An Exome-wide Association Study for Type 2 Diabetes-Attributed End-Stage Kidney Disease in African Americans.

Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs.

Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations ( P  < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals.

Results: A total of 11 suggestive T2D-ESKD associations ( P  < 1 x 10-4 ) from 8 loci ( PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1 ) were apparent in the meta-analysis. Exclusion of APOL1  renal-risk genotype carriers identified 3 additional suggestive loci ( OTUD7B, IFITM3, DLGAP5 ). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P  = 1.2 x 10-6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals).

Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs.