The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Leah C Kottyan, Erin E Zoller, Jessica Bene, Xiaoming Lu, Jennifer A Kelly, Andrew M Rupert, Christopher J Lessard, Samuel E Vaughn, Miranda Marion, Matthew T Weirauch, Bahram Namjou, Adam Adler, Astrid Rasmussen, Stuart Glenn, Courtney G Montgomery, Gideon M Hirschfield, Gang Xie, Catalina Coltescu, Chris Amos, He LiJohn A Ice, Swapan K Nath, Xavier Mariette, Simon Bowman, Maureen Rischmueller, Sue Lester, Johan G Brun, Lasse G Gøransson, Erna Harboe, Roald Omdal, Deborah S Cunninghame-Graham, Tim Vyse, Corinne Miceli-Richard, Michael T Brennan, James A Lessard, Marie Wahren-Herlenius, Marika Kvarnström, Gabor G Illei, Torsten Witte, Roland Jonsson, Per Eriksson, Gunnel Nordmark, Wan-Fai Ng, Juan-Manuel Anaya, Nelson L Rhodus, Barbara M Segal, Joan T Merrill, Judith A James, Joel M Guthridge, R Hal Scofield, UK Primary Sjögren’s Syndrome Registry

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


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 = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified 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, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. 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 Sjögren'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.

Original languageEnglish
Pages (from-to)582-96
Number of pages15
JournalHuman Molecular Genetics
Issue number2
Publication statusPublished - 15 Jan 2015

Bibliographical note

Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.


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