title: Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis.
abstract: Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-β, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms.
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Munroe
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pezant
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.|Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Fife
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Graham
authors.initials: G
authors.lastname: Wiley
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.|Department of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.|Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Montgomery
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics*; D016899:Interferon-beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1