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Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression
Título de la revista
Autores
Lu, Xiaoming
Zoller, Erin E.
Weirauch, Matthew T.
Wu, Zhiguo
Namjou, Bahram
Williams, Adrienne H.
Ziegler, Julie T.
Comeau, Mary E.
Marion, Miranda C.
Glenn, Stuart B.
Fecha
2015
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Cell Press
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Resumen
Abstract
Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1. © 2015 by The American Society of Human Genetics. All rights reserved.
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Keywords
Dna , systemic , Microrna , human , Stat1 protein , Transcription factor , Transcription factor ets 1 , Ets1 protein , Protein binding , Stat1 protein , Transcription factor ets 1 , Allele , Article , Asian , Autoimmunity , B lymphocyte , Bayesian learning , Chromatin , Chromatin immunoprecipitation , Gene locus , Gene mapping , Genetic model , Genetic risk , Genetic variability , Genotype , Han chinese , Human , Immunoblotting , Mass spectrometry , Model , Priority journal , Protein binding , Systemic lupus erythematosus , Animal , Asian continental ancestry group , Bayes theorem , Genetic predisposition , Genetics , Haplotype , Metabolism , Mouse , Systemic lupus erythematosus , Mus , Alleles , Animals , Asian continental ancestry group , Bayes theorem , Genetic predisposition to disease , Genotype , Haplotypes , Humans , Lupus erythematosus , Mice , Protein binding , Proto-oncogene protein c-ets-1 , Stat1 transcription factor
