Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

Xiaoming Lu, Erin 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. Gilkeson & 26 otros Graciela S. Alarcón, John D. Reveille, Juan-Manuel Anaya, Judith A. James, Kathy L. Moser 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 RevistaArtículo

21 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 originalEnglish (US)
Páginas (desde-hasta)731-739
Número de páginas9
PublicaciónAmerican Journal of Human Genetics
Volumen96
N.º5
DOI
EstadoPublished - may 7 2015
Publicado de forma externa

Huella dactilar

Alleles
Systemic Lupus Erythematosus
STAT1 Transcription Factor
B-Lymphocytes
Transcription Factors
Bayes Theorem
Chromatin Immunoprecipitation
Quantitative Trait Loci
Genetic Models
MicroRNAs
Autoimmunity
Chromatin
Cell Differentiation
Mass Spectrometry
DNA
Genes

Citar esto

Lu, X., Zoller, E., Weirauch, M. T., Wu, Z., Namjou, B., Williams, A. H., ... Kottyan, L. C. (2015). Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. American Journal of Human Genetics, 96(5), 731-739. https://doi.org/10.1016/j.ajhg.2015.03.002
Lu, Xiaoming ; Zoller, Erin ; Weirauch, Matthew T. ; Wu, Zhiguo ; Namjou, Bahram ; Williams, Adrienne H. ; Ziegler, Julie T. ; Comeau, Mary E. ; Marion, Miranda C. ; Glenn, Stuart B. ; Adler, Adam ; Shen, Nan ; Nath, Swapan K. ; Stevens, Anne M. ; Freedman, Barry I. ; Tsao, Betty P. ; Jacob, Chaim O. ; Kamen, Diane L. ; Brown, Elizabeth E. ; Gilkeson, Gary S. ; Alarcón, Graciela S. ; Reveille, John D. ; Anaya, Juan-Manuel ; James, Judith A. ; Moser Sivils, Kathy L. ; Criswell, Lindsey A. ; Vilá, Luis M. ; Alarcón-Riquelme, Marta E. ; Petri, Michelle ; Scofield, R. Hal ; Kimberly, Robert P. ; Ramsey-Goldman, Rosalind ; Joo, Young Bin ; Choi, Jeongim ; Bae, Sang Cheol ; Boackle, Susan A. ; Graham, Deborah Cunninghame ; Vyse, Timothy J. ; Guthridge, Joel M. ; Gaffney, Patrick M. ; Langefeld, Carl D. ; Kelly, Jennifer A. ; Greis, Kenneth D. ; Kaufman, Kenneth M. ; Harley, John B. ; Kottyan, Leah C. / Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. En: American Journal of Human Genetics. 2015 ; Vol. 96, N.º 5. pp. 731-739.
@article{2cbd6d8580854d27b02bea64aed3fb36,
title = "Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression",
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.",
author = "Xiaoming Lu and Erin Zoller and Weirauch, {Matthew T.} and Zhiguo Wu and Bahram Namjou and Williams, {Adrienne H.} and Ziegler, {Julie T.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Glenn, {Stuart B.} and Adam Adler and Nan Shen and Nath, {Swapan K.} and Stevens, {Anne M.} and Freedman, {Barry I.} and Tsao, {Betty P.} and Jacob, {Chaim O.} and Kamen, {Diane L.} and Brown, {Elizabeth E.} and Gilkeson, {Gary S.} and Alarc{\'o}n, {Graciela S.} and Reveille, {John D.} and Juan-Manuel Anaya and James, {Judith A.} and {Moser Sivils}, {Kathy L.} and Criswell, {Lindsey A.} and Vil{\'a}, {Luis M.} and Alarc{\'o}n-Riquelme, {Marta E.} and Michelle Petri and Scofield, {R. Hal} and Kimberly, {Robert P.} and Rosalind Ramsey-Goldman and Joo, {Young Bin} and Jeongim Choi and Bae, {Sang Cheol} and Boackle, {Susan A.} and Graham, {Deborah Cunninghame} and Vyse, {Timothy J.} and Guthridge, {Joel M.} and Gaffney, {Patrick M.} and Langefeld, {Carl D.} and Kelly, {Jennifer A.} and Greis, {Kenneth D.} and Kaufman, {Kenneth M.} and Harley, {John B.} and Kottyan, {Leah C.}",
note = "Copyright {\circledC} 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2015",
month = "5",
day = "7",
doi = "10.1016/j.ajhg.2015.03.002",
language = "English (US)",
volume = "96",
pages = "731--739",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
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number = "5",

