Autoimmune Disease Risk Variant of IFIH1 Is Associated with Increased Sensitivity to IFN-alpha and Serologic Autoimmunity in Lupus Patients

作者：Robinson Talin; Kariuki Silvia N; Franek Beverly S; Kumabe Marissa; Kumar Akaash A; Badaracco Maria; Mikolaitis Rachel A; Guerrero Galen; Utset Tammy O; Drevlow Barbara E; Zaacks Laura S; Grober James S; Cohen Lewis M; Kirou Kyriakos A; Crow Mary K; Jolly Meenakshi; Niewold Timothy B^*

来源：The Journal of Immunology, 2011, 187(3): 1298-1303.

DOI：10.4049/jimmunol.1100857

Increased IFN-alpha 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-alpha pathway signaling. We studied the impact of the autoimmune-disease-associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-alpha 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-alpha-induced gene expression in PBMCs in the context of serum IFN-alpha 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-alpha 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-alpha in anti-dsDNA-positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-alpha in a similar way. Thus, the IFIH1 rs1990760 Tallele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-alpha signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo. The Journal of Immunology, 2011, 187: 1298-1303.

• 出版日期2011-8-1