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Association of IFIH1 and pro-inflammatory mediators: Potential new clues in
SLE-associated pathogenesis
#MMPMID28234905
Munroe ME
; Pezant N
; Brown MA
; Fife DA
; Guthridge JM
; Kelly JA
; Wiley G
; Gaffney PM
; James JA
; Montgomery CG
PLoS One
2017[]; 12
(2
): e0171193
PMID28234905
show ga
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-?, IFN-?, 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.
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