The Association Between Interleukin-23 Receptor Gene Polymorphisms and Systemic Lupus Erythematosus

Introduction

S ystemic lupus erythematosus (SLE), a chronic autoimmune disease, is related to many factors, such as genetic factors, ultraviolet radiation, levels of estrogen in the body, certain drugs, food, and infections. Many genes and susceptibility genes, including interleukin (IL)-18, IL-21, PTPN22, CD24, and IRF5, have been shown to be associated with an increased risk of developing SLE (Chung and Criswell, 2007; Sánchez et al., 2007a; Lee and Song, 2008; Sawalha et al., 2008; Hirankarn et al., 2009).

IL-23 affects interferon-γ (IFN-γ) production by T and natural killer cells, activates memory T cells, stimulates Th1-cell responses, and enhances inflammation through stimulating the production of proinflammatory cytokines (Oppmann et al., 2000; Trinchieri et al., 2003). IL-23 mediates these effects through a receptor that has one subunit in common with IL-12 and IL-12Rb1, and a unique subunit called IL-23 receptor (IL-23R). IL-23R is located on chromosome 1p31.3. Recently, many studies have reported the significant relationship between IL-23R polymorphisms and inflammatory bowel disease (IBD), ankylosing spondylitis, relapsing-remitting multiple sclerosis, psoriasis, Crohn's disease, Grave's ophthalmopathy, and rheumatoid arthritis (Cargill et al., 2007; Cummings et al., 2007; Ferguson et al., 2007; Faragó et al., 2008; Huber et al., 2008; Illes et al., 2008; Rahman et al., 2008). However, Sánchez et al. (2007a) and Kim et al. (2009) reported that IL-23R polymorphisms do not appear to play an important role in the susceptibility or severity of SLE in the Spanish and Korean populations. We examined the association between three IL-23R polymorphisms and the risk of SLE in a Chinese population.

Materials and Methods

Results

The genotype and allele frequencies of rs10889677, rs1884444, and rs7517847 polymorphisms between the controls and the cases are shown in Table 3. The frequencies of AA, AC, and CC genotypes of rs10889677 were 60.4%, 30.9%, and 8.6% in the cases and 56.0%, 39.9%, and 4.2% in the controls, respectively. The frequencies of A and C alleles of rs10889677 were 75.9% and 24.1% in the cases, which were similar to those in the controls. The frequencies of GG, GT, and TT genotypes of rs1884444 were 18.7%, 40.3%, and 41.0% in the cases and 16.1%, 43.5% and 40.5% in the controls, respectively. The frequencies of G and T alleles of rs1884444 were 38.8% and 61.2% in the cases and 37.8% and 62.2% in the controls, respectively. The frequencies of GG, GT, and TT of rs7517847 were 24.5%, 42.4%, and 33.1% in the cases and 20.2%, 47.0%, and 32.7% in the controls, respectively. The frequencies of G and T alleles of rs7517847 were 45.7% and 54.3% in the cases and 43.8% and 56.3% in the controls, respectively. No significant differences were observed in the genotype distributions and allele frequencies of the rs10889677, rs1884444, and rs7517847 polymorphisms between the cases and controls (for rs10889677: OR = 1.00, 95% CI = 0.69–1.45; for rs1884444: OR = 0.96, 95% CI = 0.69–1.33; and for rs7517847: OR = 0.93, 95% CI = 0.67–1.27).

Discussion

To our best knowledge, this is the first study to assess the correlation between IL-23R genetic polymorphisms and SLE in a Chinese population, and no significant differences were observed in our study. It is unlikely that the genetic polymorphisms of IL-23R affect the risk of incidence of SLE.

Many studies have shown that a variety of cytokines, such as IL-2, IL-10, and IL-18 are associated with SLE. For example, Lin et al. (2008) reported a significantly higher G allele frequency of IL-2 in SLE patients in Taiwan, suggesting that this polymorphism may be involved in the genetic background of Chinese SLE. Wu et al. (2003) described a novel association between RPl/RPl of the intron 3 and T/T homozygous carriage of the −159 polymorphism of the IL-4 gene and Chinese SLE patients with discoid rash in Taiwan. Rovin et al. (2002) reported that the polymorphism of IL-8-845C is associated with severe SLE in African-Americans. Polymorphisms of IL-18 have been found to be associated with SLE patients both in Singapore Chinese and Thai populations (Xu et al., 2007; Hirankarn et al., 2009). In contrast, Huang et al. (2006) have found that the polymorphisms of IL-6 and IL-8 were not associated with Chinese SLE patients in Taiwan, which is similar to the result found by Schotte et al. (2001). Schotte et al. pointed out that in Caucasian German patients with SLE, the IL-6 promoter polymorphism (−174G/C) does not contribute significantly to disease susceptibility. Polymorphisms located in IL-12B, IL-12RB1, and IL-23A genes may not play a relevant role in the susceptibility or severity of SLE in the Spanish population (Sánchez et al., 2005).

IL-23 can stimulate CD4⁺ T cell to produce IL-17 and IFN-γ, which is related to the development and maintenance of the disease process in SLE (Rönnblom et al., 2006). Moreover, it is known that IL-23 is a critical cytokine for pathogenesis of organ-specific autoimmune diseases, just like experimental autoimmune encephalomyelitis (Cua et al., 2003), IBD (Yen et al., 2006), rheumatoid arthritis (Faragó et al., 2008), but not for the developed lupus-like autoimmune disease in mice models (Dai et al., 2007). Therefore, it is possible that IL-23R may not play much important role in systemic inflammation.

In conclusion, we found that polymorphisms of IL-23R were not associated with SLE patients in a Chinese population. However, additional studies in larger number of SLE patients and in different populations are needed to better understand the factors contributing to the occurrence of SLE.