title: Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-α and serologic autoimmunity in lupus patients.
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.
authors.affiliation: Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Talin
authors.initials: T
authors.lastname: Robinson
authors.forename: Silvia N
authors.initials: SN
authors.lastname: Kariuki
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Franek
authors.forename: Marissa
authors.initials: M
authors.lastname: Kumabe
authors.forename: Akaash A
authors.initials: AA
authors.lastname: Kumar
authors.forename: Maria
authors.initials: M
authors.lastname: Badaracco
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Mikolaitis
authors.forename: Galen
authors.initials: G
authors.lastname: Guerrero
authors.forename: Tammy O
authors.initials: TO
authors.lastname: Utset
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Drevlow
authors.forename: Laura S
authors.initials: LS
authors.lastname: Zaacks
authors.forename: James S
authors.initials: JS
authors.lastname: Grober
authors.forename: Lewis M
authors.initials: LM
authors.lastname: Cohen
authors.forename: Kyriakos A
authors.initials: KA
authors.lastname: Kirou
authors.forename: Mary K
authors.initials: MK
authors.lastname: Crow
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Jolly
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood*; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D016898:Interferon-alpha; D004247:DNA; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1