Genetic Modifiers of Renal Dysfunction in African-American APOL1 Carriers Identified Through a Genome-Wide Screen

Introduction: G1 and G2 variants in the apoliprotein L1 ( APOL1 ) gene confer increased risk of chronic kidney disease (CKD) in African Americans, but there is heterogeneity in the development of CKD in individuals carrying these alleles. Thus, we used genome-wide association (GWAS) to identify potential genetic modifiers of renal function in APOL1 carriers in a large cardiovascular cohort. Methods: The study population consisted of African-Americans from the CATHGEN study which enrolled patients undergoing cardiac catheterization at Duke University with available GWAS data (N=687). Two analytic approaches were used: (1) GWAS of single nucleotide polymorphisms (SNPs) associated with baseline estimated glomerular filtration rate (eGFR) in African Americans who are homozygote APOL1 risk allele carriers (n = 93); and (2) GWAS of SNP- APOL1 genotype interactions associated with baseline eGFR in all African Americans regardless of APOL1 genotype (n = 687). Linear regression models were fitted to test for SNP (additive model) and SNP -APOL1 interaction (additive-recessive model) effects respectively, adjusting for race-specific principal components and diabetes status. Genome-wide significance was defined as a p ≤ 5.8 x 10 -8 using Bonferroni correction. Results: In model 1, among APOL1 homozgyotes, no SNPs were associated with baseline eGFR, although two approached genome-wide significance: rs7233527 (MAF = 0.16, near gene METTL4 , p = 8.3 x 10 -8 ) and rs9399258 (MAF = 0.29, in ECT2L , p = 1.6 x 10 -7 ). In model 2, SNP- APOL1 interaction analysis identified 3 significant SNPs, including both of the two SNPs most significantly associated with baseline eGFR in APOL1 homozygotes (rs7233527: p = 2.3 x 10 -10 ; rs9399258: p = 3.6 x 10 -8 ). METTL4 encodes for a nucleic acid binding protein, while ECT2L is involved in regulation of Rho protein signal transduction and has been associated with cancers and cholesterol metabolism. Both genes are expressed in kidneys. Conclusions: Using genome-wide analysis in African Americans from a large cardiovascular cohort, we have identified the same two genes from two different models that modulate renal function in addition to APOL1 genotype. These genes are potential candidates as genetic modifiers to APOL1 for CKD.