Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population
Introduction
Behcet's disease (BD) is a multi-systemic, chronic relapsing inflammatory disorder characterized by recurrent ulcerations of the oral cavity and genitalia as well as ocular inflammation. Other organ involvement such as the skin, joints, blood vessels, gastrointestinal tract, and central nervous system may occur concurrently. This disease is predominantly found in East Asia and in the Mediterranean countries and is relatively uncommon in the United States and Northern Europe (Dilsen, 1996, James, 1979). Although epidemiologic studies have shown that the development of the disease might be attributable to both genetic and environmental factors, the exact etiology has yet to be fully identified (Sakane et al., 1999). The disease can be classified as “intestinal BD” when patients with BD present with gastrointestinal symptoms and show typical intestinal ulcerations (Baba et al., 1976, Kasahara et al., 1981). While the prevalence of intestinal BD varies from 3 to 16% of all patients with BD by area, it appears to be more prevalent in East Asian countries (Kobayashi et al., 2007). The most frequent clinical symptom of intestinal BD is abdominal pain, followed by bleeding and diarrhea (Cheon et al., 2009). The most common site of involvement in the gastrointestinal tract is the ileocecal area, and lesions typically appear as ovoid-shaped deep ulcers with discrete borders (Lee et al., 2001, Sakane et al., 1999). Because of its scarcity and the lack of clinical evidence, it has been a great challenge for clinicians to make an accurate diagnosis of intestinal BD. Given the chronologic delay in systemic manifestations of BD, we have argued that the patients who do not fully satisfy the diagnostic criteria of systemic BD should be included in the category of intestinal BD patients when typical intestinal lesions are identified, and we have reported previously regarding this issue (Cheon et al., 2009, Shin et al., 2010).
The cytokines IL-23 and IL-17 are essential inflammatory mediators of various autoimmune pathologies such as multiple sclerosis, rheumatoid arthritis (RA), psoriasis, and Crohn's disease (CD). IL-23 is produced mainly by antigen-presenting dendritic cells and macrophages. IL-23 drives and promotes the development of a unique T-helper cell population (Th17 cells) that produces IL-17. These IL-23-driven Th17 cells are highly pathogenic and elicit IL-17-dependent inflammation in autoimmune diseases (Langrish et al., 2005). This effect of IL-23 is mediated through the IL-23 receptor (IL-23R), which is a heterodimer of the IL-12RB1 subunit. IL-17 is a pleiotropic inflammatory cytokine that plays a pivotal role in a variety of pathologic conditions by inducing numerous inflammatory molecules and the recruitment of neutrophils (Kolls and Linden, 2004). IL-17 expression is increased in patients with CD, ulcerative colitis (UC), RA, asthma, and BD compared to healthy individuals (Chabaud et al., 1999, Fujino et al., 2003, Hamzaoui et al., 2002, Linden, 2001, Lubberts et al., 2001, Zhang et al., 2006). In addition, serum IL-17A levels increase in active BD patients, suggesting that Th17 and IL-17 pathway has an important role in acute attacks of the disease (Ekinci et al., 2010). The signal transducer and activator of transcription 4 (STAT4) protein regulates the immune response by transmitting signals activated in response to several cytokines such as IFN, IL-12, and IL-23 (Watford et al., 2004). Furthermore, STAT4 is essential for the expansion of Th17 cells activated by IL-23, which perpetuates chronic inflammation in adaptive and innate immune responses and contributes to the development of many autoimmune diseases (Mathur et al., 2007). Taken together, it can be postulated that interactions among IL17, IL23R, and STAT4 variants may be involved in the pathogenesis of autoimmune diseases such as BD.
Recently, genome-wide association (GWA) studies have revealed that variants in IL10 and IL23R-IL12RB2 are associated with BD (Mizuki et al., 2010, Remmers et al., 2010). Other studies have also identified a strong relationship between polymorphisms of IL23R and IL17 and BD (Jang et al., 2008, Jiang et al., 2010). However, to the best of our knowledge, no studies on genetic variants in intestinal BD have been conducted to date. Therefore, our aim in this study was to evaluate the association between polymorphisms of IL17A, IL23R, and STAT4 genes and susceptibility to intestinal BD in the Korean population. Furthermore, we assessed the relationships between these genetic variants and disease phenotypes.
Section snippets
Subject population
A total of 400 unrelated Korean subjects (intestinal BD, 141; healthy controls, 259) were enrolled consecutively in this study. All patients were diagnosed at Severance Hospital, Yonsei University, Seoul, Korea. The diagnosis of intestinal BD was based on a combination of clinical criteria for the diagnosis of systemic BD and the identification of intestinal ulcerations by endoscopy or radiographic imaging (Baba et al., 1976, Kobayashi et al., 2007, Lee et al., 2001). To be included in this
Association of IL17A, IL23R, and STAT4 polymorphisms with intestinal BD susceptibility
The distributions of the genotypes of SNPs in IL17A, IL23R, and STAT4 among patients and controls are presented in Table 2. The genotype distributions of all SNPs among the controls were in HWE. IL17A rs8193036 was associated with a significantly increased risk of intestinal BD under a recessive model for the variant T allele (OR 2.10, 95% CI 1.12–3.92, p = 0.021). Among the SNPs in IL23R, rs1884444 was associated with a significantly decreased risk of intestinal BD under a recessive model for
Discussion
IL17-producing Th17 cells, a novel T cell population, play a major role in autoimmunity. Th17 cell differentiation from naïve CD4+ T cells is facilitated by various cytokines, including IL–1ß, IL-6, IL-21, and IL-23 (Aggarwal et al., 2003, Bettelli et al., 2006). A critical feature of Th17 cells is the expression of IL-17A and IL-17F. The association between IL-17F genetic polymorphisms and autoimmune diseases has been extensively evaluated in various ethnic populations (Chen et al., 2009,
Conclusions
Our results indicate that the joint effect of SNPs of IL17A, IL23R, and STAT4 may modulate susceptibility to intestinal BD in the Korean population, suggesting a potential significance of the IL-17/23 axis in the pathogenesis of intestinal BD.
Conflict of interest statement
The authors declare no conflict of interest.
Acknowledgements
This research was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-331-E00105), a grant from the Korea Healthcare Technology R&D Project (A080588), the Ministry for Health, Welfare & Family Affairs, Republic of Korea, a grant from the 2009 Good Health R&D Project, Ministry of Health and Welfare, Republic of Korea (A084943), and the Basic Science Research Program through the National Research Foundation of Korea
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