APOH Variant Linked to Higher Autoantibody Levels but Lower Venous Thromboembolism Risk

Anti–β2-glycoprotein I (anti-β2GPI) antibodies are central to antiphospholipid syndrome, but the relationship between APOH variation, antibody levels and thrombosis remains unclear. Researchers conducted a multiancestry genome-wide association study of quantitative total anti-β2GPI levels in 5,969 Multi-Ethnic Study of Atherosclerosis participants. They assessed associations with venous thromboembolism (VTE) using two-sample Mendelian randomization and Bayesian colocalization, supplemented by fine-mapping, functional genomic analyses and molecular dynamics simulations.

The lead variant, rs1801690-G, was associated with higher antibody levels (β = 0.21; P = 1.08 × 10⁻¹⁰). Genetic variation at APOH associated with higher antibody levels was also associated with lower VTE risk (β = −0.25; P = 3.95 × 10⁻⁶). Colocalization supported a shared genetic signal (PP4 = 0.97). Fine-mapping prioritized the missense variant rs1801690, encoding W335S, as the most likely causal variant. Simulations suggested that W335S impairs domain V phospholipid binding while increasing epitope exposure in domains I and II.

The authors interpret the inverse VTE association as likely horizontal pleiotropy, not evidence that higher antibody levels protect against thrombosis. The findings support a mechanistic role for phospholipid binding, but genotype-guided clinical decisions require further investigation. This report is based on the abstract; full-text methods and limitations were unavailable.