The IRF5-TNPO3 association has two components in systemic lupus erythematosus, which are shared with other autoimmune disorders (P3315)

Abstract

Abstract Improved technical and bioinformatics genetic methods now allows us to capture more complete relevant genetic variation for candidate causal disease risk variant identification. Exploiting genotyping, DNA sequencing, imputation, and trans-ancestral mapping, we modeled the IRF5-TNPO3 genetic association on chromosome 7, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE) we resolve separate associations in the IRF5 promoter (all ancestries) and an extended European haplotype. We capture 7,650 IRF5-TNPO3 genetic variants across five ethnicities in 8,395 SLE cases and 7,367 controls. The six plausible causative IRF5 promoter variants are confined to 5.7 kb (meta-analysis p-value=6x10^-49; Odds Ratio=1.38-1.97). The 22 potentially causal variants of an 85.5 kb haplotype of IRF5 and TNPO3 (haplotypic p-value in European Americans=2.4x10^-45, Odds Ratio=0.58) (individual p-value in European Americans=10^-27 - 10^-32, Odds Ratio=1.7-1.81). The possible models from this sample virtually eliminate the previously purported IRF5 functional variants as causal. Finally, this model also appears to operate in Sjögren’s syndrome and systemic sclerosis (both components) and primary biliary cirrhosis (haplotype only), demonstrating the nuances of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.