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Association Study of MAFA and MAFB Genes Related to Organ-Specific Autoimmunity, with Susceptibility to Type-1 Diabetes in Japanese and Caucasian Populations

Shinsuke Noso, Yumiko Kawabata, Naru Babaya, Yoshihisa Hiromine, Eiji Kawasaki, Takuya Awata, Taro Maruyama, Sunanda Babu, Naoki Oiso, Akira Kawada, Tamio Suzuki, George S Eisenbarth and Hiroshi Ikegami

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] (pA) 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.