High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups

Bahram Namjou, Andrea L. Sestak, Don L. Armstrong, Raphael Zidovetzki, Jennifer A. Kelly, Noam Jacob Voicu Ciobanu, Kenneth M. Kaufman, Joshua O. Ojwang, Julie Ziegler, Francesco P. Quismorio, Andreas Reiff, Barry L. Myones, Joel M. Guthridge, Swapan K. Nath, Gail R. Bruner, Ruth Mehrian-Shai, Earl Silverman, Marisa Klein-Gitelman, Deborah Mccurdy, Linda Wagner-WeinerJames J. Nocton, Chaim Putterman, Sang Cheol Bae, Yun Jung Kim, Michelle Petri, John D. Reveille, Timothy J. Vyse, Gary S. Gilkeson, Diane L. Kamen, Marta E. Alarcón-Riquelme, Patrick M. Gaffney, Kathy L. Moser, Joan T. Merrill, R. Hal Scofield, Judith A. James, Carl D. Langefeld, John B. Harley, Chaim O. Jacob

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Objective. Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods. Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results. We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10 -25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. Conclusion. Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1085-1095
Number of pages11
JournalArthritis and Rheumatism
Volume60
Issue number4
DOIs
StatePublished - Apr 2009

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Systemic Lupus Erythematosus
Interferons
Single Nucleotide Polymorphism
STAT Transcription Factors
Chromosomes, Human, Pair 2
Principal Component Analysis
Ethnic Groups
Haplotypes
Genes
Odds Ratio
Confidence Intervals
DNA
Population

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Namjou, B., Sestak, A. L., Armstrong, D. L., Zidovetzki, R., Kelly, J. A., Ciobanu, N. J. V., ... Jacob, C. O. (2009). High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups. Arthritis and Rheumatism, 60(4), 1085-1095. https://doi.org/10.1002/art.24387

High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups. / Namjou, Bahram; Sestak, Andrea L.; Armstrong, Don L.; Zidovetzki, Raphael; Kelly, Jennifer A.; Ciobanu, Noam Jacob Voicu; Kaufman, Kenneth M.; Ojwang, Joshua O.; Ziegler, Julie; Quismorio, Francesco P.; Reiff, Andreas; Myones, Barry L.; Guthridge, Joel M.; Nath, Swapan K.; Bruner, Gail R.; Mehrian-Shai, Ruth; Silverman, Earl; Klein-Gitelman, Marisa; Mccurdy, Deborah; Wagner-Weiner, Linda; Nocton, James J.; Putterman, Chaim; Bae, Sang Cheol; Kim, Yun Jung; Petri, Michelle; Reveille, John D.; Vyse, Timothy J.; Gilkeson, Gary S.; Kamen, Diane L.; Alarcón-Riquelme, Marta E.; Gaffney, Patrick M.; Moser, Kathy L.; Merrill, Joan T.; Scofield, R. Hal; James, Judith A.; Langefeld, Carl D.; Harley, John B.; Jacob, Chaim O.

In: Arthritis and Rheumatism, Vol. 60, No. 4, 04.2009, p. 1085-1095.

Research output: Contribution to journalArticle

Namjou, B, Sestak, AL, Armstrong, DL, Zidovetzki, R, Kelly, JA, Ciobanu, NJV, Kaufman, KM, Ojwang, JO, Ziegler, J, Quismorio, FP, Reiff, A, Myones, BL, Guthridge, JM, Nath, SK, Bruner, GR, Mehrian-Shai, R, Silverman, E, Klein-Gitelman, M, Mccurdy, D, Wagner-Weiner, L, Nocton, JJ, Putterman, C, Bae, SC, Kim, YJ, Petri, M, Reveille, JD, Vyse, TJ, Gilkeson, GS, Kamen, DL, Alarcón-Riquelme, ME, Gaffney, PM, Moser, KL, Merrill, JT, Scofield, RH, James, JA, Langefeld, CD, Harley, JB & Jacob, CO 2009, 'High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups', Arthritis and Rheumatism, vol. 60, no. 4, pp. 1085-1095. https://doi.org/10.1002/art.24387
Namjou, Bahram ; Sestak, Andrea L. ; Armstrong, Don L. ; Zidovetzki, Raphael ; Kelly, Jennifer A. ; Ciobanu, Noam Jacob Voicu ; Kaufman, Kenneth M. ; Ojwang, Joshua O. ; Ziegler, Julie ; Quismorio, Francesco P. ; Reiff, Andreas ; Myones, Barry L. ; Guthridge, Joel M. ; Nath, Swapan K. ; Bruner, Gail R. ; Mehrian-Shai, Ruth ; Silverman, Earl ; Klein-Gitelman, Marisa ; Mccurdy, Deborah ; Wagner-Weiner, Linda ; Nocton, James J. ; Putterman, Chaim ; Bae, Sang Cheol ; Kim, Yun Jung ; Petri, Michelle ; Reveille, John D. ; Vyse, Timothy J. ; Gilkeson, Gary S. ; Kamen, Diane L. ; Alarcón-Riquelme, Marta E. ; Gaffney, Patrick M. ; Moser, Kathy L. ; Merrill, Joan T. ; Scofield, R. Hal ; James, Judith A. ; Langefeld, Carl D. ; Harley, John B. ; Jacob, Chaim O. / High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups. In: Arthritis and Rheumatism. 2009 ; Vol. 60, No. 4. pp. 1085-1095.
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title = "High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups",
abstract = "Objective. Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods. Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95{\%} confidence intervals were calculated. Results. We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10 -25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. Conclusion. Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.",
author = "Bahram Namjou and Sestak, {Andrea L.} and Armstrong, {Don L.} and Raphael Zidovetzki and Kelly, {Jennifer A.} and Ciobanu, {Noam Jacob Voicu} and Kaufman, {Kenneth M.} and Ojwang, {Joshua O.} and Julie Ziegler and Quismorio, {Francesco P.} and Andreas Reiff and Myones, {Barry L.} and Guthridge, {Joel M.} and Nath, {Swapan K.} and Bruner, {Gail R.} and Ruth Mehrian-Shai and Earl Silverman and Marisa Klein-Gitelman and Deborah Mccurdy and Linda Wagner-Weiner and Nocton, {James J.} and Chaim Putterman and Bae, {Sang Cheol} and Kim, {Yun Jung} and Michelle Petri and Reveille, {John D.} and Vyse, {Timothy J.} and Gilkeson, {Gary S.} and Kamen, {Diane L.} and Alarc{\'o}n-Riquelme, {Marta E.} and Gaffney, {Patrick M.} and Moser, {Kathy L.} and Merrill, {Joan T.} and Scofield, {R. Hal} and James, {Judith A.} and Langefeld, {Carl D.} and Harley, {John B.} and Jacob, {Chaim O.}",
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TY - JOUR

T1 - High-density genotyping of STAT4 reveals multiple haplotypic associations with Systemic lupus erythematosus in different racial groups

AU - Namjou, Bahram

AU - Sestak, Andrea L.

AU - Armstrong, Don L.

AU - Zidovetzki, Raphael

AU - Kelly, Jennifer A.

AU - Ciobanu, Noam Jacob Voicu

AU - Kaufman, Kenneth M.

AU - Ojwang, Joshua O.

AU - Ziegler, Julie

AU - Quismorio, Francesco P.

AU - Reiff, Andreas

AU - Myones, Barry L.

AU - Guthridge, Joel M.

AU - Nath, Swapan K.

AU - Bruner, Gail R.

AU - Mehrian-Shai, Ruth

AU - Silverman, Earl

AU - Klein-Gitelman, Marisa

AU - Mccurdy, Deborah

AU - Wagner-Weiner, Linda

AU - Nocton, James J.

AU - Putterman, Chaim

AU - Bae, Sang Cheol

AU - Kim, Yun Jung

AU - Petri, Michelle

AU - Reveille, John D.

AU - Vyse, Timothy J.

AU - Gilkeson, Gary S.

AU - Kamen, Diane L.

AU - Alarcón-Riquelme, Marta E.

AU - Gaffney, Patrick M.

AU - Moser, Kathy L.

AU - Merrill, Joan T.

AU - Scofield, R. Hal

AU - James, Judith A.

AU - Langefeld, Carl D.

AU - Harley, John B.

AU - Jacob, Chaim O.

PY - 2009/4

Y1 - 2009/4

N2 - Objective. Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods. Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results. We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10 -25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. Conclusion. Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

AB - Objective. Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder, with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility. Methods. Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated. Results. We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 × 10 -25). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 and, in particular, a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to its proximity to STAT4. Conclusion. Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

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