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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-?, 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.

SUBMITTER: Munroe ME

PROVIDER: S-EPMC5325200 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Munroe Melissa E ME Pezant Nathan N Brown Michael A MA Fife Dustin A DA Guthridge Joel M JM Kelly Jennifer A JA Wiley Graham G Gaffney Patrick M PM James Judith A JA Montgomery Courtney G CG

PloS one 20170224 2

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 ...[more]

PMID: 28234905

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Project description:Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. 114 top genes were differentially expressed in RT (p<0.001, fold change >2 or <0.5). Among these were down-regulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK). 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply down-regulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133 and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells demonstrated significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin dependent kinase inhibition, and trithorax/polycomb dysregulation. Keywords: Gene expression; rhabdoid tumor; pediatric renal tumors; neural crest The goal of this study is to identify genetic pathways that will clarify the nature of RT and enable the identification of therapeutic targets. Experimental Design: Frozen tissue samples were obtained from the Renal Tumor Bank of the Children's Oncology Group (COG). A total of 53 tumors were hybridized to Affymetrix U133A arrays and analyzed including 10 RT, 12 cellular mesoblastic nephromas (CMN), also known as infantile fibrosarcomas, 16 clear cell sarcomas of the kidney (CCSK) and 15 Wilms tumors (WT). Quality control steps taken: 1. Samples were snap frozen immediately following surgery and were mailed on dry ice to the Tumor Bank and retained at -80Â°C. 2. Frozen sections were evaluated histologically and tumors with less than 80% viable tumor cellularity were excluded. 3. Array images were assessed by eye to confirm scanner alignment and the absence of significant bubbles or scratches. 4. Samples for which the 3'/5' ratios for GAPDH were greater than 3.4 were excluded. 5. The BioB spike controls were confirmed as present 90% of the time; BioC, BioD and cre were confirmed as increasing intensity in all samples. 6. When scaled to a target intensity of 2500, scaling factors were between 13 and 52; background levels were 34-115: Raw Q values were 1.3-3.7 and mean intensities were within acceptable limits. 7. The range of percent present calls was from 30% to 52%. Statistical Analysis: Positional-dependent-nearest-neighbor model (PDNN) software was used to translate the scanned images into expression analysis files and to normalize the data across all arrays (http://odin.mdacc.tmc.edu/~zhangli/PerfectMatch/). To establish a broad list of probesets containing the majority of genes significant in the pathogenesis of RT, the expression of 10 RT was compared with the 43 other tumor types combined (non-RT) using the two-sample t-test, resulting in 2921 probesets with p-value <0.005 and false discovery rate of <1%. This data is provided in the attached supplementary file 'Supplemental Table 1'. To define probesets more uniquely expressed in RT, the gene expression of RT was compared with each of the other tumor types separately (CCSK, CMN, and WT) using the two-sample t-test, and genes present in each one of the resulting four comparisons (RT vs. CCSK, RT vs. CMN, RT vs. WT and RT vs non-RT) with a p-value of <0.001 are provided in the attached supplementary file 'Supplemental Table 2'. Lastly, the 766 genes differentially expressed between RT and non-RT (p<0.0001) were analyzed in PANTHER (Protein ANalysis THrough Evolutionary Relationships), and those groups within the biologic process category over-represented with a Bonferoni corrected p value<0.05 are listed in the attached file labelled âSupplemental Table 3â.

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

Publications

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

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