The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis

Abstract

Regulatory T cells (T regs ) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor a (IL2RA) is an important T reg marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P FDR ¼ 2.07 Â 10 À4 , odds ratio ¼ 1.30 (1.14 -1.47)). The associations of rs11594656 and rs12722495 were lost

Unraveling the genetic component of systemic sclerosis

“…This variant is a non-synonymous polymorphism in exon 3 which aVects the structure of the protein and is the most likely causal variant for the association of this gene with SLE (Carmona et al 2011). This study showed signiWcant association of this SNP with SSc and lcSSc, and a trend of association with the ACA positive subgroup of patients (Carmona et al 2011).…”

Genetic Basis of Alopecia Areata

“…The IL-2-receptor α (IL2RA or CD25) is an important regulatory T cell marker, and genetic polymorphisms of IL2RA gene are associated with a number of autoimmune diseases, such as T1D, MS, GD, SLE, RA, systemic sclerosis and now AA (17, 53–57). Regulatory T cells function to maintain the immune tolerance and have been reported to have an important role in several autoimmune diseases.…”

Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis–Associated Genetic and Environmental Factors

“…Using LMM model assuming an additive genetic model, we found several genetic loci with SNPs significantly associated with expression of the ECM genes in this cohort (Table 2). Among them, three previously reported SSc loci including multiple SNPs of TNFAIP3 (6q23) (10, 37), IL2RA (10p15-p14) (15) and ITGAM (16p11.2) (12, 38) showed strong associations with the expression of MMP1 and/or MMP3 of the fibroblasts in responses to dosage-dependent and/or time-course stimulations of silica particles (Table 2). SNPs of CASC9 (8q21.11), intergenic region between LINC00284 and SMIM2-AS1 (13q14.11), FGFR1OP (6q27) and THADA (2p21) also showed associations with the expression of specific ECM genes of the fibroblasts (Table 2), but these genes have not been reported as SSc-associated.…”

“…IL2RA stands for interleukin 2 receptor α. IL2RA is involved in various pathways that help control the differentiation of effector cells, T-cell proliferation, and immune tolerance (48). A meta-analysis study with a large Caucasian European cohort revealed an association between rs2104286 of IL2RA and ACA positive SSc patients (15). LD analysis using the SNAP software showed that MMP1/MMP3 expression associated rs41290329 was in complete LD with rs2104286 (D’ = 1), but in low LD as measured by r 2 (=0.06), due to the disparate MAFs of the two SNPs (0.013 and 0.225 in the 1000 Genomes CEU population, respectively).…”