Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Abstract

Background APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self‐identified black participants of MESA (Multi‐Ethnic Study of Atherosclerosis).Methods and ResultsCross‐sectional associations of APOL1 genotypes (high‐risk=2 alleles; low‐risk=0 or 1 allele) with coronary artery calcification, carotid‐intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C–based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high‐risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid‐intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high‐risk group was 82% more likely to develop incident heart failure compared with the low‐risk group (95% confidence interval, 1.01–3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00–3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03–3.35) slightly attenuated this association. The APOL1 high‐risk genotypes were not significantly associated with other clinical CVD outcomes.ConclusionsAmong blacks without baseline CVD, the APOL1 high‐risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.

Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women

“…In the Multiethnic Study of Atherosclerosis, the association with overall heart failure was unchanged when adjusting for baseline eGFR or urine albumin excretion. 16 These findings suggest that additional factors account for the APOL1-HFpEF associations. Variants of APOL1 may modulate furosemide-induced diuresis in heart failure.…”

“…Supporting our findings, a recent publication from the Multiethnic Study of Atherosclerosis showed an 82% increased hazard of overall heart failure for carriers of high-risk APOL1 variants (95% CI, 1.01-3.28), although the study did not report associations with heart failure subtypes. 16 The diagnosis of HFpEF is based on typical symptoms and signs of heart failure in a patient with normal LVEF as detected by echocardiography. 32 The condition is present in 30% to 50% of all patients with heart failure, and the prevalence is 2-fold higher in older women than older men.…”

“…12 Associations of APOL1 alleles with cardiovascular disease and mortality were reported in African American participants of the Jackson Heart Study and among Medicareeligible participants of the Cardiovascular Health Study but not in subsequent cross-sectional and longitudinal studies. 5,[13][14][15][16][17] Differences in study design, outcome type, and the number of events in these studies may account for inconsistencies.…”

APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis

“…19 The CHS, the JHS, and the Women's Health Initiative cohorts also reported associations between APOL1 kidney risk variants and incident cardiovascular disease, 13,18 whereas the AA-DHS, the AASK, the ARIC study, the MESA, and the SPRINT did not. 10,12,17,21 The JHS and the AA-DHS reported paradoxical protective relationships between APOL1 kidney risk variants with subclinical cardiovascular disease (calcified atherosclerotic plaque), although in the MESA, there was no significant association. 21,29 Results for mortality have been similarly heterogeneous: the APOL1 kidney risk variants were protective in the AA-DHS (additive genetic model), harmful in the CHS (recessive genetic model), and null in the ARIC study (recessive genetic model).…”

“…However, the literature on APOL1 risk variants and cardiovascular disease is mixed, with some studies finding an association of APOL1 risk variants with cardiovascular disease and death and other studies finding null or protective associations. [13][14][15][16][17][18][19][20][21][22][23][24][25][26] Methods differed across studies, particularly with respect to the genetic model, and many had limited statistical power because of low numbers of events.…”