Evaluation of Candidate Nephropathy Susceptibility Genes in a Genome-Wide Association Study of African American Diabetic Kidney Disease

Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05<P(emp)<0.049). Among these, variants in MYH9 were the most significant (1.6E-05<P(emp)<0.049), followed by additional chromosome 22 loci (APOL1, SFI1, and LIMK2). Nominal signals were observed in AGTR1, RPS12, CHN2 and CNDP1. Additional adjustment for APOL1 G1/G2 risk variants attenuated association at MYH9 (P(emp) = 0.00026-0.043) while marginally improving significance of other APOL1 SNPs (rs136161, rs713753, and rs767855; P(emp) = 0.0060-0.037); association at other loci was markedly reduced except for CHN2 (chimerin; rs17157914, P(emp)= 0.029). In addition, SNPs in other candidate loci (FRMD3 and TRPC6) trended toward association with T2D-ESKD (P(emp)<0.05). These results suggest that risk contributed by putative nephropathy genes is shared across populations of African and European ancestry.