|
埼玉医科大学雑誌 第30巻 第1号 (2003年1月) 29-36頁 ◇論文(図表を含む全文)は，PDFファイルとなっています． PDF (1.4 MB) 原 著 IL-4遺伝子プロモーター多型と1型糖尿病との関連 大久保 智子 埼玉医科大学第4内科学教室〔平成14年12月10日 受付〕 A Novel Polymorphism in the Promoter Region of the Interleukin-4 Gene and Association with Type 1 Diabetes Mellitus Tomoko Ohkubo (Fourth Department of Internal Medicine, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan) Interleukin-4 (IL-4), one of the key regulators of the Th1-Th2 balance, promotes the differentiation of CD4＋ helper lymphocytes into Th2 cells. It is assumed that the Th1 predominance over Th2 has an important role in the development organ-specific autoimmune diseases, such as type 1 diabetes and Hashimoto's thyroiditis. In the present study, therefore, we investigated the possible role of the IL-4 gene in type 1 diabetes and autoimmune thyroid disease. First, we screened for variations in the promoter region ( position−1,105 to＋38; ＋1＝translation start site) and exons of the IL-4 gene in 24 patients by PCR direct sequencing, and detected five polymorphisms: C(−589)T, C(−144)T, C(−33)T, A363T and A8411C. Among them, A363T and A8411C are located in introns and were not further analyzed. Genotyping of other polymorphisms were performed by PCR-RFLP on 114 patients with type 1 diabetes, 92 patients with Graves'disease, 57 patients with Hashimoto's thyroiditis and 221 control subjects. C(−144)T is a novel and relatively rare polymorphism, and it was revealed that the distribution of the C(−144)T genotypes was significantly different between type 1 diabetic patients and control subjects (p＝0.0035); the CT genotype was observed in six type 1 diabetic patients and one control subject, and the remainder were all CC genotype. The frequency of the CT genotype was also increased in patients with autoimmune thyroid disease compared to control subjects, but the difference was not significant. No significant difference was observed in the distribution of C(−589)T and C(−33)T genotypes between patients with type 1 diabetes or autoimmune thyroid disease and control subjects. Then, effects of the C(−144)T polymorphism on promoter activity of IL-4 gene were assessed by luciferase reporter gene assays. Transcriptional activity of the −144T allele, both stimulated and unstimulated, was significantly lower than that of the −144C allele. These data suggest that the C(−144)T polymorphism in the IL-4 gene reduces the IL-4 synthesis and contributes to the development of type 1 diabetes. Keywords: type 1 diabetes, interleukin-4 (IL-4), promoter, polymorphism, association J Saitama Med School 2003; 30:29-36 ( Received December 10, 2002)
|