Platform-dependent effects of genetic variants on plasma APOL1

Mutations in apolipoprotein L1 (APOL1) are strongly associated with protection against parasitic infections and increased risk of kidney disease in individuals of African ancestry. To better understand the mechanisms underlying APOL1-related pathologies, we examined genetic drivers of circulating APOL1 in individuals of African and European ancestry from four independent cohorts (UK Biobank, AASK, deCODE, and Health ABC) using three proteomic technologies (Olink, SomaLogic, and mass spectrometry). We found that disease-associated APOL1 G1 and G2 variants are strong cis-pQTLs for plasma APOL1 measured by Olink and SomaLogic, but not mass spectrometry. Critically, the direction of variant effects differed between proteomic platforms, being positive with Olink and negative with SomaLogic. We identified an additional APOL1 missense variant (rs2239785), common in Europeans, exhibiting the same platform-dependent directional discrepancy. Furthermore, variants in the kallikrein-kinin system (KKS), involving KLKB1, F12, and KNG1, and their genetic interactions showed strong trans-pQTL effects on APOL1 measured by Olink, but not SomaLogic. These platform-dependent discrepancies raise the possibility that both intrinsic APOL1 mutations and extrinsic KKS activity induce conformational changes in the APOL1 protein that are differentially recognized by the proteomic platforms.