}

Lu, X, Zoller, E, Weirauch, MT, Wu, Z, Namjou, B, Williams, AH, Ziegler, JT, Comeau, ME, Marion, MC, Glenn, SB, Adler, A, Shen, N, Nath, SK, Stevens, AM, Freedman, BI, Tsao, BP, Jacob, CO, Kamen, DL, Brown, EE, Gilkeson, GS, Alarcón, GS, Reveille, JD, Anaya, J-M, James, JA, Moser Sivils, KL, Criswell, LA, Vilá, LM, Alarcón-Riquelme, ME, Petri, M, Scofield, RH, Kimberly, RP, Ramsey-Goldman, R, Joo, YB, Choi, J, Bae, SC, Boackle, SA, Graham, DC, Vyse, TJ, Guthridge, JM, Gaffney, PM, Langefeld, CD, Kelly, JA, Greis, KD, Kaufman, KM, Harley, JB & Kottyan, LC 2015, 'Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression', American Journal of Human Genetics, vol. 96, n.º 5, pp. 731-739. https://doi.org/10.1016/j.ajhg.2015.03.002

Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. / Lu, Xiaoming; Zoller, Erin; Weirauch, Matthew T.; Wu, Zhiguo; Namjou, Bahram; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Marion, Miranda C.; Glenn, Stuart B.; Adler, Adam; Shen, Nan; Nath, Swapan K.; Stevens, Anne M.; Freedman, Barry I.; Tsao, Betty P.; Jacob, Chaim O.; Kamen, Diane L.; Brown, Elizabeth E.; Gilkeson, Gary S.; Alarcón, Graciela S.; Reveille, John D.; Anaya, Juan-Manuel; James, Judith A.; Moser Sivils, Kathy L.; Criswell, Lindsey A.; Vilá, Luis M.; Alarcón-Riquelme, Marta E.; Petri, Michelle; Scofield, R. Hal; Kimberly, Robert P.; Ramsey-Goldman, Rosalind; Joo, Young Bin; Choi, Jeongim; Bae, Sang Cheol; Boackle, Susan A.; Graham, Deborah Cunninghame; Vyse, Timothy J.; Guthridge, Joel M.; Gaffney, Patrick M.; Langefeld, Carl D.; Kelly, Jennifer A.; Greis, Kenneth D.; Kaufman, Kenneth M.; Harley, John B.; Kottyan, Leah C.

En: American Journal of Human Genetics, Vol. 96, N.º 5, 07.05.2015, p. 731-739.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

AU - Lu, Xiaoming

AU - Zoller, Erin

AU - Weirauch, Matthew T.

AU - Wu, Zhiguo

AU - Namjou, Bahram

AU - Williams, Adrienne H.

AU - Ziegler, Julie T.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Glenn, Stuart B.

AU - Adler, Adam

AU - Shen, Nan

AU - Nath, Swapan K.

AU - Stevens, Anne M.

AU - Freedman, Barry I.

AU - Tsao, Betty P.

AU - Jacob, Chaim O.

AU - Kamen, Diane L.

AU - Brown, Elizabeth E.

AU - Gilkeson, Gary S.

AU - Alarcón, Graciela S.

AU - Reveille, John D.

AU - Anaya, Juan-Manuel

AU - James, Judith A.

AU - Moser Sivils, Kathy L.

AU - Criswell, Lindsey A.

AU - Vilá, Luis M.

AU - Alarcón-Riquelme, Marta E.

AU - Petri, Michelle

AU - Scofield, R. Hal

AU - Kimberly, Robert P.

AU - Ramsey-Goldman, Rosalind

AU - Joo, Young Bin

AU - Choi, Jeongim

AU - Bae, Sang Cheol

AU - Boackle, Susan A.

AU - Graham, Deborah Cunninghame

AU - Vyse, Timothy J.

AU - Guthridge, Joel M.

AU - Gaffney, Patrick M.

AU - Langefeld, Carl D.

AU - Kelly, Jennifer A.

AU - Greis, Kenneth D.

AU - Kaufman, Kenneth M.

AU - Harley, John B.

AU - Kottyan, Leah C.

N1 - Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2015/5/7

Y1 - 2015/5/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2015.03.002

DO - 10.1016/j.ajhg.2015.03.002

M3 - Article

VL - 96

SP - 731

EP - 739

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -