APOL1 variants G1, G2 and N264K affect APOL1 plasma protein concentration: a UK Biobank study

Abstract

BackgroundAPOL1variants G1 and G2 are common in populations with recent sub-Saharan African ancestry. They are known to influence health conditions: most notably being associated with protection from human African trypanosomiasis and increased risk of susceptibility to chronic kidney disease. Association studies have often considered G1 and G2 as equivalent, however we recently presented evidence of substantial phenotypic differences between carriers of the two variants. An additionalAPOL1variant, N264K, has previously been shown to modify the damaging effect of G2 on the kidney. Here, we examine the influence of these variants on APOL1 protein concentration. Methods Using a cohort of 1,050 UK Biobank participants with recent African ancestry, we compared APOL1 protein concentration in carriers of variants G1, G2, and N264K and performed a genome-wide association study to identify additional modifiers of APOL1 concentration. We also compared APOL1 concentration across self-reported ethnicities for all 43,330 UK Biobank participants for whom APOL1 concentration data was available. Findings APOL1 G1 and G2 are both associated with increased APOL1 protein concentration, however the effect of G2 is more marked, and it was the only locus that reached genome-wide significance in terms of association with APOL1 concentration (p = 3x10-155). In a G2 background, the presence of N264K is associated with a reduction in APOL1 concentration (p = 6 x 10-5). People with self-reported Black or Black British ethnicity have higher APOL1 concentrations all other self-reported ethnicities in the UK Biobank. Interpretation These findings demonstrate the influence ofAPOL1variants and APOL1 protein concentration and identify additional phenotypic differences between the G1 and G2, highlighting the value in considering them as distinct in molecular and association studies. This work also provides further detail on the relationship between the G2 and N264K variants, which has significant implications for diagnosis and therapy in kidney disease.