Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression

Xiaoming Lu, Erin E. Zoller, Matthew T. Weirauch, Zhiguo Wu, Bahram Namjou, Adrienne H. Williams, Julie T. Ziegler, Mary E. Comeau, Miranda C. Marion, Stuart B. Glenn, Adam Adler, Nan Shen, Swapan K. Nath, Anne M. Stevens, Barry I. Freedman, Betty P. Tsao, Chaim O. Jacob, Diane L. Kamen, Elizabeth E. Brown, Gary S. GilkesonGraciela S. Alarcón, John D. Reveille, Juan Manuel Anaya, Judith A. James, Kathy L. Sivils, Lindsey A. Criswell, Luis M. Vilá, Marta E. Alarcón-Riquelme, Michelle Petri, R. Hal Scofield, Robert P. Kimberly, Rosalind Ramsey-Goldman, Young Bin Joo, Jeongim Choi, Sang Cheol Bae, Susan A. Boackle, Deborah Cunninghame Graham, Timothy J. Vyse, Joel M. Guthridge, Patrick M. Gaffney, Carl D. Langefeld, Jennifer A. Kelly, Kenneth D. Greis, Kenneth M. Kaufman, John B. Harley, Leah C. Kottyan

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

25 Citas (Scopus)

Resumen

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.

Idioma originalInglés estadounidense
Páginas (desde-hasta)731-739
Número de páginas9
PublicaciónAmerican Journal of Human Genetics
Volumen96
N.º5
DOI
EstadoPublicada - may 7 2015

All Science Journal Classification (ASJC) codes

  • Genética
  • Genética (clínica)

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