Identification of susceptibility gene of diabetes mellitus by QTL analysis in the genetic modified mice

糖尿病是典型的“常见病”之一，是日本的一个重大公共卫生问题。2型糖尿病（T2D）是遗传因素和环境因素相互作用的结果。确定糖尿病的疾病易感基因具有重要意义。人类疾病的小鼠模型为分析人类疾病提供了一种强有力的方法。为了确定T2D的易感基因，我们对携带瘦素受体（BKS-db/+m）突变的db小鼠与C3H/HeJ （C3H）小鼠的788代F_2杂交进行了全基因组数量性状位点（QTL）分析。BKS-db/db小鼠（BKS-db/db）具有瘦素受体基因突变，是人类T2D的动物模型。测定其表型，包括体重、空腹血糖（BG）浓度、脂肪重量和腹腔内糖耐量试验。研究了全基因组203微卫星标记基因型与db纯合子组（F_2-db/db）和db杂合子组(F2 db/+m}和野生型组（f_2 -野生）基因型之间的相关性。Vie发现了18个与糖尿病相关表型（包括体重、脂肪体重和葡萄糖耐量）相关的qtl （Lod Score bbb2.8具有提示价值）。这些基因座也提供了人类糖尿病的易感性候选区域。基因小鼠的生产正在我们的实验室进行

Diabetes is one of the typical "common diseases" and a major public health problem in Japan. Type 2 diabetes mellitus (T2D) results from the interaction between "genetic" and "environmental" factors. It is very important to identify the disease-susceptibility genes of diabetes. Mouse models of human diseases offer a powerful method to analyze human diseases. To identify the susceptibility genes of T2D, we performed genome-wide quantitative trait loci (QTL) analysis in 788 F_2 intercross generation between db mice carrying a mutation of leptin receptor (BKS-db/+m) with C3H/HeJ (C3H) mice. db mouse (BKS-db/db) having a mutation in the leptin receptor gene, is an animal model for T2D in humansThe phenotypes, including body weight, fasting blood glucose (BG) concentrations, fat weight, and intraperitoneal glucose tolerance test were determined. Correlation between genotypes with the whole genome 203 microsatellite markers and these quantitative phenotypes, were examined in a diabetic group including those homozygous for db (F_2-db/db) and a non-diabetic group including those heterozygous (F2 db/+m} and wild type (F_2-wild) for db. Vie found 18 QTLs (Lod Score >2.8 of suggestive value} for diabetes-related phenotypes including body weight, fat weight, and glucose tolerance. These loci also provide the susceptibility candidate regions to diabetes in humans. Production of the congenic mice is under way in our laboratory