Genetic variations in the gene encoding ELM01 are associated with susceptibility to diabetic nephropathy
Genetic variations in the gene encoding ELM01 are associated with susceptibility to diabetic nephropathy
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DOI：
10.2337/diabetes.54.4.1171
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Maeda, S
中科院分区：
文献类型：
--
作者：
Shimazaki, A;Kawamura, Y;Maeda, S
为了寻找赋予糖尿病肾病（DN）易感性的基因，我们对日本患者中超过80，000个基于基因的单核苷酸多态性（SNP）进行了基因分型，并确定了吞噬和细胞运动1基因（ELMO 1）是赋予DN易感性的可能候选者，因为该基因中的SNP与该疾病显著相关（内含子18+9170，GG vs. GA+AA，x（2）= 19.9，P = 0.000008;比值比2.67，95% CI 1.71-4.16）。原位杂交（ISH）使用正常和糖尿病小鼠的肾脏显示，ELMO 1的表达是微弱的检测主要在正常小鼠肾脏的肾小管和肾小球上皮细胞，并在糖尿病小鼠的肾脏明显升高。随后的体外分析显示，与正常葡萄糖条件下培养的细胞（5.5 mmol/l）相比，在高葡萄糖条件下培养的细胞（25 mmol/l）中ELMO 1表达升高。此外，我们发现，细胞外基质蛋白基因的表达，如1型胶原和纤连蛋白，在过表达ELMO 1的细胞中增加，而基质金属蛋白酶的表达减少。这些结果表明，ELMO 1是一个新的候选基因，既赋予糖尿病肾病的易感性，并在这种疾病的发展和进展中发挥重要作用。
To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 genebased single nucleotide polymorphisms (SNPs) in Japanese patients and identified that the engulfinent 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, x(2) = 19.9, P = 0.000008; odds ratio 2.67, 95% Cl 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.