| Literature DB >> 25205108 |
Leah C Kottyan1, Erin E Zoller2, Jessica Bene3, Xiaoming Lu3, Jennifer A Kelly4, Andrew M Rupert5, Christopher J Lessard6, Samuel E Vaughn3, Miranda Marion7, Matthew T Weirauch8, Bahram Namjou3, Adam Adler4, Astrid Rasmussen4, Stuart Glenn4, Courtney G Montgomery4, Gideon M Hirschfield9, Gang Xie10, Catalina Coltescu11, Chris Amos12, He Li6, John A Ice4, Swapan K Nath4, Xavier Mariette13, Simon Bowman14, Maureen Rischmueller15, Sue Lester16, Johan G Brun17, Lasse G Gøransson18, Erna Harboe18, Roald Omdal18, Deborah S Cunninghame-Graham19, Tim Vyse19, Corinne Miceli-Richard13, Michael T Brennan20, James A Lessard21, Marie Wahren-Herlenius22, Marika Kvarnström22, Gabor G Illei23, Torsten Witte24, Roland Jonsson25, Per Eriksson26, Gunnel Nordmark27, Wan-Fai Ng28, Juan-Manuel Anaya29, Nelson L Rhodus30, Barbara M Segal31, Joan T Merrill4, Judith A James32, Joel M Guthridge4, R Hal Scofield33, Marta Alarcon-Riquelme34, Sang-Cheol Bae35, Susan A Boackle36, Lindsey A Criswell37, Gary Gilkeson38, Diane L Kamen38, Chaim O Jacob39, Robert Kimberly40, Elizabeth Brown40, Jeffrey Edberg40, Graciela S Alarcón40, John D Reveille41, Luis M Vilá42, Michelle Petri43, Rosalind Ramsey-Goldman44, Barry I Freedman45, Timothy Niewold46, Anne M Stevens47, Betty P Tsao48, Jun Ying49, Maureen D Mayes49, Olga Y Gorlova49, Ward Wakeland50, Timothy Radstake51, Ezequiel Martin52, Javier Martin52, Katherine Siminovitch53, Kathy L Moser Sivils4, Patrick M Gaffney4, Carl D Langefeld7, John B Harley54, Kenneth M Kaufman54.
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. 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.Entities:
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Year: 2014 PMID： 25205108 PMCID： PMC4275071 DOI： 10.1093/hmg/ddu455
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150