Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis.
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 t...
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doaj-b0a35b4198304640bf25761b2bf70b962020-11-25T01:04:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01122e017119310.1371/journal.pone.0171193Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis.Melissa E MunroeNathan PezantMichael A BrownDustin A FifeJoel M GuthridgeJennifer A KellyGraham WileyPatrick M GaffneyJudith A JamesCourtney G MontgomeryAntiviral 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.http://europepmc.org/articles/PMC5325200?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Melissa E Munroe Nathan Pezant Michael A Brown Dustin A Fife Joel M Guthridge Jennifer A Kelly Graham Wiley Patrick M Gaffney Judith A James Courtney G Montgomery |
spellingShingle |
Melissa E Munroe Nathan Pezant Michael A Brown Dustin A Fife Joel M Guthridge Jennifer A Kelly Graham Wiley Patrick M Gaffney Judith A James Courtney G Montgomery Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. PLoS ONE |
author_facet |
Melissa E Munroe Nathan Pezant Michael A Brown Dustin A Fife Joel M Guthridge Jennifer A Kelly Graham Wiley Patrick M Gaffney Judith A James Courtney G Montgomery |
author_sort |
Melissa E Munroe |
title |
Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. |
title_short |
Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. |
title_full |
Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. |
title_fullStr |
Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. |
title_full_unstemmed |
Association of IFIH1 and pro-inflammatory mediators: Potential new clues in SLE-associated pathogenesis. |
title_sort |
association of ifih1 and pro-inflammatory mediators: potential new clues in sle-associated pathogenesis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2017-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5325200?pdf=render |
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