1. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share
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Ward Wakeland, Rosalind Ramsey-Goldman, Robert P. Kimberly, Elizabeth E. Brown, Leah C. Kottyan, Carl D. Langefeld, Matthew T. Weirauch, Bahram Namjou, Jun Ying, Roald Omdal, James A. Lessard, Wan-Fai Ng, Catalina Coltescu, Anne M. Stevens, Katherine A. Siminovitch, Xavier Mariette, John B. Harley, Luis M. Vilá, Courtney G. Montgomery, Marika Kvarnström, Maureen Rischmueller, E. Martin, Samuel E. Vaughn, Kenneth M. Kaufman, Betty P. Tsao, Michael T. Brennan, Gunnel Nordmark, Johan G. Brun, Stuart B. Glenn, Jeffrey C. Edberg, Adam Adler, Torsten Witte, Joel M. Guthridge, Per Eriksson, Graciela S. Alarcón, Timothy B. Niewold, Kathy L. Sivils, Olga Y. Gorlova, He Li, Christopher I. Amos, Susan A. Boackle, Juan-Manuel Anaya, Erna Harboe, Erin E. Zoller, Barbara M. Segal, Barry I. Freedman, Gary S. Gilkeson, Gang Xie, Roland Jonsson, Diane L. Kamen, Corinne Miceli-Richard, Jessica Bene, Nelson L. Rhodus, Timothy J. Vyse, Judith A. James, Andrew M. Rupert, John D. Reveille, Deborah S. Cunninghame-Graham, Simon J Bowman, Christopher J. Lessard, Patrick M. Gaffney, Jennifer A. Kelly, Michelle Petri, John A. Ice, Gabor G. Illei, Timothy R D J Radstake, Marie Wahren-Herlenius, Javier Martin, Joan T. Merrill, R. Hal Scofield, Marta E. Alarcón-Riquelme, Sang Cheol Bae, Gideon M. Hirschfield, Maureen D. Mayes, Lasse G. Gøransson, Astrid Rasmussen, Susan C. Lester, Lindsey A. Criswell, Swapan K. Nath, Xiaoming Lu, Chaim O. Jacob, and Miranda C. Marion more...
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single nucleotide ,Male ,Bayes theorem ,Unclassified drug ,Autoimmune diseases ,Dna sequence ,Tnpo3 gene ,Gene ,Gene locus ,Ancestry group ,Cohort Studies ,Karyopherin beta ,Autoimmune disease ,Haplotype ,Lupus Erythematosus, Systemic ,Promoter Regions, Genetic ,Genetics (clinical) ,Priority journal ,Allele ,Tnpo3 protein ,Genetics ,Association Studies Articles ,Promoter region ,General Medicine ,beta Karyopherins ,DNA-Binding Proteins ,Interferon regulatory factors ,Interferon regulatory factor ,Primary biliary cirrhosis ,Interferon Regulatory Factors ,Systemic sclerosis ,Cohort studies ,Medical genetics ,Beta Karyopherins ,Cohort analysis ,Human ,medicine.medical_specialty ,Genotype ,Case control study ,Locus (genetics) ,Single-nucleotide polymorphism ,Major clinical study ,Case-control studies ,Biology ,European ,Polymorphism, Single Nucleotide ,Article ,Autoimmune Diseases ,Systemic lupus erythematosus ,Gene mapping ,medicine ,Transcription factor zbtb3 ,Humans ,Polymorphism ,Zbtb3 protein ,Molecular Biology ,Genotyping ,Genetic association ,Lupus erythematosus ,Dna binding protein ,Irf5 gene ,Promoter regions ,Bayes Theorem ,systemic ,Disease assessment ,Dna-binding proteins ,Single nucleotide polymorphism ,Haplotypes ,Beta karyopherins ,Case-Control Studies ,Genetic variability ,Gene expression ,Transcription factor ,genetic ,Controlled study ,Sjoegren syndrome ,Irf5 protein ,Imputation (genetics) - 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 credibleset 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. © The Author 2014. more...
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- 2014
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