Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy.
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.
Shimazaki
Atsuyuki
A
SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Kawamura
Yoshihiro
Y
Kanazawa
Akio
A
Sekine
Akihiro
A
Saito
Susumu
S
Tsunoda
Tatsuhiko
T
Koya
Daisuke
D
Babazono
Tetsuya
T
Tanaka
Yasushi
Y
Matsuda
Masafumi
M
Kawai
Koichi
K
Iiizumi
Tomohiro
T
Imanishi
Masahito
M
Shinosaki
Toshihiro
T
Yanagimoto
Toru
T
Ikeda
Minoru
M
Omachi
Shigeki
S
Kashiwagi
Atsunori
A
Kaku
Kohei
K
Iwamoto
Yasuhiko
Y
Kawamori
Ryuzou
R
Kikkawa
Ryuichi
R
Nakajima
Masatoshi
M
Nakamura
Yusuke
Y
Maeda
Shiro
S
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D020641:Polymorphism, Single Nucleotide; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human; D016326:Extracellular Matrix Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020782:Matrix Metalloproteinases