Abstract Body: Introduction:
Apolipoprotein L1 (APOL1) G1 and G2 risk variants are highly prevalent among African American individuals and are strongly associated with an increased risk of kidney disease. Several studies have also linked these variants to a higher burden of cardiovascular disease, sepsis, and severe COVID-19. Pathological mechanisms associated with APOL1 risk variants include increased APOL1 expression in endothelial cells and accumulation of APOL1 within coronary atherosclerotic plaques among variant carriers. However, the relationship between APOL1 risk variants and circulating APOL1 protein levels remains poorly characterized.
Hypothesis:
We hypothesized that APOL1 risk variants are associated with higher plasma APOL1 concentrations.
Methods:
We conducted a cross-sectional analysis of 500 African American adults recruited through the University of California, San Francisco Lipid Clinic. Genomic DNA, plasma samples, and linked clinical and questionnaire data were used to assess APOL1 genotype, plasma APOL1 concentration, smoking status, and cardiometabolic traits. APOL1 genotype was modeled additively according to the number of risk alleles (0, 1, or 2), with two risk alleles defined as G1/G1, G2/G2, or G1/G2; one risk allele defined as G1/G0 or G2/G0; and zero risk alleles defined as G0/G0. Multivariable linear regression model was used to evaluate the association between APOL1 genotype and plasma APOL1 concentration, adjusting for age, sex, smoking status, body mass index, dyslipidemia, diabetes, and hypertension.
Results:
Plasma APOL1 concentration was significantly associated with APOL1 genotype in a dose-dependent manner. Compared with non-carriers, individuals carrying one APOL1 risk allele had higher plasma APOL1 concentration (β = 2.53, p = 0.018), while those carrying two risk alleles exhibited substantially higher concentration (β = 6.07, p < 0.001), adjusted for covariates. Female sex was independently associated with higher plasma APOL1 concentration (p < 0.001).
Conclusions:
APOL1 genotype is independently and additively associated with circulating plasma APOL1 concentration. Together, these findings demonstrate that G1 and G2 genetic variants in APOL1 and biological sex influence systemic APOL1 levels and support further investigation into the biological and clinical relevance of circulating APOL1.