Platform-dependent effects of genetic variants on plasma APOL1.

Mutations in apolipoprotein L1 (APOL1) provide protection against parasitic infections but increase kidney disease risk in individuals of African ancestry. To better understand APOL1-related pathologies, we examined genetic drivers of circulating APOL1 in individuals of African and European ancestry across multiple cohorts using three proteomic technologies (Olink, SomaLogic, mass spectrometry). Disease-associated APOL1 G1 and G2 variants were strong cis-pQTLs for plasma APOL1 measured by Olink and SomaLogic, but not mass spectrometry. Critically, variant effect directions differed between proteomic platforms: positive with Olink and negative with SomaLogic. An additional APOL1 missense variant (rs2239785), common in Europeans, exhibited the same discrepancy. Furthermore, variants in the kallikrein-kinin system (KLKB1, F12, and KNG1) showed strong trans-pQTL effects via Olink, but not SomaLogic. These results suggest that both intrinsic APOL1 mutations and extrinsic KKS activity induce conformational changes in the APOL1 protein that are differentially recognized by the proteomic platforms.