A Common Missense Variant, W335S, in β2-Glycoprotein I (APOH) is Associated with Increased Autoantibody Levels but Reduced Venous Thromboembolism Risk

Anti-β2-glycoprotein I (anti-β2GPI) antibodies are central to the pathogenesis of antiphospholipid syndrome (APS), an autoimmune disease characterized by a strong predisposition to venous thromboembolism (VTE). In this study, we conducted a multi-ancestry genome-wide association study (GWAS) of quantitative total anti-β2GPI levels in 5,969 participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) and identified a genome-wide significant association at the <i>APOH</i> locus. Paradoxically, genetically determined increases in anti-β2GPI levels at this locus were associated with lower VTE risk. Fine-mapping and functional genomics prioritized the missense variant rs1801690 (W335S) in β2GPI (apolipoprotein H, [APOH]) as the most likely causal variant. This variant has an allele frequency of 5-6% in European and East Asian ancestries but only 1% in African ancestries. Integrating prior experimental studies, molecular dynamics simulations and structure-based epitope prediction, we propose a dual-effect mechanism whereby W335S reduces thrombotic risk by disrupting phospholipid binding in Domain V, yet increases autoantibody production through conformational changes that enhance epitope exposure in Domains I and II. These findings mechanistically uncouple autoantibody formation from thrombotic risk in carriers of the W335S variant, and suggest that <i>APOH</i> genotype may represent a clinically relevant genetic biomarker with potential utility for thrombotic risk stratification in anti-β2GPI-positive individuals.