PT2:08 Serum IgA2 anti-dsDNA as a theragnostic biomarker for low disease activity with belimumab after rituximab therapy in systemic lupus erythematosus

MethodsWe performed a genome-wide association study in 5,969 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort on the quantitative trait of total anti-B2G-PI antibody levels.We detected a significant association at the APOH locus, with the lead variant rs1801690-G (B = 0.21, p = 1.08 x 10^(-10)).Genetically determined anti-B2GPI antibody levels at this locus were inversely associated with venous thromboembolism (VTE, B = -0.25,p = 3.95 x 10-6), with strong evidence of colocalization between the two traits (PP4 = 0.97).We hypothesized this paradoxical relationship is mediated by a downstream consequence of the mutation.Subsequent statistical fine-mapping, colocalization analyses with APOH (B2GPI) expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL), and functional annotation collectively prioritized rs1801690-G, the missense variant W335S, as the sole causal variant underlying increased anti-B2GPI levels but reduced risk of VTE.Results We performed molecular simulations of the wild type (WT) and W335S, and compared the results.In the linear shapes, several aDI antibody binding motifs become more exposed compared to the circular form.These motifs were more exposed in the linear shapes of W335S compared to the WT.The phospholipid binding loops of W335S showed a decrease in surface area and stability compared to the WT.Conclusions We showed that WT and W335S B2GPI explored the same conformations, but residue properties were different between them.Combining the increased exposure of the DI binding motifs and the reduced exposure of the phospholipid binding loops provides a direct correlation to findings showing increased anti-B2GPI levels but decreased clotting events.