2009/02/27 by Marcus G. Pezzolesi, G. David Poznik, Josyf C. Mychaleckyj +32 · 293 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Biology #Chronic Kidney Disease and Diabetes #Diabetes mellitus #Diabetic nephropathy #Disease #Endocrinology #Gene #Genetic predisposition #Genetics #Genome-wide association study #Genotype #Internal medicine #Medicine #Nephropathy #Odds ratio #Renal Diseases and Glomerulopathies #Single-nucleotide polymorphism #Type 1 diabetes #Wnt/β-catenin signaling in development and cancer
paper · pdf · doi:10.2337/db08-1514
published in Diabetes 58(6), 1403-1410 (American Diabetes Association)
openalex publication_date 2009/02/27 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
OBJECTIVE: Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS: We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications. RESULTS: A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney. CONCLUSIONS: We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.