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

. 2011 Aug 1;187(3):1298-303.

doi: 10.4049/jimmunol.1100857. Epub 2011 Jun 24.

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

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

Talin Robinson et al. J Immunol. 2011.

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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Figures

FIGURE 1

FIGURE 1

Serum IFN-α activity in SLE patients stratified by rs1990760 genotype and anti-dsDNA autoantibodies. A, All patients in aggregate. B, Patients stratified by presence or absence of anti-dsDNA Abs. The line indicating the central tendency represents the median, the error bars show the interquartile range, and the p value was calculated using the Mann–Whitney U test.

FIGURE 2

FIGURE 2

Difference in IFIT1 and MX1 expression in reporter cells versus PBMCs stratified by IFIH1 genotype. Relative expression values were log10-transformed, and the relative expression of each transcript in reporter cells exposed to patient sera was subtracted from the relative expression of the same transcript in PBMCs from the same blood sample. A, IFIT1. B, MX1. Lines indicate the mean, and error bars show the SDs. Data were distributed normally, and the p value was calculated using an unpaired t test for the difference between CC and CT or TT genotypes.

FIGURE 3

FIGURE 3

IFN-β–induced gene expression in PBMCs versus serum IFN-β activity in anti-dsDNA–positive SLE patients. Patients were stratified by IFIH1 rs1990760 and STAT4 rs7574865 genotypes. T indicates carriage of the risk allele in each case (includes both heterozygous and homozygous risk allele genotypes). Data were log-transformed, and the lines shown are the result of linear regression in each genotype category. The p values were calculated by the sum-of-squares F test for a difference in the slope of the regression line between genotype categories.

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