Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients

Timothy B. Niewold, Jennifer A. Kelly, Marie H. Flesch, Luis R. Espinoza, John B. Harley, Mary K. Crow

Research output: Contribution to journalArticle

197 Citations (Scopus)

Abstract

Objective. A haplotype of the interferon regula-tory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity. Methods. IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. Results. SLE patients with risk/risk and risk/ neutral IRF5 genotypes had higher serum IFNa activity than did those with protective/protective and neutral/ protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNa levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was in-dependently associated with high serum IFNa in this autoantibody group. We found no difference in IFNa activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. Conclusion. The IRF5 SLE risk haplotype is associated with higher serum IFNa activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.

Original languageEnglish (US)
Pages (from-to)2481-2487
Number of pages7
JournalArthritis and Rheumatism
Volume58
Issue number8
DOIs
StatePublished - Aug 2008
Externally publishedYes

Fingerprint

Systemic Lupus Erythematosus
Haplotypes
Interferons
Serum
Autoantibodies
Genotype
RNA-Binding Proteins
Hispanic Americans
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Niewold, T. B., Kelly, J. A., Flesch, M. H., Espinoza, L. R., Harley, J. B., & Crow, M. K. (2008). Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients. Arthritis and Rheumatism, 58(8), 2481-2487. https://doi.org/10.1002/art.23613

Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients. / Niewold, Timothy B.; Kelly, Jennifer A.; Flesch, Marie H.; Espinoza, Luis R.; Harley, John B.; Crow, Mary K.

In: Arthritis and Rheumatism, Vol. 58, No. 8, 08.2008, p. 2481-2487.

Research output: Contribution to journalArticle

Niewold, Timothy B. ; Kelly, Jennifer A. ; Flesch, Marie H. ; Espinoza, Luis R. ; Harley, John B. ; Crow, Mary K. / Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients. In: Arthritis and Rheumatism. 2008 ; Vol. 58, No. 8. pp. 2481-2487.
@article{0cbf78c0c5844ca4bbaaaa931ec038bc,
title = "Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients",
abstract = "Objective. A haplotype of the interferon regula-tory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity. Methods. IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. Results. SLE patients with risk/risk and risk/ neutral IRF5 genotypes had higher serum IFNa activity than did those with protective/protective and neutral/ protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNa levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was in-dependently associated with high serum IFNa in this autoantibody group. We found no difference in IFNa activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. Conclusion. The IRF5 SLE risk haplotype is associated with higher serum IFNa activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.",
author = "Niewold, {Timothy B.} and Kelly, {Jennifer A.} and Flesch, {Marie H.} and Espinoza, {Luis R.} and Harley, {John B.} and Crow, {Mary K.}",
year = "2008",
month = "8",
doi = "10.1002/art.23613",
language = "English (US)",
volume = "58",
pages = "2481--2487",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "8",

}

TY - JOUR

T1 - Association of the IRF5 risk haplotype with high serum interferon-α activity in systemic lupus erythematosus patients

AU - Niewold, Timothy B.

AU - Kelly, Jennifer A.

AU - Flesch, Marie H.

AU - Espinoza, Luis R.

AU - Harley, John B.

AU - Crow, Mary K.

PY - 2008/8

Y1 - 2008/8

N2 - Objective. A haplotype of the interferon regula-tory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity. Methods. IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. Results. SLE patients with risk/risk and risk/ neutral IRF5 genotypes had higher serum IFNa activity than did those with protective/protective and neutral/ protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNa levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was in-dependently associated with high serum IFNa in this autoantibody group. We found no difference in IFNa activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. Conclusion. The IRF5 SLE risk haplotype is associated with higher serum IFNa activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.

AB - Objective. A haplotype of the interferon regula-tory factor 5 (IRF5) gene has been associated with the risk of developing systemic lupus erythematosus (SLE), and our previous studies have demonstrated that high levels of serum interferon-α (IFNα) activity are a heritable risk factor for SLE. The aim of this study was to determine whether the IRF5 SLE risk haplotype mediates the risk of SLE by predisposing patients to the development of high levels of serum IFNα activity. Methods. IFNα levels in 199 SLE patients of European and Hispanic ancestry were measured with a sensitive functional reporter cell assay. The rs2004640, rs3807306, rs10488631, and rs2280714 single-nucleotide polymorphisms (SNPs) in IRF5 were genotyped in these patients. Haplotypes were categorized as SLE risk, neutral, or protective based on published data. Results. SLE patients with risk/risk and risk/ neutral IRF5 genotypes had higher serum IFNa activity than did those with protective/protective and neutral/ protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNa levels was driven largely by SLE patients who were positive for either anti-RNA binding protein (anti-RBP) or anti-double-stranded DNA (anti-dsDNA) autoantibodies (P = 0.012 for risk/risk or risk/neutral versus protective/protective or neutral/protective). The rs3807306 genotype was in-dependently associated with high serum IFNa in this autoantibody group. We found no difference in IFNa activity according to IRF5 genotype in patients lacking either type of autoantibody or in patients positive for both classes of autoantibody. Conclusion. The IRF5 SLE risk haplotype is associated with higher serum IFNa activity in SLE patients, and this effect is most prominent in patients positive for either anti-RBP or anti-dsDNA autoantibodies. This study demonstrates the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.

UR - http://www.scopus.com/inward/record.url?scp=49449104525&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49449104525&partnerID=8YFLogxK

U2 - 10.1002/art.23613

DO - 10.1002/art.23613

M3 - Article

C2 - 18668568

AN - SCOPUS:49449104525

VL - 58

SP - 2481

EP - 2487

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 8

ER -