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Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis.

ABSTRACT: BACKGROUND:Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS. METHODS:Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex). RESULTS:Nine polymorphisms were associated with risk of AS (p??A (rs1800629), and?-?238 G?>?A (rs361525); TNFRSF1A -609 G?>?T (rs4149570), and PTPN22 1858 G?>?A (rs2476601)), b: the IL23/IL17 pathway (IL23R G?>?A (rs11209026), and IL18-137 G?>?C (rs187238)), or c: the NFkB pathway (TLR1 743 T?>?C (rs4833095), TLR4 T?>?C (rs1554973), and LY96-1625 C?>?G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T?>?C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p?=?0.04), and TNFRSF1A -609 G?>?T (rs4149570) (OR: 1.79, 95% CI: 1.31-2.41, p?=?0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G?>?A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p?=?0.0002) were associated with reduced risk of AS. CONCLUSION:We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-?, IL23/IL17, and NFkB pathways increase risk of AS.

SUBMITTER: Sode J

PROVIDER: S-EPMC6136164 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis.

Sode Jacob J Bank Steffen S Vogel Ulla U Andersen Paal Skytt PS Sørensen Signe Bek SB Bojesen Anders Bo AB Andersen Malene Rohr MR Brandslund Ivan I Dessau Ram Benny RB Hoffmann Hans Jürgen HJ Glintborg Bente B Hetland Merete Lund ML Locht Henning H Heegaard Niels Henrik NH Andersen Vibeke V

BMC medical genetics 20180912 1

<h4>Background</h4>Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS.<h4>Methods</h4>Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the D ...[more]

PMID: 30208882

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Dataset Information

Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis.

Publications

Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis.

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