Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-α and serologic autoimmunity in lupus patients

J Immunol. 2011 Aug 1;187(3):1298-303. doi: 10.4049/jimmunol.1100857. Epub 2011 Jun 24.

Abstract

Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease-associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α-induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA-positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 T allele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Autoantibodies / biosynthesis
  • Autoantibodies / blood*
  • Cell Line
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / physiology*
  • DNA / immunology
  • Genetic Variation / immunology*
  • Humans
  • Interferon-Induced Helicase, IFIH1
  • Interferon-alpha / blood
  • Interferon-alpha / genetics
  • Interferon-alpha / physiology*
  • Lupus Erythematosus, Systemic / enzymology*
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Polymorphism, Single Nucleotide / immunology
  • Risk Factors
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Autoantibodies
  • Interferon-alpha
  • DNA
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1