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Intronic Polymorphisms within TFAP2B Regulate Transcriptional Activity and Affect Adipocytokine Gene Expression in Differentiated Adipocytes

Laboratory for Diabetic Nephropathy (S.T., S.M.), SNP Research Center, Institute of Physical and Chemical Research, Kanagawa 230-0045, Japan; Department of Medicine, Metabolism and Endocrinology (Y.T., R.K.), School of Medicine, Juntendo University, Tokyo 113-8421, Japan; and Department of Internal Medicine (H.M., A.K.), Shiga University of Medical Science, Shiga 520-2192, Japan

Address all correspondence and requests for reprints to: Shiro Maeda, Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, 1–7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: smaeda{at}src.riken.jp.

We have identified a gene encoding transcription factor activating enhancer binding protein-2ß (TFAP2B) as a candidate for conferring susceptibility to type 2 diabetes. Although we have also found that TFAP2B was preferentially expressed in adipose cells in a differentiation-dependent manner, the mechanisms by which the gene and gene polymorphisms contribute to conferring susceptibility to the disease have not yet been elucidated. The aim of this study was to evaluate the impact of the polymorphisms within the TFAP2B gene on conferring susceptibility to type 2 diabetes. We identified that a 300-bp DNA fragment in intron 1 of TFAP2B had significant enhancer activity, and the variations of this region affected this enhancer activity in differentiated adipocytes. In an experiment using adenovirus vectors encoding TFAP2B, the expression of TNF- gene was shown to be elevated in the TFAP2B overexpressing cells compared with those in control cells. Furthermore, we demonstrated that the expression of TFAP2B was increased in the adipose tissues of subjects with the disease-susceptibility allele, and the plasma levels of TNF- and high sensitivity C-reactive peptide were significantly elevated in the patients with the disease-susceptibility allele. These results suggest that TFAP2B may contribute to the pathogenesis of type 2 diabetes through regulation of adipocytokine gene expression, and that TFAP2B may be a promising target for treatment or prevention of this disease.

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