Genetic Variations in the Gene Encoding ELMO1 Are Associated With Susceptibility to Diabetic Nephropathy
Atsuyuki Shimazaki 1 ,
Yoshihiro Kawamura 1 ,
Akio Kanazawa 1 ,
Akihiro Sekine 1 ,
Susumu Saito 1 ,
Tatsuhiko Tsunoda 1 ,
Daisuke Koya 2 ,
Tetsuya Babazono 3 ,
Yasushi Tanaka 4 ,
Masafumi Matsuda 5 ,
Koichi Kawai 6 ,
Tomohiro Iiizumi 7 ,
Masahito Imanishi 8 ,
Toshihiro Shinosaki 9 ,
Toru Yanagimoto 9 ,
Minoru Ikeda 9 ,
Shigeki Omachi 9 ,
Atsunori Kashiwagi 2 ,
Kohei Kaku 5 ,
Yasuhiko Iwamoto 3 ,
Ryuzou Kawamori 4 ,
Ryuichi Kikkawa 2 ,
Masatoshi Nakajima 9 ,
Yusuke Nakamura 1 10 and
Shiro Maeda 1
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
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
Abstract
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, χ 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.
AER, albumin excretion rate
Alb/Cr, albumin-to-creatinine ratio
DIG, digoxigenine
DN, diabetic nephropathy
ISH, in situ hybridization
LD, linkage disequilibrium
MMP, matrix metalloproteinase
SNP, single nucleotide polymorphism
SSC, sodium chloride–sodium citrate
TGF, transforming growth factor
Footnotes
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
Accepted December 20, 2004.
Received November 11, 2004.
DIABETES...

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

10.2337/diabetes.54.4.1171