Abstract
BackgroundEnd-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.ResultsSix 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.ConclusionsFindings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.
Highlights
Increasing evidence suggests that genetic factors play a major role in susceptibility to end-stage kidney disease (ESKD)
End-stage kidney disease (ESKD) cases were recruited from the Wake Forest School of Medicine (WFSM) (Affy6.0, Axiom, and Multi-Ethnic Genotyping Array (MEGA)), Family Investigation of Nephropathy and Diabetes (FIND), and Atherosclerosis Risk in Communities Study (ARIC) studies
Controls with Type 2 diabetes (T2D)-lacking nephropathy were more obese than T2D-ESKD or non-diabetic ESKD cases and non-diabetic, non-nephropathy controls, except that T2D-ESKD cases in ARIC were more obese than the other groups
Summary
Increasing evidence suggests that genetic factors play a major role in susceptibility to end-stage kidney disease (ESKD). This is relevant in African Americans (AAs) where incidence rates of ESKD are more than threefold greater than European Americans (EAs) [1]. Of which 95% of patients have type 2 diabetes (T2D), remains the leading reported cause of ESKD in the USA accounting for > 44% of cases [1]. 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.
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