Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

Abstract

Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.

Cytokines of the Immune System

“…The results showed that allelic combination (haplotype) consisting of rs2069762A-rs6822844T-rs6835457G-rs907715T was associated with systemic sclerosis and limited cutaneous systemic sclerosis subtype. 42 An association between IL2 and IgE-mediated allergy, asthma, and atopic eczema, has been mapped to the IL2 gene (but not IL15). Using 235 families to study the genetic predisposition to these diseases, two SNPs in the IL2 gene were found significantly linked, and one of them (rs2069762), located in the IL2 promoter, influences the level of IL-2 expression.…”

Association of IL-21 polymorphisms (rs907715, rs2221903) with susceptibility to multiple autoimmune diseases: A meta-analysis

“…(3) genotype frequencies in cases and controls were both available for estimating an odds ratios (OR) and their 95% confidence interval (CI); (4) studies that included ADs that were diagnosed according to the respective classification criteria [6][7][8][9][21][22][23][24][25]; (5) the papers should be published with full-text articles. The exclusion criteria included: (1) studies that contained overlapping data with other literatures;…”

“…Genotype distributions of the SNPs in the control groups were consistent with HWE, with the exception of one study [24]. The ethnicities encompassed in qualified studies were stratified into Caucasian, African-American, and Asian populations [6][7][8][9][21][22][23][24][25]. The ADs studied in the articles included SLE [6,21,22], GD [8,24], HT [24], RA [7,23], SSc [9], and Uveitis [25].…”

“…Published data indicated that interleukin-21 (IL-21) gene variants might predispose to multiple ADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), Grave's disease (GD), systemic sclerosis (SSc), and inflammatory bowel disease (IBD) [6][7][8][9][10][11], etc. In humans, the gene encoding IL-21 is located on chromosome 4q26-q27, which consists of 5 exons spanning approximately 8.44 kb of genomic DNA.…”

“…Many case-control studies have been conducted to evaluate associations between IL-21 rs907715 and rs2221903 polymorphisms and multiple ADs, including SLE [6,21,22], RA [7,23], GD [8,24], Hashimoto's thyroiditis (HT) [24], multiple sclerosis (MS) [9], uveitis [25]. However, the results were controversial and inconsistent.…”