The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus

Highlights

• IL-21 gene rs2055979 C/A polymorphism was significantly associated with SLE.

• There were significant differences in the sIL-21 levels between SLE and controls.

• We found that TTA haplotype was associated with a significantly increased risk of SLE.

• IL-21 gene polymorphism may affect the levels of sIL-21 in patients with SLE.

Abstract

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Interleukin-21 (IL-21) is the most recently discovered member of the type-I cytokine family, which has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. Previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and SLE. Variations in the DNA sequence in the IL-21 gene may lead to altered IL-21 production and/or activity, and thus this can modulate an individual's susceptibility to SLE. To test this hypothesis, we investigated the association of the IL-21 polymorphisms and its serum levels with the risk of SLE in a Chinese population. We analyzed three single nucleotide polymorphisms of IL-21 gene rs907715 C/T, rs2221903 T/C and rs2055979 C/A in 175 patients with SLE and 190 age- and sex-matched controls, using Snapshot SNP genotyping assays and DNA sequencing method. Soluble IL-21 (sIL-21) levels were measured by ELISA. There were significant differences in the genotype and allele frequencies of IL-21 gene rs2055979 C/A polymorphism between the group of patients with SLE and the control group (P < 0.05). sIL-21 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the IL-21 rs2055979 A variant allele were associated with increased IL-21 levels compared to the homozygous wild-type genotype in patients with SLE. The rs2055979 C/A polymorphism of IL-21 and its sIL-21 levels were associated with SLE in the Chinese population. Our data suggests that IL-21 gene may play a role in the development of SLE.

Introduction

Many factors have been proposed in the pathogenesis of systemic lupus erythematosus (SLE), such as genetic factors, environmental factors, hormonal action, viruses and dysregulation of cytokine production. The etiology and pathogenetic mechanisms of SLE have not been clearly elucidated. Genetic factors seem to play a significant role in the susceptibility to SLE. However, familial aggregation and a higher rate of concordance for SLE in monozygotic than in dizygotic twins provide strong support for the role of genetic factors in the pathogenesis of this disorder (Costa-Reis and Sullivan, 2013, Grennan et al., 1997, Shai et al., 1999). Subjects who have a first-degree relative with SLE are over six times more likely to develop the disease than those without such relatives (Bengtsson et al., 2002). Association studies have shown a genetic association with cytokine network (Asano et al., 2013, Wang et al., 2013, Warchoł et al., 2011). Moreover, the unbalanced cytokine regulation which contributed to the pathogenesis of SLE development has been investigated. A number of cytokines which were associated with the pathogenesis of SLE including interleukin-12 (IL-12), IL-17, IL-27, IL-10 and tumor necrosis factor-a (TNF-a) have been reported (Duarte et al., 2013, Qiu et al., 2013, Robak et al., 2013, Smiljanovic et al., 2012, Sun et al., 2012).

Interleukin-21 (IL-21) is a novel four helix bundle class I cytokine produced endogenously by activated CD4 + T cells, natural killer T (NKT) cells and T helper (Th) cells (Coquet et al., 2007, Monteleone et al., 2009, Parrish-Novak et al., 2000). IL-21 exerts a variety of effects on the immune system and has an important role in B cell responsiveness, proliferation, plasma cell differentiation, and immunoglobulin production (Kuchen et al., 2007, Ozaki et al., 2004). Furthermore, IL-21 is involved in Th17 cell differentiation (Yang et al., 2008) and modulates the function of both dendritic cells and NK cells (Maeda et al., 2007). More recently, it has been demonstrated that IL-21 not only regulates normal lymphoid development and function, but also has crucial roles in pathological responses, including allergy and autoimmunity (Spolski and Leonard, 2008). Animal studies of SLE have indicated that IL-21 is important in the pathogenesis of murine lupus. SLE patients have higher serum levels of IL-21 than healthy controls. Moreover, association of IL-21 and IL-21R polymorphisms with susceptibility to SLE has been reported (Sawalha et al., 2008, Webb et al., 2009). All these evidences indicate that IL-21 may represent a novel target for the treatment of SLE.

The gene encoding IL-21 is located on chromosome 4q26–q27 in humans, which consists of 5 exons spanning approximately 8.44 kb of genomic DNA. Recently, a number of polymorphisms in the gene encoding IL-21 have been identified and a relationship between the IL-21 gene polymorphisms and risk of different autoimmune and inflammatory diseases, such as multiple autoimmune diseases, Graves' disease and inflammatory bowel disease has been reported (Jia et al., 2011, Maiti et al., 2010, Márquez et al., 2009). However, very little data has examined the association between rs907715 C/T, rs2221903 T/C and rs2055979 C/A polymorphisms in IL-21 gene and SLE. Furthermore, the relationship between the IL-21 gene polymorphisms and the plasma level of IL-21 is unknown. In this study, we investigated the relationship of IL-21 gene rs907715 C/T, rs2221903 T/C and rs2055979 C/A polymorphisms and their IL-21 levels were associated with SLE in a Chinese population.