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

Authors

  • Timothy B. Niewold,

    Corresponding author
    1. University of Chicago, Chicago, Illinois
    • University of Chicago, Section of Rheumatology, 5841 South Maryland Avenue, Mail Code 0930, Chicago, IL 60637
    Search for more papers by this author
  • Jennifer A. Kelly,

    1. Oklahoma Medical Research Foundation, Oklahoma City
    Search for more papers by this author
  • Marie H. Flesch,

    1. Oklahoma Medical Research Foundation, Oklahoma City
    Search for more papers by this author
  • Luis R. Espinoza,

    1. Louisiana State University, New Orleans
    Search for more papers by this author
  • John B. Harley,

    1. Oklahoma Medical Research Foundation, Oklahoma City VAMC, and University of Oklahoma, Oklahoma City
    Search for more papers by this author
    • Dr. Harley has received consulting fees, speaking fees, and/or honoraria from Bio-Rad Industries, Inc., and IVAX Diagnostics, Inc. (more than $10,000 each), and owns stock or stock options in IVAX Diagnostics, Inc.

  • Mary K. Crow

    1. Hospital for Special Surgery, New York, New York
    Search for more papers by this author
    • Dr. Crow has received consulting fees, speaking fees, and/or honoraria from Genentech, Novo Nordisk, and ZymoGenetics (less than $10,000 each), owns stock or stock options in XDx, Inc., and has a patent pending for an interferon assay.


Abstract

Objective

A haplotype of the interferon regulatory 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 IFNα activity than did those with protective/protective and neutral/protective genotypes (P = 0.025). This differential effect of IRF5 genotype on serum IFNα 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 independently associated with high serum IFNα in this autoantibody group. We found no difference in IFNα 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 IFNα 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.

Ancillary