; p=0.001, respectively). These findings provide nominal evidence supporting a role between CNDP1 variants and diabetic kidney disease.
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Affiliation(s)
- Harini A Chakkera
- Divisions of Nephrology and Transplantation, Mayo Clinic, Phoenix, AZ 85054, USA.
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Rosset S, Tzur S, Behar DM, Wasser WG, Skorecki K. The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus. Nat Rev Nephrol 2011; 7:313-26. [PMID: 21537348 DOI: 10.1038/nrneph.2011.52] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research.
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Affiliation(s)
- Saharon Rosset
- Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv 69978, Israel
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Alvarez ML, DiStefano JK. Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy. PLoS One 2011; 6:e18671. [PMID: 21526116 PMCID: PMC3081298 DOI: 10.1371/journal.pone.0018671] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 03/14/2011] [Indexed: 01/12/2023] Open
Abstract
We previously observed association between variants in the plasmacytoma variant translocation 1 gene (PVT1) and end-stage renal disease (ESRD) attributed to both type 1 and type 2 diabetes, and demonstrated PVT1 expression in a variety of renal cell types. While these findings suggest a role for PVT1 in the development of ESRD, potential mechanisms for involvement remain unknown. The goal of this study was to identify possible molecular mechanisms by which PVT1 may contribute to the development and progression of diabetic kidney disease. We knocked-down PVT1 expression in mesangial cells using RNA interference, and analyzed RNA and protein levels of fibronectin 1 (FN1), collagen, type IV, alpha 1 (COL4A1), transforming growth factor beta 1 (TGFB1) and plasminogen activator inhibitor-1 (SERPINE1 or PAI-1) by qPCR and ELISA, respectively. PVT1 expression was significantly upregulated by glucose treatment in human mesangial cells, as were levels of FN1, COL4A1, TGFB1, and PAI-1. Importantly, PVT1 knockdown significantly reduced mRNA and protein levels of the major ECM proteins, FN1 and COL4A1, and two key regulators of ECM proteins, TGFB1 and PAI-1. However, we observed a higher and more rapid reduction in levels of secreted FN1, COL4A1, and PAI-1 compared with TGFB1, suggesting that at least some of the PVT1 effects on ECM proteins may be independent of this cytokine. These results indicate that PVT1 may mediate the development and progression of diabetic nephropathy through mechanisms involving ECM accumulation.
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Affiliation(s)
- M. Lucrecia Alvarez
- Diabetes, Cardiovascular and Metabolic Diseases Center, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Johanna K. DiStefano
- Diabetes, Cardiovascular and Metabolic Diseases Center, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
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Stieger N, Worthmann K, Schiffer M. The role of metabolic and haemodynamic factors in podocyte injury in diabetes. Diabetes Metab Res Rev 2011; 27:207-15. [PMID: 21309047 DOI: 10.1002/dmrr.1164] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Podocyte loss is a common feature in human diabetes as well as in experimental diabetes in rodents. Almost all components of the diabetic milieu lead to serious podocyte stress, driving the cells towards cell cycle arrest and hypertrophy, detachment and apoptosis. Common pathway components induced by high glucose and advanced glycation end-products are reactive oxygen species, cyclin-dependent kinases (p27(Kip1)) and transforming growth factor-beta. In addition, mechanical stresses by stretch or shear forces, insulin deficiency or insulin resistance are independent components resulting in podocyte apoptosis and detachment. In this review, we discuss the common pathways leading to podocyte death as well as novel pathways and concepts of podocyte dedifferentiation and detachment that influence the progression of diabetic glomerulopathy.
