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

Background APOL1 variants 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 additional APOL1 variant, 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 = 3×10−155). In a G2 background, the presence of N264K is associated with a reduction in APOL1 concentration (p = 6 × 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 of APOL1 variants 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. ### Competing Interest Statement Parekh has received research funding and consulting fees from Vertex Pharmaceuticals. MacLeod has received research funding from Astra Zeneca. ### Funding Statement This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Access to the UK Biobank data was granted for this work under UK Biobank application number 66821. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This research has been conducted using data from the UK Biobank, a major biomedical database.