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

T Robinson, SN Kariuki, BS Franek… - The Journal of …, 2011 - journals.aai.org
T Robinson, SN Kariuki, BS Franek, M Kumabe, AA Kumar, M Badaracco, RA Mikolaitis…
The Journal of Immunology, 2011journals.aai.org
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 …
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.
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