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Affiliation(s)
- Nicole Stieger
- Division of Nephrology, Department of Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany
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Hanson RL, Millis MP, Young NJ, Kobes S, Nelson RG, Knowler WC, DiStefano JK. ELMO1 variants and susceptibility to diabetic nephropathy in American Indians. Mol Genet Metab 2010; 101:383-90. [PMID: 20826100 PMCID: PMC6542634 DOI: 10.1016/j.ymgme.2010.08.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Revised: 08/12/2010] [Accepted: 08/12/2010] [Indexed: 11/27/2022]
Abstract
Variants in the engulfment and cell motility 1 gene, ELMO1, have previously been associated with kidney disease attributed to type 2 diabetes. The Pima Indians of Arizona have high rates of diabetic nephropathy, which is strongly dependent on genetic determinants; thus, we sought to investigate the role of ELMO1 polymorphisms in mediating susceptibility to this disease in this population. Genotype distributions were compared among 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships, and 107 cases with diabetic ESRD and 108 controls with long duration diabetes and no nephropathy. We sequenced 17.4 kb of ELMO1 and identified 19 variants. We genotyped 12 markers, excluding those in 100% genotypic concordance with other variants or with a minor allele frequency <0.05, plus 21 additional markers showing association with ESRD in earlier studies. In the family study, the strongest evidence for association was with rs1345365 (odds ratio [OR]=2.42 per copy of A allele [1.35-4.32]; P=0.001) and rs10951509 (OR=2.42 per copy of A allele [1.31-4.48]; P=0.002), both of which are located in intron 13 and are in strong pairwise linkage disequilibrium (r(2)=0.97). These associations were in the opposite direction from those observed in African Americans, which suggests that the relationship between diabetic kidney disease and ELMO1 variation may involve as yet undiscovered functional variants or complex interactions with other biological variables.
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Affiliation(s)
- Robert L. Hanson
- Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014
| | - Meredith P. Millis
- Translational Genomics Research Institute, Diabetes, Cardiovascular and Metabolic Diseases Division, 445 North Fifth Street, Phoenix, AZ 85004
| | - Naomi J. Young
- Translational Genomics Research Institute, Diabetes, Cardiovascular and Metabolic Diseases Division, 445 North Fifth Street, Phoenix, AZ 85004
| | - Sayuko Kobes
- Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014
| | - Robert G. Nelson
- Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014
| | - William C. Knowler
- Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014
| | - Johanna K. DiStefano
- Translational Genomics Research Institute, Diabetes, Cardiovascular and Metabolic Diseases Division, 445 North Fifth Street, Phoenix, AZ 85004
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44
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DiStefano JK. Identification of novel genetic markers and improved treatment options for diabetic kidney disease. Biomark Med 2010; 4:739-41. [DOI: 10.2217/bmm.10.83] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Affiliation(s)
- Johanna K DiStefano
- Translational Genomics Research Institute, 445 North 5th Street, Phoenix, AZ 85004, USA
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Köttgen A. Genome-wide association studies in nephrology research. Am J Kidney Dis 2010; 56:743-58. [PMID: 20728256 DOI: 10.1053/j.ajkd.2010.05.018] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Accepted: 05/11/2010] [Indexed: 12/20/2022]
Abstract
Kidney diseases constitute a serious public health burden worldwide, with substantial associated morbidity and mortality. The role of a genetic contribution to kidney disease is supported by heritability studies of kidney function measures, the presence of monogenic diseases with renal manifestations, and familial aggregation studies of complex kidney diseases, such as chronic kidney disease. Because complex diseases arise from the combination of multiple genetic and environmental risk factors, the identification of underlying genetic susceptibility variants has been challenging. Recently, genome-wide association studies have emerged as a method to conduct searches for such susceptibility variants. They have successfully identified genomic loci that contain variants associated with kidney diseases and measures of kidney function. For example, common variants in the UMOD and PRKAG2 genes are associated with risk of chronic kidney disease; variants in CLDN14 with risk of kidney stone disease; and variants in or near SHROOM3, STC1, LASS2, GCKR, NAT8/ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, FAM122A/PIP5K1B, ATXN2, DACH1, UBE2Q2/FBXO22, and SLC7A9, with differences in glomerular filtration rate. The purpose of this review is to provide an overview of the genome-wide association study method as it relates to nephrology research and summarize recent findings in the field. Results from genome-wide association studies of renal phenotypes represent a first step toward improving our knowledge about underlying mechanisms of kidney function and disease and ultimately may aid in the improved treatment and prevention of kidney diseases.
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Affiliation(s)
- Anna Köttgen
- Renal Division, University Hospital Freiburg, Germany.
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