Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

Abstract

Background African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans. Study Design Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. Setting & Participants Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls. Predictors Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes. Outcomes APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1. Results The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001). Limitations Non-pooled GWAS have not been performed in AA nondiabetic nephropathy. Conclusions This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.

APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations

“…25,33–36 APOL1 G1 and G2 variants are also recessively associated with overall burden of nondiabetic CKD, but not diabetic CKD, in the Dallas Heart Study a large population-based cohort study. 37 In the Atherosclerosis Risk in Communities study APOL1 risk alleles were associated with a 1.5-fold increased risk for CKD, and among those who developed CKD, there was a 1.9-fold increased risk of progression to ESKD regardless of diabetic status at study entry.…”

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…Many genes have reproducible effects on risk for nondiabetic ESRD, and several genes seem to be major modifiers. This field has been hampered by the lack of a directly genotyped genome-wide association study (GWAS) in large numbers of African Americans with nondiabetic ESRD (65,66).…”

“…Gene-gene interaction analyses were reported on the basis of a pooled GWAS in African American nondiabetic ESRD patients and African American non-nephropathy controls (66). This analysis revealed that APOL1 was independently associated with nondiabetic ESRD, and genegene interaction analyses revealed several polymorphic genetic markers termed single-nucleotide polymorphisms (SNPs) that significantly interacted with APOL1.…”

Race, APOL1 Risk, and eGFR Decline in the General Population

“…6 Patterns of eGFR decline may differ between general and CKD populations. A "second hit" may be needed to induce kidney function decline in those with an APOL1 high-risk genotype, 8,12,13 and persons with APOL1 high-risk status in a CKD population may have already experienced the necessary instigating event. Long-term follow-up of APOL1 high-risk individuals in the general population is necessary to determine the natural history of kidney disease, as well as other meaningful adverse health events associated with APOL1 genetic risk variants.…”