Identification of type 2 diabetes mellitus susceptibility candidate genes in loci detected by QTL analysis of diabetic db mice,

我们之前绘制了4个主要的2型糖尿病（T2D）数量性状位点（qtl），它们影响BKS生成的F_2群体的T2D表型。Cg-m+ /+ Lepr^<db>与C3H或DBA2 （D2）交叉。为了确定T2D的疾病易感基因，我们使用同源小鼠绘制了该区域。我们的研究结果如下：1)将D2株的供体（db）小鼠与携带特定QTL基因组区域的受体小鼠进行重复回交，生成同源小鼠，检测各QTL对糖尿病表型的影响。在4个qtl中，D2小鼠的两个区域的渗渗与携带BKS等位基因的对照小鼠有显著差异。表型差异体现在体重、脂肪垫重量、空腹BG浓度和胰岛素水平（A区）；体重，脂肪垫重量和总胆固醇水平（B区）。2)从BKS/D2基因区衍生出16个（A区）和22个（B区）基因子系，为两个qtl的精细定位提供了便利。3)对1只基因小鼠的7个亚系进行分析，鉴定出3个Mb区域，影响体重，脂肪垫重量在A区域。对另一只基因小鼠的5个亚系的分析发现了8个Mb区域，该区域影响B区域的体重和脂肪垫重量。然而，我们无法绘制出与A区空腹BG浓度相关的区域。这些同源亚系为精细定位表型分配QTL区域提供了有力的工具。为了鉴定靶基因，我们的实验室正在对亚基因小鼠和对照小鼠的各种组织中的mRNA和蛋白表达进行分析。

We previously mapped four major quantitative trait loci (QTLs) for type 2 diabetes mellitus (T2D), which affect T2D phenotypes in F_2 populations generated from a BKS.Cg-m+ /+ Lepr^<db> and C3H or DBA2 (D2) intercross. To identify the disease-susceptibility genes of T2D, we mapped the region using congenic mice. Our findings are as follows ; 1) We generated congenic mice by repeated backcross of donor (db) mice to recipient mice of D2 strain carrying a given QTL-containing genome region to test the effect of each QTL on diabetic phenotypes. Out of four QTLs, introgression of two regions of D2 mice was significantly different from that of control mice carrying BKS alleles. Differences in phenotypes were replicated in body weight, fat pad weight, fasting BG concentrations, and insulin level (A region) ; body weight, fat pad weight, and total cholesterol level (B region). 2) We generated 16 (for A region) or 22 (for B region) congenic sub-lines derived from BKS/D2 congenic region for two QTLs to facilitate fine mapping. 3) Analyses of seven sub-lines in one congenic mouse identified the region of three Mb, which affects body weight, fat pad weight in A region. Analyses of five sub-lines in another congenic mouse revealed the region of eight Mb, which affects body weight and fat pad weight in B region. However, we could not map the region correlating fasting BG concentrations in A region. These congenic sub-lines offered a powerful tool for fine mapping phenotypes-assigned QTL region. To identify the target gene, mRNA and protein expression analyses in various tissues from subcongenic and control mice are under way in our laboratory.