scholarly journals Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

2018 ◽  
Author(s):  
Rany M. Salem ◽  
Jennifer N. Todd ◽  
Niina Sandholm ◽  
Joanne B. Cole ◽  
Wei-Min Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Basement Membrane ◽  
Diabetic Kidney Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Collagen Type Iv ◽  
Diabetic Kidney ◽  
Association Analyses ◽  
Biological Targets ◽  
Genome Wide

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

scholarly journals Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

2019 ◽  
Vol 30 (10) ◽  
pp. 2000-2016 ◽  
Author(s):  
Rany M. Salem ◽  
Jennifer N. Todd ◽  
Niina Sandholm ◽  
Joanne B. Cole ◽  
Wei-Min Chen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Diabetic Kidney Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Diabetic Kidney ◽  
Genome Wide

BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

scholarly journals A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (7) ◽  
pp. 1414-1427 ◽  
Author(s):  
Natalie R. van Zuydam ◽  
Emma Ahlqvist ◽  
Niina Sandholm ◽  
Harshal Deshmukh ◽  
N. William Rayner ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Association Study ◽  
Diabetic Kidney Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Diabetic Kidney ◽  
Genome Wide ◽  
A Genome

scholarly journals Evaluation of Candidate Nephropathy Susceptibility Genes in a Genome-Wide Association Study of African American Diabetic Kidney Disease

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e88273 ◽  
Author(s):  
Nicholette D. Palmer ◽  
Maggie C. Y. Ng ◽  
Pamela J. Hicks ◽  
Poorva Mudgal ◽  
Carl D. Langefeld ◽  
...  
Keyword(s):  
African American ◽  
Kidney Disease ◽  
Association Study ◽  
Diabetic Kidney Disease ◽  
Genome Wide Association Study ◽  
Susceptibility Genes ◽  
Genome Wide Association ◽  
Diabetic Kidney ◽  
Genome Wide ◽  
A Genome

scholarly journals Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

PLoS Genetics ◽  
2015 ◽  
Vol 11 (8) ◽  
pp. e1005352 ◽  
Author(s):  
Sudha K. Iyengar ◽  
John R. Sedor ◽  
Barry I. Freedman ◽  
W. H. Linda Kao ◽  
Matthias Kretzler ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Diabetic Kidney ◽  
Genome Wide ◽  
Family Investigation ◽  
Disease Family

scholarly journals Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

2021 ◽  
Author(s):  
Niina Sandholm ◽  
Joanne B Cole ◽  
Viji Nair ◽  
Xin Sheng ◽  
Hongbo Liu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Association Study ◽  
Diabetic Kidney Disease ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Transmembrane Protein ◽  
Meta Analysis ◽  
Novel Genes ◽  
Diabetic Kidney ◽  
Genome Wide

Background: Diabetes is the leading cause of kidney disease, and heritability studies demonstrate a substantial, yet poorly understood, contribution of genetics to kidney complications in people with diabetes. Methods: We performed genome-wide association study (GWAS) meta-analyses using ten different phenotypic definitions of diabetic kidney disease (DKD), including nearly 27,000 individuals with diabetes, and integrated the results with various kidney omics datasets. Results: The meta-analysis identified a novel low frequency intronic variant (rs72831309) in the TENM2 gene encoding teneurin transmembrane protein 2 associated with a lower risk of the combined chronic kidney disease (CKD; eGFR<60 ml/min/1.73 m2) and DKD (microalbuminuria or worse) phenotype ("CKD-DKD", odds ratio 2.08, p=9.8×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN - RESP18, GPR158, INIP - SNX30, LSM14A, and MFF, p<2.7×10-6). Integration of GWAS data with human glomerular and tubular expression data in a transcriptome-wide association study demonstrated higher tubular AKIRIN2 gene expression in DKD versus non-DKD controls (p=1.1×10-6). The lead SNPs within the DCLK1, AKIRIN2, SNX30 and three other gene regions significantly alterated the methylation at this region in kidneys (p<2.2×10-11). Expression of target genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes. For example, tubular TENM2 expression positively correlated with eGFR (p=2.3×10-9) and negatively with tubulointerstitial fibrosis (p=4.7×10-9), tubular DCLK1 expression positively correlated with fibrosis (p=1.6×10-12), and SNX30 level positively correlated with eGFR (p=7.6×10-13) and negatively with fibrosis (p<2×10-16). Conclusions: GWAS meta-analysis and integration with renal omics data points to novel genes contributing to pathogenesis of DKD.

scholarly journals A Genome-Wide Association Study for Hypertensive Kidney Disease in Korean Men

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 751
Author(s):  
Hye-Rim Kim ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Integrated Analysis ◽  
Eqtl Analysis ◽  
Strong Linkage Disequilibrium ◽  
Genome Wide ◽  
A Genome

Hypertension is one of the major risk factors for chronic kidney disease (CKD), and the coexistence of hypertension and CKD increases morbidity and mortality. Although many genetic factors have been identified separately for hypertension and kidney disease, studies specifically focused on hypertensive kidney disease (HKD) have been rare. Therefore, this study aimed to identify loci or genes associated with HKD. A genome-wide association study (GWAS) was conducted using two Korean cohorts, the Health Examinee (HEXA) and Korean Association REsource (KARE). Consequently, 19 single nucleotide polymorphisms (SNPs) were found to be significantly associated with HKD in the discovery and replication phases (p < 5 × 10−8, p < 0.05, respectively). We further analyzed HKD-related traits such as the estimated glomerular filtration rate (eGFR), creatinine, blood urea nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the 14q21.2 locus, which showed a strong linkage disequilibrium (LD). Expression quantitative trait loci (eQTL) analysis was also performed to determine whether HKD-related SNPs affect gene expression changes in glomerular and arterial tissues. The results suggested that the FANCM gene may affect the development of HKD through an integrated analysis of eQTL and GWAS and was the most significantly associated candidate gene. Taken together, this study indicated that the FANCM gene is involved in the pathogenesis of HKD. Additionally, our results will be useful in prioritizing other genes for further experiments.

scholarly journals Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Masahiro Miyake ◽  
Rosa L. Schellevis ◽  
Camiel J. F. Boon ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Central Serous Chorioretinopathy ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Association Analyses ◽  
Age Related ◽  
Genome Wide

AbstractThe recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

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