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

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 = 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.

SUBMITTER: Kottyan LC

PROVIDER: S-EPMC4275071 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Kottyan Leah C LC Zoller Erin E EE Bene Jessica J Lu Xiaoming X Kelly Jennifer A JA Rupert Andrew M AM Lessard Christopher J CJ Vaughn Samuel E SE Marion Miranda M Weirauch Matthew T MT Namjou Bahram B Adler Adam A Rasmussen Astrid A Glenn Stuart S Montgomery Courtney G CG Hirschfield Gideon M GM Xie Gang G Coltescu Catalina C Amos Chris C Li He H Ice John A JA Nath Swapan K SK Mariette Xavier X Bowman Simon S Rischmueller Maureen M Lester Sue S Brun Johan G JG Gøransson Lasse G LG Harboe Erna E Omdal Roald R Cunninghame-Graham Deborah S DS Vyse Tim T Miceli-Richard Corinne C Brennan Michael T MT Lessard James A JA Wahren-Herlenius Marie M Kvarnström Marika M Illei Gabor G GG Witte Torsten T Jonsson Roland R Eriksson Per P Nordmark Gunnel G Ng Wan-Fai WF Anaya Juan-Manuel JM Rhodus Nelson L NL Segal Barbara M BM Merrill Joan T JT James Judith A JA Guthridge Joel M JM Scofield R Hal RH Alarcon-Riquelme Marta M Bae Sang-Cheol SC Boackle Susan A SA Criswell Lindsey A LA Gilkeson Gary G Kamen Diane L DL Jacob Chaim O CO Kimberly Robert R Brown Elizabeth E Edberg Jeffrey J Alarcón Graciela S GS Reveille John D JD Vilá Luis M LM Petri Michelle M Ramsey-Goldman Rosalind R Freedman Barry I BI Niewold Timothy T Stevens Anne M AM Tsao Betty P BP Ying Jun J Mayes Maureen D MD Gorlova Olga Y OY Wakeland Ward W Radstake Timothy T Martin Ezequiel E Martin Javier J Siminovitch Katherine K Moser Sivils Kathy L KL Gaffney Patrick M PM Langefeld Carl D CD Harley John B JB Kaufman Kenneth M KM

Human molecular genetics 20140908 2

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 an ...[more]

PMID: 25205108

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Project description:Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P ?=?1.34×10(-8), OR ?=?1.22, CI 95% ?=?1.14-1.30; rs2004640: P ?=?4.60×10(-7), OR ?=?0.84, CI 95% ?=?0.78-0.90; rs10488631: P ?=?7.53×10(-20), OR ?=?1.63, CI 95% ?=?1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P ?=?0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P ?=?9.04×10(-22), OR ?=?1.75, CI 95% ?=?1.56-1.97) better explained the observed association (likelihood P-value ?=?1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

Dataset Information

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

Publications

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

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