Abstract
IntroductionInterleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case–control study based on Chinese Han population.MethodsA three-stage case–control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model.ResultsIn the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (Phet = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype.ConclusionThe CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA.
Highlights
Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA)
When we divided the RA patients into different subgroups by anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) status, the results showed that the CC genotype of rs7044343 was associated with RA patients without
A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% confidence interval (CI), 0.67 to -0.89)
Summary
Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial joints without precisely known pathogenesis. Current genome-wide association studies (GWASs) have identified 46 genetic loci, such as HLA, PTPN22, and CTLA4 associated with RA [2]; the identified risk loci of RA have modest effect sizes (odds ratios in Interleukin (IL)-33 was recently identified as a member of the IL-1 family and a ligand for the IL-1 family receptor ST2 [4]. The level of IL-33 was elevated in both serum and synovial fluid and associated with autoantibody production, bone erosion, and interstitial lung disease [6,7]. IL-33 could exacerbate collagen-induced arthritis (CIA) and elevate the production of proinflammatory cytokines and anticollagen
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