Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes
Introduction
Type 1 diabetes is an autoimmune disease characterized by T-cell mediated destruction of pancreatic β-cells. A variety of environmental and genetic factors are involved in the development of the disease. Most important genetic determinants are polymorphisms in the HLA region (IDDM1) on chromosome 6p21, estimated to account for 40–50% of the inheritable diabetes risk [1]. However, more than 20 putative non-HLA genes, including a VNTR in the 5′ region of the insulin gene (IDDM2) and the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene (IDDM12), have been identified by linkage and association studies [2], [3]. From mouse and human studies, there are evidences that the genes causing type 1 diabetes might be acting epistatically [4], [5], [6], [7].
The cytokine interleukin-18 (IL-18), a member of the IL-1 superfamily, elicits several biological activities that initiate and promote host defense and inflammation following infection or injury [8], [9]. IL-18, which is mainly produced by activated macrophages and dendritic cells, has the ability (i) to stimulate IFN-γ production in established Th1 cells; (ii) to augment T- and natural killer-cell cytotoxicity through upregulation of Fas ligand; (iii) to enhance perforin-mediated killing, and (iv) to induce proinflammatory cytokines and chemokines. It has been reported that increased production of IL-18 was observed in the acute phase of experimental autoimmune encephalomyelitis (EAE) [10]and antibodies to IL-18 were able to prevent EAE in Lewis rats [11]. A rise in IL-18 also preceded development of the acute phase of diabetes in the NOD mouse [12]and human type 1 diabetes [13]. Indeed mRNA for IL-18 was increased in the pancreas of NOD mice after induction of diabetes by cyclophosphamide, suggesting that IL-18 could be a diabetogenic molecule in these animals [12], [14]. The importance of IL-18 for the occurrence of type 1 diabetes is underscored by the observation that the murine IL-18 gene maps to an interval on chromosome 9 in the vicinity of the diabetes susceptibility gene from the NOD mouse, Idd2 [14]. Several polymorphisms in the promoter region of human IL-18 gene, located at chromosome 11q22.2–q22.3, have been identified [15]. Recently, Kretowski and coworkers reported the role of IL-18 gene polymorphism in the predisposition to type 1 diabetes in Polish population [16]. In this study, we conducted the case-control study to clarify the association of IL-18 gene polymorphism with susceptibility to or clinical presentation of type 1 diabetes in Japanese population. Furthermore, genetic interactions between IL-18 gene and HLA class II gene and CTLA-4 gene were also investigated.
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Patients
A total of 116 Japanese unrelated patients with type 1 diabetes (55 men and 61 women; median onset age 22.0 years; range, 1.0 to 66.0) and 114 Japanese healthy control subjects (61 men and 53 women; median age 30.0 years; range, 10.0 to 54.0) with no family history of diabetes were studied after giving informed consent, and protocol was approved by the Institutional Review Board of the Nagasaki University School of Medicine. The diagnosis of type 1 diabetes was based on the criteria of the
IL-18 gene polymorphisms in patients with type 1 diabetes and healthy control subjects
The allele frequencies of –607C and –137G were 53.4% and 87.9%, respectively, in 116 patients with type 1 diabetes, which were similar to those observed in 114 healthy control subjects (Table 1). However, the distribution of genotypes on the polymorphism at position –607, but not those at position –137, was significantly different between patients with type 1 diabetes and healthy controls (χ2=7.54, df=2, P=0.023). Genotypic frequencies of these SNPs in healthy control subjects were
Discussion
In the present study we demonstrated that the IL-18 gene polymorphism is associated with the susceptibility to type 1 diabetes. IL-18 is a pleiotropic proinflammatory cytokine that plays a pivotal part in the generation of Th1 cytokine responses through its ability to up-regulate IFN-γ production and IL-12-driven Th1 phenotype polarization [8], [9]. It has been reported that the serum IL-18 level was elevated in subclinical stage of type 1 diabetes in anti-islet autoantibody-positive relatives
Acknowledgements
We thank Ms Ayako Kaneko for her skilful technical assistance. This work was supported by a grant from the Japan Study Group for Pediatric and Adolescent Diabetes.
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2013, CytokineCitation Excerpt :Kretowski et al. [11], in a Polish population, described that the −137GC genotypes in combination with −607AA gene was associated with susceptibility to T1D, but noted an increase in the frequency of −137C allele in T1D patients. In Chinese Han and Japanese populations the −607C alleles and −607CA genotype, respectively, and the haplotypes −607C/−137G were more frequently in T1D patients [12,13]. These data are according with the present report.