Serum IL-37 levels are elevated in Iraqi women with rheumatoid arthritis and IL37 missense variants (rs3811046 and rs3811047) are associated with disease susceptibility

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disorder, in which anti-inflammatory cytokines are proposed to play a key mediating role. Interleukin (IL)-37, a recently assigned anti-inflammatory member of IL-1 cytokine family, has been linked to RA pathogenesis. Interestingly, two IL37 missense single nucleotide polymorphisms (SNPs: rs3811046 G > T and rs3811047 A > G) have been suggested to influence susceptibility to some inflammatory and autoimmune disorders, while their relationship to RA risk has not been well defined. Therefore, 120 Iraqi females with RA and 110 control females were enrolled in a case–control study to explore IL-37 role in RA etiopathogenesis in terms of serum levels and two polymorphisms (rs3811046 and rs3811047). IL-37 concentrations were quantified using an ELISA kit, while SNPs were genotyped using a method based on real-time PCR principles. IL-37 concentrations were presented as median and interquartile range (25–75%), and significant differences were assessed using Mann–Whitney U test or Kruskal–Wallis test (for comparison between two or more groups, respectively). SNP-disease association analysis was presented using odds ratio (OR) and 95% confidence interval (CI). Results Patients showed significantly higher IL-37 concentrations compared to controls (88.8 [79.1‑100.0] vs . 59.5 [44.1‑78.6] ng/L; probability [ p ] < 0.001), and IL-37 showed a reliable discriminatory area under the curve of 0.758 (95% CI = 0.691–0.826; p < 0.001) as demonstrated by receiver operating characteristic curve analysis. Association analysis disclosed that T (rs3811046) and G (rs3811047) alleles, as well as homozygous genotypes (TT and GG, respectively), were significantly linked to a lower RA susceptibility (OR [95% CI] = 0.52 [0.36‑0.76], 0.37 [0.24‑0.55], 0.30 [0.14‑0.64], and 0.15 [0.06‑0.38]; adjusted p = 0.005, 0.001, 0.01, and 0.001, respectively). Additionally, G-A and T-G haplotypes (rs3811046-rs3811047) were associated with higher (OR [95% CI] = 2.72 [1.64‑4.51]; adjusted p = 0.001) and lower (OR [95% CI] = 0.41 [0.28‑0.60]; adjusted p = 0.001) risk of developing RA, respectively. IL-37 levels were not significantly affected by SNP genotypes or laboratory and clinical variables of RA. Conclusions IL-37 concentrations were up-regulated in RA patients. Additionally, IL37 missense variants (rs3811046 and rss3811047) were associated with RA susceptibility in Iraqi females.