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