Abstract
The transcriptional factor MAFA is specifically expressed in beta cells of pancreatic islets, and activates tissuespecific transcription of insulin. We previously reported that MAFA is also expressed in the thymus and regulates intrathymic expression of insulin in the mouse. In humans, we identified a functional polymorphism of MAFA, Gly346Cys, which was suggested to be associated with type 1 diabetes. This study aimed to validate the association of MAFA with type 1 diabetes in a larger number of subjects. In addition, molecular scanning of MAFB another member of the large MAFA transcription family, and an association study with type 1 diabetes were also performed. A total of 1733 subjects, including newly recruited Japanese (346 controls and 532 cases) and Caucasians (223 controls and 228 cases), were studied. In newly recruited Japanese subjects, the minor allele frequency of MAFAGly346Cys was lower in cases than in controls (2.9 vs. 5.1%, odds ratio [95%CI]: 0.56 [0.34-0.91], p=0.02). Meta-analysis with our previous data showed a significant association of MAFA with type 1 diabetes (summary odds ratio [95%CI]: 0.49 [0.32-0.76], p=0.0013). When cases were limited to subjects with a risk genotype of INS, the association was further strengthened (odds ratio [95%CI]: 0.47 [0.30-0.74], p=0.00097). In the Caucasian population, the difference in minor allele frequency of MAFA between cases and controls was not significant (6.4% vs. 5.4%, odds ratio [95%CI]: 1.14 [0.66-1.99], NS). When data from Japanese and Caucasians were combined, summary odds ratio was 0.68 [95%CI: 0.48-0.95] (p G and 618C>A) were identified, but neither was significantly associated with type 1 diabetes. In conclusion, MAFA Gly346Cys is associated with type 1 diabetes, especially in the Japanese population, which possesses the high-risk INS genotype.
Highlights
Type 1 diabetes is an organ-specific autoimmune disease against pancreatic islets, characterized by targeted destruction of insulinproducing beta cells by infiltrated lymphocytes in genetically susceptible individuals [1]
Meta-analysis of the 2nd panel with our previous data (1st panel, Supplementary Table 1) showed that the MAFAGly346Cys polymorphism was significantly associated with susceptibility to type 1 diabetes in the Japanese population (Table 4)
When the subjects were limited to type 1 diabetic patients with the risk genotype of INS (VNTR class I/I) as “high-risk type 1 diabetes”, the association was concentrated in the Japanese population with the high risk INS genotype (odds ratio [95%CI]: 0.47 [0.30-0.74], p=0.00097, p value for heterogeneity: p=0.15 (Table 5)
Summary
Type 1 diabetes is an organ-specific autoimmune disease against pancreatic islets, characterized by targeted destruction of insulinproducing beta cells by infiltrated lymphocytes in genetically susceptible individuals [1]. The functions of LYP (Lymphoid-specific tyrosine phosphatase: a protein of PTPN22) and CTLA4 are related to regulation of immune response in general, but not to beta-cell-specific autoimmune response as evidenced by association with multiple autoimmune diseases including Graves’ disease and Rheumatoid Arthritis (RA) [7,8]. In contrast to these immune-regulating genes, the insulin gene (INS), located at the IDDM2 locus on chromosome 11p15, is a unique susceptibility gene showing association with type 1 diabetes only, suggesting a function related to beta-cell-specific autoimmunity. Pugliese et al reported that a Variable Number of Tandem Repeats (VNTR) in the promoter region of INS is associated
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