Increased burden of cardiovascular disease in carriers of APOL1 genetic variants

Abstract

Rationale: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population.

Objective: We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans.

Methods and results: We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4×10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4×10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37×10(-3); JHS and WHI combined, P=8.5×10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease.

Conclusions: APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Keywords: atherosclerosis; continental population groups; epidemiology; genetics; renal insufficiency, chronic; risk factors.

Figure 1

Cardiovascular disease (CVD) and/or chronic kidney disease (CKD) in 2708 individuals with APOL1 genotypes. Associations were initially performed in 1959 random participants in the Jackson Heart Study (JHS) who were fully sequenced for the APOL1 gene. Replication of the CVD association was performed 749 African American participants in the Women’s Health Initiative (WHI) with exome sequence data.

Figure 2

Major adverse cardiac event (MACE) free survival Kaplan-Meier curves stratified by genotype (Ref/Ref, no APOL1 risk alleles versus two risk alleles) for (a) JHS and (b) WHI. P-value and hazard ratios calculated by multivariable cox-proportional hazards model adjusted for gender, BMI, smoking, LDL-C (JHS), HDL-C (JHS), diabetes, hypertension and CKD.