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- Title
The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- Authors
Kottyan, Leah C.; Zoller, Erin E.; Bene, Jessica; Lu, Xiaoming; Kelly, Jennifer A.; Rupert, Andrew M.; Lessard, Christopher J.; Vaughn, Samuel E.; Marion, Miranda; Weirauch, Matthew T.; Namjou, Bahram; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G.; Hirschfield, Gideon M.; Xie, Gang; Coltescu, Catalina; Amos, Chris; Li, He
- Abstract
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5–TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5–TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta=5 6x10-49; OR 5 1.38–1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included thegenesIRF5andTNPO3(P-valuesEU 5 10-27–10-32,OR 5 1.7–1.81).Manyvariants at the IRF5 locus with previously assigned biological function are notmembersof either final credibleset of potential causal variantsidentified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability,wascorrelated withIRF5 expressionanddifferentially binds the transcription factorZBTB3.Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjo¨ gren’s syndrome and systemic sclerosis whereas only the IRF5–TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5–TNPO3.
- Publication
Human Molecular Genetics, 2015, Vol 24, Issue 2, p582
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu455