Variation in APOL1 Contributes to Ancestry-Level Differences in HDLc-Kidney Function Association

Abstract

Low levels of high-density cholesterol (HDLc) accompany chronic kidney disease, but the association between HDLc and the estimated glomerular filtration rate (eGFR) in the general population is unclear. We investigated the HDLc-eGFR association in nondiabetic Han Chinese (HC, n = 1100), West Africans (WA, n = 1497), and African Americans (AA, n = 1539). There were significant differences by ancestry: HDLc was positively associated with eGFR in HC (β = 0.13, P < 0.0001), but negatively associated among African ancestry populations (WA: -0.19, P < 0.0001; AA: -0.09, P = 0.02). These differences were also seen in nationally-representative NHANES data (among European Americans: 0.09, P = 0.005; among African Americans -0.14, P = 0.03). To further explore the findings in African ancestry populations, we investigated the role of an African ancestry-specific nephropathy risk variant, rs73885319, in the gene encoding HDL-associated APOL1. Among AA, an inverse HDLc-eGFR association was observed only with the risk genotype (-0.38 versus 0.001; P = 0.03). This interaction was not seen in WA. In summary, counter to expectation, an inverse HDLc-eGFR association was observed among those of African ancestry. Given the APOL1 × HDLc interaction among AA, genetic factors may contribute to this paradoxical association. Notably, these findings suggest that the unexplained mechanism by which APOL1 affects kidney-disease risk may involve HDLc.

Figure 1

Association between HDLc and eGFR in Diverse Populations. The association of HDLc and eGFR in West Africans (WA), African Americans (from Howard University Family Study, AA), African Americans (from National Health and Nutrition Examination Survey, NHAA), Han Chinese (HC), European Americans (NHEA). Linear models adjusted for age, age², sex, BMI, triglycerides, LDLc, alcohol use, and smoking (and random effect of family for WA and AA).

Figure 2

Mean HDLc and eGFR by rs73885319 Genotype among African Americans and West AfricansMean HDLc and eGFR by rs73885319 genotype (GG = nephropathy risk genotype), as estimated from linear mixed effect models adjusting for age, age², sex, and overall proportion of admixture (African Americans only), with random clustering for family. There were no statistically significant differences in HDLc or eGFR by genotype.

Figure 3

Association between HDLc and eGFR among African Americans and West Africans by rs73885319 Genotype. The modification of the association between HDLc and eGFR by rs73885319 genotype (GG = nephropathy risk genotype), as estimated from a linear mixed model of HDLc × rs73885319, adjusting for HDLc rs73885319, age, age², sex, and overall proportion of admixture (African Americans only), with random clustering for family. Among those with the nephropathy risk genotype, the association was much more negative than among those without this genotype (β: −0.38 versus 0.001, P _interaction = 0.03).