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Diabetes 54:1171-1178, 2005
© 2005 by the American Diabetes Association, Inc.

Genetic Variations in the Gene Encoding ELMO1 Are Associated With Susceptibility to Diabetic Nephropathy

Atsuyuki Shimazaki1, Yoshihiro Kawamura1, Akio Kanazawa1, Akihiro Sekine1, Susumu Saito1, Tatsuhiko Tsunoda1, Daisuke Koya2, Tetsuya Babazono3, Yasushi Tanaka4, Masafumi Matsuda5, Koichi Kawai6, Tomohiro Iiizumi7, Masahito Imanishi8, Toshihiro Shinosaki9, Toru Yanagimoto9, Minoru Ikeda9, Shigeki Omachi9, Atsunori Kashiwagi2, Kohei Kaku5, Yasuhiko Iwamoto3, Ryuzou Kawamori4, Ryuichi Kikkawa2, Masatoshi Nakajima9, Yusuke Nakamura1,10, and Shiro Maeda1

1 SNP Research Center, The Institute of Physical and Chemical Research, Yokohama, Kanagawa, Japan
2 Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
3 Diabetes Center, Tokyo Women’s Medical University, Tokyo, Japan
4 Department of Medicine, Metabolism & Endocrinology, School of Medicine, Juntendo University, Tokyo, Japan
5 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
6 Kawai Clinic, Tsukuba, Ibaragi, Japan
7 Department of Internal Medicine, Toride Kyodo Hospital, Toride, Ibaragi, Japan
8 Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan
9 Discovery Research Laboratories, Shionogi Co. Ltd., Toyonaka, Osaka, Japan
10 Laboratory for Molecular Medicine, Human Genome Center, The Institute of Medical Science, University of Tokyo, Tokyo, Japan

To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 gene-based single nucleotide polymorphisms (SNPs) in Japanese patients and identified that the engulfment and cell motility 1 gene (ELMO1) was a likely candidate for conferring susceptibility to DN, in view of the significant association of an SNP in this gene with the disease (intron 18+9170, GG vs. GA+AA, {chi}2 = 19.9, P = 0.000008; odds ratio 2.67, 95% CI 1.71–4.16). In situ hybridization (ISH) using the kidney of normal and diabetic mice revealed that ELMO1 expression was weakly detectable mainly in tubular and glomerular epithelial cells in normal mouse kidney and was clearly elevated in the kidney of diabetic mice. Subsequent in vitro analysis revealed that ELMO1 expression was elevated in cells cultured under high glucose conditions (25 mmol/l) compared with cells cultured under normal glucose conditions (5.5 mmol/l). Furthermore, we identified that the expression of extracellular matrix protein genes, such as type 1 collagen and fibronectin, were increased in cells that overexpress ELMO1, whereas the expression of matrix metalloproteinases was decreased. These results indicate that ELMO1 is a novel candidate gene that both confers susceptibility to DN and plays an important role in the development and progression of this disease.

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


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