Confirmation of an association between rs6822844 at the Il2–Il21 region and multiple autoimmune diseases: Evidence of a general susceptibility locus

Abstract

Objective. Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in nonEuropean populations, and to perform disease-specific and overall meta-analyses using data from previously published studies.Methods. We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies.Results. We detected significant associations of rs6822844 with SLE (P ‫؍‬ 0.008), type 1 DM (P ‫؍‬ 0.014), RA (P ‫؍‬ 0.019), and primary SS (P ‫؍‬ 0.033) but not with BD (P ‫؍‬ 0.34) or CD (P ‫؍‬ 0.98). We identified little evidence of population differentiation (F ST ‫؍‬ 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P meta ‫؍‬ 3.61 ؋ 10 ؊6 ), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (P meta ‫؍‬ 3.48 ؋ 10 Conclusion. Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Metaanalysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.Genetic susceptibility plays an important role in autoimmune diseases.

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

“…þ T-helper 17 (Th) 17 cells. Experimental data from murine studies suggested that the capacity of CD4…”

“…10 The IL-12 p40 subunit can also form heterodimers with p19 resulting in formation of IL-23. IL-23 is a key player in IL-17A-mediated inflammation, maintaining the expansion of human Th 17 cells. This function of IL-23 is mediated by the IL-23 receptor (IL-23R), which is composed of two subunits; the IL-23R subunit, encoded by the IL-23R gene, and the IL-12Rb1 subunit.…”

“…IL-21 is a pleiotropic inflammatory cytokine and the intergenic SNP rs6822844 (G to T substitution) has been associated with several autoimmune diseases including RA. 17 Given the role of IL-23 and IL-12 in Th 17 cell development, we hypothesized that genetic variations in IL-23R and IL-12 would influence the cytokine profile of Th 17 cells. The aim of this study was to investigate the relationships between genetic variants in IL-23R, IL-12B and IL-21 and related serum cytokine concentrations.…”

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

“…STAT4 polymorphism was also associated with SS (Nordmark et al, 2009;Korman et al, 2008;Gestermann et al, 2010;Palomino-Morales et al, 2010). MECP2 and IL2-IL21 polymorphisms have also been associated with SS (Cobb et al, 2010;Maiti et al, 2010). Gene polymorphisms in IL-10, IL-6, IL-1 receptor antagonist, IL-4 receptor , TNF-, IFN- and TGF-1 have also been associated with pSS (Cobb et al, 2008).…”

Generation and characterization of human anti-human IL-21 neutralizing monoclonal antibodies

“…[3][4][5][26][27][28][29] Polymorphisms in the IL-2/IL-21 and IL-21R loci have also been associated with multiple autoimmune disorders including RA, Type 1 diabetes, IBD and SLE. [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] The important role of IL-21 in promoting humoral immune responses suggest that neutralizing IL-21 activity might represent an effective therapeutic intervention for both systemic and organ-specific autoimmunity. 48 Indeed, blocking IL-21 activity has been shown to reduce disease symptoms in a variety of animal disease and xenograft models (ref.…”