A Coding Single Nucleotide Polymorphism in β2-Glycoprotein I (APOH) is Associated with Increased Autoantibody Levels...

Anti-β2-glycoprotein I (anti-β2GPI) antibodies are central to antiphospholipid syndrome. The APOH locus has been associated with anti-β2GPI, but the causal variant and thrombotic risk implications remain unclear.

We performed a multi-ancestry genome-wide association study (GWAS) of quantitative total anti-β2GPI antibody levels in 5,969 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). The relationship between genetically determined anti-β2GPI levels and venous thromboembolism (VTE) risk was evaluated using two-sample Mendelian randomization (MR) 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.

We identified a genome-wide significant association at the APOH locus (lead SNP rs1801690-G, β = 0.21, p = 1.08 × 10^-10). Paradoxically, genetic variation at the APOH locus associated with higher anti-β2GPI levels was associated with reduced VTE risk (β = -0.25, p = 3.95 × 10^-6; 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-II.

The APOH genetic signal associated with higher anti-β2GPI 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 by DV is essential for anti-β2GPI-mediated thrombosis. The clinical utility of APOH genotype warrants further investigation.