Association of <i>APOL1</i> Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Abstract

Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (<i>APOL1</i>) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between <i>APOL1</i> risk alleles and cardiovascular disease (CVD) that is independent of the effects of <i>APOL1</i> on kidney disease. We sought to test the association of <i>APOL1</i> G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was <i>APOL1</i> risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of <i>APOL1</i> risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 <i>APOL1</i> risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; <i>P</i>=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; <i>P</i>=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; <i>P</i>=0.031). When both cardiovascular and renal outcomes were modeled, <i>APOL1</i> was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. <i>APOL1</i> risk variants display a modest association with CVD, and this association is likely mediated by the known <i>APOL1</i> association with chronic kidney disease.