A Coding Single‐Nucleotide Polymorphism in β 2 ‐Glycoprotein I ( APOH ) Is Associated With Increased Autoantibody Levels but Reduced Venous Thromboembolism Risk

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Abstract
Objective: Anti–β 2 ‐glycoprotein I (anti‐β 2 GPI) antibodies are central to antiphospholipid syndrome. The APOH locus has been associated with anti‐β 2 GPI, but the causal variant and thrombotic risk implications remain unclear. Methods: We performed a multiancestry genome‐wide association study of quantitative total anti‐β 2 GPI antibody levels in 5,969 participants from the Multi‐Ethnic Study of Atherosclerosis (MESA). The relationship between genetically determined anti‐β 2 GPI levels and venous thromboembolism (VTE) risk was evaluated using two‐sample Mendelian randomization and Bayesian colocalization. Candidate causal variants were prioritized by fine‐mapping and integrative functional genomic analyses. Molecular dynamics simulations were used to investigate the structural effects. Results: We identified a genome‐wide significant association at the APOH locus (lead single‐nucleotide polymorphism rs1801690‐G, β = 0.21, P = 1.08 × 10 −10 ). Paradoxically, genetic variation at the APOH locus associated with higher anti‐β 2 GPI levels was associated with reduced VTE risk (β = −0.25, P = 3.95 × 10 −6 ; posterior probability for hypothesis 4 (PP4) = 0.97), likely reflecting horizontal pleiotropy rather than a true protective antibody effect. Fine‐mapping and functional genomics prioritized the missense variant rs1801690 (W335S) as the most likely causal variant. Molecular dynamics simulations support a dual‐effect mechanism whereby W335S impairs phospholipid binding in domain V while increasing epitope exposure in domains I and II. Conclusion: The APOH genetic signal associated with higher anti‐β 2 GPI levels paradoxically reduced VTE risk, likely mediated by W335S via epitope accessibility and disrupted phospholipid binding. These findings provide human genetic evidence that phospholipid binding in domain V is essential for anti‐β 2 GPI–mediated thrombosis. The clinical utility of the APOH genotype warrants further investigation.
Funding Information
  • National Institute of Diabetes and Digestive and Kidney Diseases (K01‐DK‐137031)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23‐AR‐084061)

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