Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis

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dc.contributor.authorMelissa E. Munroe
dc.contributor.authorNathan Pezant
dc.contributor.authorMichael A. Brown
dc.contributor.authorDustin A. Fife
dc.contributor.authorJoel M. Guthridge
dc.contributor.authorJennifer A. Kelly
dc.contributor.authorGraham Wiley
dc.contributor.authorPatrick M. Gaffney
dc.contributor.authorJudith A. James
dc.contributor.authorCourtney G. Montgomery
dc.date.accessioned2017-04-10T23:19:02Z
dc.date.available2017-04-10T23:19:02Z
dc.date.issued2017-02-24
dc.descriptionThis study was supported by the National Institute of Allergy, Immunology and Infectious Diseases, Office of Research on Women’s Health, National Institute of General Medical Sciences, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases under award numbers U01AI101934, R01AI024717, U19AI082714, U54GM104938, P30GM103510, P30GM110766, P30AR053483, RC1AR058554, U34AR067392, and HHSN266200500026C. This publication is the sole responsibility of the authors and does not represent the views of the National Institutes of Health.en_US
dc.descriptionen_US
dc.description.abstractAntiviral 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.en_US
dc.description.peerreviewYesen_US
dc.description.peerreviewnoteshttp://www.plosone.org/static/editorial#peeren_US
dc.identifier.citationMunroe ME, Pezant N, Brown MA, Fife DA, Guthridge JM, Kelly JA, et al. (2017) Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. PLoS ONE 12(2): e0171193. doi:10.1371/journal.pone.0171193en_US
dc.identifier.doi10.1371/journal.pone.0171193en_US
dc.identifier.urihttp://hdl.handle.net/11244/50425
dc.language.isoen_USen_US
dc.publisherPLos One
dc.relation.ispartofseriesPLoS ONE 12(2): e0171193
dc.relation.urihttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0171193
dc.rightsAttribution 3.0 United States
dc.rights.requestablefalseen_US
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.subjectSystemic lupus erythematosus,Autoantibodies,Human genetics,Exon mapping,Genetics of disease,Inflammatory diseases,Mouse models,Pathogenesisen_US
dc.titleAssociation of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesisen_US
dc.typeResearch Articleen_US

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