1. Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression
- Author
-
Marta E. Alarcón-Riquelme, Rosalind Ramsey-Goldman, Judith A. James, Young Bin Joo, John B. Harley, Anne M. Stevens, Timothy J. Vyse, Nan Shen, Matthew T. Weirauch, Gary S. Gilkeson, Susan A. Boackle, Stuart B. Glenn, Robert P. Kimberly, Swapan K. Nath, Kenneth D. Greis, Jennifer A. Kelly, Leah C. Kottyan, Michelle Petri, Bahram Namjou, Adrienne H. Williams, Luis M. Vilá, Betty P. Tsao, Miranda C. Marion, Patrick M. Gaffney, R. Hal Scofield, Graciela S. Alarcón, Barry I. Freedman, Deborah S. Cunninghame Graham, Zhiguo Wu, Jeongim Choi, Lindsey A. Criswell, Elizabeth E. Brown, Adam Adler, Kenneth M. Kaufman, Erin E. Zoller, Joel M. Guthridge, Sang Cheol Bae, Kathy L. Sivils, Mary E. Comeau, Julie T. Ziegler, John D. Reveille, Carl D. Langefeld, Juan-Manuel Anaya, Diane L. Kamen, Xiaoming Lu, and Chaim O. Jacob
- Subjects
Mouse ,Genetic model ,Autoimmunity ,Gene locus ,Medical and Health Sciences ,Microrna ,Mice ,Haplotype ,Lupus Erythematosus, Systemic ,2.1 Biological and endogenous factors ,Genetics(clinical) ,Aetiology ,Genetics (clinical) ,Priority journal ,Transcription factor ets 1 ,Allele ,Genetics ,Genetics & Heredity ,Bayesian learning ,Mus ,Biological Sciences ,Chromatin immunoprecipitation ,Chromatin ,3. Good health ,Asians ,STAT1 Transcription Factor ,Chromosomal region ,Han chinese ,Ets1 protein ,Protein Binding ,Biotechnology ,Genotype ,Immunoblotting ,Lupus ,MiRNA binding ,Biology ,Stat1 protein ,Autoimmune Disease ,Article ,Proto-Oncogene Protein c-ets-1 ,Systemic lupus erythematosus ,Asian People ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,human ,Transcription factor ,Gene mapping ,Alleles ,Genetic risk ,Lupus erythematosus ,Asian ,B lymphocyte ,Mass spectrometry ,Lupus Erythematosus ,Animal ,Genetic predisposition ,Inflammatory and immune system ,Systemic ,Human Genome ,Bayes Theorem ,Dna ,medicine.disease ,Metabolism ,Haplotypes ,Expression quantitative trait loci ,Genetic variability ,Asian continental ancestry group ,Model - 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.
- Full Text
- View/download PDF