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

Lookup NU author(s): Professor Fai NgORCiD


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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-value(meta) = 6 x 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-values(EU) = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5locus 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 IRF5expression 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 Sjogren'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 metadata

Author(s): Kottyan LC, Zoller EE, Bene J, Lu XM, Kelly JA, Rupert AM, Lessard CJ, Vaughn SE, Marion M, Weirauch MT, Namjou B, Adler A, Rasmussen A, Glenn S, Montgomery CG, Hirschfield GM, Xie G, Coltescu C, Amos C, Li H, Ice JA, Nath SK, Mariette X, Bowman S, Rischmueller M, Lester S, Brun JG, Goransson LG, Harboe E, Omdal R, Cunninghame-Graham DS, Vyse T, Miceli-Richard C, Brennan MT, Lessard JA, Wahren-Herlenius M, Kvarnstrom M, Illei GG, Witte T, Jonsson R, Eriksson P, Nordmark G, Ng WF, Anaya JM, Rhodus NL, Sega BM, Merrill JT, James JA, Guthridge JM, Scofield RH, Alarcon-Riquelme M, Bae SC, Boackle SA, Criswell LA, Gilkeson G, Kamen DL, Jacob CO, Kimberly R, Brown E, Edberg J, Alarcon GS, Reveille JD, Vila LM, Petri M, Ramsey-Goldman R, Freedman BI, Niewold T, Stevens AM, Tsao BP, Ying J, Mayes MD, Gorlova OY, Wakeland W, Radstake T, Martin E, Martin J, Siminovitch K, Sivils KLM, Gaffney PM, Langefeld CD, Harley JB, Kaufman KM, UK Primary Sjogrens Syndrome Regis

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2015

Volume: 24

Issue: 2

Pages: 582-596

Print publication date: 15/01/2015

Online publication date: 08/09/2014

Acceptance date: 01/09/2014

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddu455


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Funder referenceFunder name
Canadian Institutes of Health Research
Korea Healthcare technology RD Project
Northumberland, Tyne Wear CLRN
Phileona Foundation
Sherman Family Chair in Genomic Medicine
Strategic Research Program at Helse Bergen
Swedish Rheumatism Association
Western Norway Regional Health Authority
Alliance for Lupus Research
American College of Rheumatology Research and Education Foundation/Abbott Healthy Professional Graduate Student Preceptorship Award
Canada Research Chair
Oklahoma Medical Research Foundation
PBC Society of Canada
4434Sjogren's Syndrome Foundation
1RR025741National Institutes of Health.
2006-AOM06133French Ministry of Health (PHRC)
AI024717National Institutes of Health
AI031584National Institutes of Health
AI070304National Institutes of Health.
AR 002138National Institutes of Health.
AR043418National Institutes of Health
AR049084National Institutes of Health
AR057172National Institutes of Health
AR0608040National Institutes of Health.
AR065626National Institutes of Health
AR43727National Institutes of Health.
AI082714National Institutes of Health
AI083194National Institutes of Health.
AI094377National Institutes of Health.
AI101934National Institutes of Health.
DE015223National Institutes of Health
AR042460National Institutes of Health
AR048940National Institutes of Health.
AR052300National Institutes of Health
AR053483National Institutes of Health.
AR058959National Institutes of Health.
AR060366National Institutes of Health
AR062277National Institutes of Health
AR062755National Institutes of Health.
AR30692National Institutes of Health.
DE018209National Institutes of Health.
DE018209-02National Institutes of Health.
G0800629Medical Research Council (UK)
HI12C1834Ministry for Health and Welfare, Republic of Korea
MOP74621Canadian Institutes for Health Research
GM103510National Institutes of Health.
IMMA 9U.S. Department of Veterans Affairs
KFO 250Broegelmann Foundation
PR094002U.S. Department of Defense
RR027190National Institutes of Health.
TR000165National Institutes of Health.
WI 1031/6-1Broegelmann Foundation
Z1Broegelmann Foundation
REO-061Ontario Research Fund
RR-000079General Center Research Center
RR020143National Institutes of Health.
RR026314National Institutes of Health.
RR029882National Institutes of Health.
TP03Broegelmann Foundation