Journal Article

Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans

Das, Swapan K., Wilson, James G., Rasmussen-Torvik, Laura J., Palmer, Nicholette D., Freedman, Barry I., Coresh, Josef, Langefeld, Carl D., Franceschini, Nora, Fornage, Myriam, Kramer, Holly, Bowden, Donald W., Post, Wendy S., Dimitrov, Latchezar, Sedor, John R., Hicks, Pamela J., Thornley-Brown, Denyse, Parekh, Rulan S., Ma, Lijun, Rotter, Jerome I., Xu, Jianzhao, Tin, Adrienne, Ng, Maggie C. Y., Rich, Stephen S., Guan, Meijian, Keaton, Jacob M., Mychaleckyj, Josyf C., Chen, Yii-Der I.

2019

Overview

Background End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls ( N  = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Results Six independent variants located in or near RND3/RBM43 , SLITRK3 , ENPP7 , GNG7 , and APOL1 achieved genome-wide significant association ( P  < 5 × 10 −8 ) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P  = 9.84 × 10 –9 ; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C . A second variant at GNG7 (rs373971520; P  = 2.17 × 10 –8 , OR = 1.46) remained associated with all-cause ESKD in the APOL1 -negative analysis. Conclusions Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: African Americans / Age / Atherosclerosis / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Consortia / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetic kidney disease / End-stage kidney disease / End-stage renal disease / Genetic factors / Genome-wide association studies / Genome-wide association study / Genomes / Genotypes / Human Genetics / Kidney diseases / Nephropathy / Population / Primary Research / Proteomics / Public health / Studies / Type 2 diabetes