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

糖尿病db小鼠QTL分析检测位点2型糖尿病易感候选基因的鉴定，

基本信息

批准号：
16390265
负责人：
ITAKURA Mitsuo
金额：
$ 8.83万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

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.

本研究在BKS、Cg-m+ /+ Lepr^与C3 H或DBA 2（D2）杂交的F_2群体中定位了影响2型糖尿病（T2 D）表型的4个主要数量性状基因座（QTL）<db>。为了确定T2 D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）我们通过将供体（db）小鼠与携带给定的含有QTL的基因组区域的D2品系受体小鼠重复回交来产生同源小鼠，以测试每个QTL对糖尿病表型的影响。在4个QTL中，D2小鼠的两个区域的渐渗与携带BKS等位基因的对照小鼠存在显著差异。表型差异在体重、脂肪垫重量、空腹血糖浓度和胰岛素水平（A区）;体重、脂肪垫重量和总胆固醇水平（B区）中重复。2)为了便于精细定位，我们从BKS/D2同源区域中分别获得了16个（A区）和22个（B区）同源亚系。3)通过对一个同系小鼠的7个亚系的分析，确定了影响体重、脂肪垫重量的3个Mb区域在A区。对另一个同源系小鼠的5个亚系进行分析，发现B区存在影响体重和脂肪垫重量的8 Mb区域。然而，我们无法在A区绘制与空腹血糖浓度相关的区域。这些同源亚系为精细定位表型QTL区域提供了有力的工具。为了鉴定靶基因，我们的实验室正在进行亚同源小鼠和对照小鼠的各种组织中的mRNA和蛋白质表达分析。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of diabetes susceptibility loci in db mice by combined quantitative trait loci analysis and haplotype mapping

DOI：
10.1016/j.ygeno.2006.07.002
发表时间：
2006-12-01
期刊：
GENOMICS
影响因子：
4.4
作者：
Monitani, Maki;Togawa, Katsuhiko;Itakura, Mitsuo
通讯作者：
Itakura, Mitsuo

Molecular characterization of GDDI/TMEM16E, the gene product responsible for autosomal dominant gnathodiaphyseal dysplasia.

GDDI/TMEM16E 的分子特征，该基因产物负责常染色体显性颌骨骨干发育不良。

DOI：
发表时间：
2007
期刊：
Biochem Biophys Res Commun (in press)
影响因子：
0
作者：
Manotham K;Tanaka T;Ohse T;et al.;Kuniko Mizuta
通讯作者：
Kuniko Mizuta

Genetic association between the PRKCH gene encoding protein kinase Ceta isozyme and rheumatoid arthritis in the Japanese population

日本人群中编码蛋白激酶 Ceta 同工酶的 PRKCH 基因与类风湿性关节炎之间的遗传关联

DOI：
发表时间：
2006
期刊：
Arthritis ＆ Rheumatism Vol.56,No.1
影响因子：
0
作者：
田仲和宏;他(分担執筆);Shunji Nakano;Nakano S.et al.;Yoichiro Takata;Yoichiro Takata;Keisuke Yagi;Takata Y.et al.;Takata Y.et al.;Yagi K.et al.;Suzue N.et al.;Yoichiro Takata
通讯作者：
Yoichiro Takata

Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese