IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

Roozbeh Sharif, Maureen D. Mayes, Filemon K. Tan, Olga Y. Gorlova, Laura Kathleen Hummers, Ami A. Shah, Daniel E. Furst, Dinesh Khanna, Javier Martin, Lara Bossini-Castillo, Emilio Gonzalez, Jun Ying, Hilda Torres Draeger, Sandeep K. Agarwal, John D. Reveille, Frank C. Arnett, Fredrick M. Wigley, Shervin Assassi

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Objective: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods: The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results: Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. Conclusion: An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

Original languageEnglish (US)
Pages (from-to)1197-1202
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume71
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Systemic Scleroderma
Polymorphism
Pulmonary diseases
Genes
Single Nucleotide Polymorphism
Interstitial Lung Diseases
Survival
Genome-Wide Association Study
Alleles
Vital Capacity
Genetic Promoter Regions
Autoantibodies
Major Histocompatibility Complex
Age of Onset
Nucleotides
Gene Frequency
Registries
Outcome Assessment (Health Care)
Genome

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Sharif, R., Mayes, M. D., Tan, F. K., Gorlova, O. Y., Hummers, L. K., Shah, A. A., ... Assassi, S. (2012). IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. Annals of the Rheumatic Diseases, 71(7), 1197-1202. https://doi.org/10.1136/annrheumdis-2011-200901

IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. / Sharif, Roozbeh; Mayes, Maureen D.; Tan, Filemon K.; Gorlova, Olga Y.; Hummers, Laura Kathleen; Shah, Ami A.; Furst, Daniel E.; Khanna, Dinesh; Martin, Javier; Bossini-Castillo, Lara; Gonzalez, Emilio; Ying, Jun; Draeger, Hilda Torres; Agarwal, Sandeep K.; Reveille, John D.; Arnett, Frank C.; Wigley, Fredrick M.; Assassi, Shervin.

In: Annals of the Rheumatic Diseases, Vol. 71, No. 7, 07.2012, p. 1197-1202.

Research output: Contribution to journalArticle

Sharif, R, Mayes, MD, Tan, FK, Gorlova, OY, Hummers, LK, Shah, AA, Furst, DE, Khanna, D, Martin, J, Bossini-Castillo, L, Gonzalez, E, Ying, J, Draeger, HT, Agarwal, SK, Reveille, JD, Arnett, FC, Wigley, FM & Assassi, S 2012, 'IRF5 polymorphism predicts prognosis in patients with systemic sclerosis', Annals of the Rheumatic Diseases, vol. 71, no. 7, pp. 1197-1202. https://doi.org/10.1136/annrheumdis-2011-200901
Sharif, Roozbeh ; Mayes, Maureen D. ; Tan, Filemon K. ; Gorlova, Olga Y. ; Hummers, Laura Kathleen ; Shah, Ami A. ; Furst, Daniel E. ; Khanna, Dinesh ; Martin, Javier ; Bossini-Castillo, Lara ; Gonzalez, Emilio ; Ying, Jun ; Draeger, Hilda Torres ; Agarwal, Sandeep K. ; Reveille, John D. ; Arnett, Frank C. ; Wigley, Fredrick M. ; Assassi, Shervin. / IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. In: Annals of the Rheumatic Diseases. 2012 ; Vol. 71, No. 7. pp. 1197-1202.
@article{e1231de35c7e45c6b3fdbb8fb5587eab,
title = "IRF5 polymorphism predicts prognosis in patients with systemic sclerosis",
abstract = "Objective: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods: The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC){\%} predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results: Overall, 15.5{\%} of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95{\%} CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4{\%}. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC{\%} predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. Conclusion: An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.",
author = "Roozbeh Sharif and Mayes, {Maureen D.} and Tan, {Filemon K.} and Gorlova, {Olga Y.} and Hummers, {Laura Kathleen} and Shah, {Ami A.} and Furst, {Daniel E.} and Dinesh Khanna and Javier Martin and Lara Bossini-Castillo and Emilio Gonzalez and Jun Ying and Draeger, {Hilda Torres} and Agarwal, {Sandeep K.} and Reveille, {John D.} and Arnett, {Frank C.} and Wigley, {Fredrick M.} and Shervin Assassi",
year = "2012",
month = "7",
doi = "10.1136/annrheumdis-2011-200901",
language = "English (US)",
volume = "71",
pages = "1197--1202",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "7",

}

TY - JOUR

T1 - IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

AU - Sharif, Roozbeh

AU - Mayes, Maureen D.

AU - Tan, Filemon K.

AU - Gorlova, Olga Y.

AU - Hummers, Laura Kathleen

AU - Shah, Ami A.

AU - Furst, Daniel E.

AU - Khanna, Dinesh

AU - Martin, Javier

AU - Bossini-Castillo, Lara

AU - Gonzalez, Emilio

AU - Ying, Jun

AU - Draeger, Hilda Torres

AU - Agarwal, Sandeep K.

AU - Reveille, John D.

AU - Arnett, Frank C.

AU - Wigley, Fredrick M.

AU - Assassi, Shervin

PY - 2012/7

Y1 - 2012/7

N2 - Objective: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods: The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results: Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. Conclusion: An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

AB - Objective: The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods: The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 - discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 - replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results: Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. Conclusion: An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

UR - http://www.scopus.com/inward/record.url?scp=84862789262&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862789262&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2011-200901

DO - 10.1136/annrheumdis-2011-200901

M3 - Article

C2 - 22440820

AN - SCOPUS:84862789262

VL - 71

SP - 1197

EP - 1202

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 7

ER -