title: Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy.
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, 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.
authors.affiliation: SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Shimazaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Akio
authors.initials: A
authors.lastname: Kanazawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Babazono
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iiizumi
authors.forename: Masahito
authors.initials: M
authors.lastname: Imanishi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shinosaki
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagimoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikeda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Omachi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Ryuzou
authors.initials: R
authors.lastname: Kawamori
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kikkawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nakajima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Shiro
authors.initials: S
authors.lastname: Maeda
mesh_terms: 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
chemical_list: 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