학술논문
Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans
Document Type
Article
Author
Guan, Meijian; Keaton, Jacob; Dimitrov, Latchezar; Hicks, Pamela; Xu, Jianzhao; Palmer, Nicholette; Ma, Lijun; Das, Swapan; Chen, Yii-Der; Coresh, Josef; Fornage, Myriam; Franceschini, Nora; Kramer, Holly; Langefeld, Carl; Mychaleckyj, Josyf; Parekh, Rulan; Post, Wendy; Rasmussen-Torvik, Laura; Rich, Stephen; Rotter, Jerome; Sedor, John; Thornley-Brown, Denyse; Tin, Adrienne; Wilson, James; Freedman, Barry; Bowden, Donald; Ng, Maggie
Source
Human Genomics; December 2019, Vol. 13 Issue: 1 p1-17, 17p
Subject
Language
ISSN
14739542; 14797364
Abstract
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. Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1achieved 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 APOL1renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3and 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. Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.