Functional analysis of susceptibility genes for diabetes: gene-gene and gene-environment interaction

为了阐明糖尿病的遗传基础，更好地了解糖尿病发病的分子机制，并开发有效的预防和干预方法，在近交系1型和2型糖尿病动物模型中进行了1型和2型糖尿病的分子遗传学研究。（NOD小鼠）和2型（NSY小鼠）糖尿病，分别侧重于基因-基因和基因-具有NSY衍生的致糖尿病染色体的同源和同源菌株的环境相互作用分析遗传背景显示小鼠11号和14号染色体上分别存在糖尿病基因。基因-基因相互作用被证明是11号和14号染色体之间的肥胖。11号和14号染色体上的致糖尿病基因显示出基因-环境相互作用，在饮用水中补充30%蔗糖后，表型明显恶化。亚同源基因分析表明，11号染色体上的糖尿病基因由多个组分组成，NOD小鼠17号染色体上Iddl 6区域的亚同源基因分析表明，Iddl 6由多个组分组成，其中一个位于I类K区。多中心协作研究团队，成立了日本1型糖尿病遗传学研究小组，并对1型糖尿病的候选基因进行了大规模的遗传关联研究。利用这些有价值的资源，INS，CTLA 4，PTPN 22和SUMO 4对日本人1型糖尿病易感性的贡献得到了证实。从本研究中产生的数据提供了有价值的信息，糖尿病的遗传学为未来开发定制药物治疗糖尿病。

To clarify genetic basis of diabetes mellitus for better understanding of molecular mechanisms of the disease pathogenesis and for the development of effective methods for prevention and intervention, molecular genetic studies on both type 1 and type 2 diabetes were performed in inbred animal models for type 1(NOD mice) and type 2 (NSY mice) diabetes, respectively with particular focus on gene-gene and gene-environmental interaction Analysis of consomic and congenic strains with NSY derived diabetogenic chromosomes introgressed onto control C3H/He genetic background revealed the existence of diabetogenic genes on mouse chromosome 11 and 14, respectively. Gene-gene interaction was demonstrated for obesity between chromosomes 11 and 14. Diabetogenic genes on both chromosomes 11 and 14 showed gene-environment interaction with markedly deteriorated phenotypes with supplementation of 30% sucrose in drinking water. Sub-congenic analysis demonstrated that diabetogenic genes on chromosome 11 consist of multiple components.Sub-congenic analysis of NOD mice congenic for Iddl6 region on chromosome 17 revealed that Iddl6 consists of multiple components and one of them is located in class I K region.Multi-center collaborative study team, termed the Japanese Study Group on Type 1 Diabetes Genetics was established and made it possible to perform large-scale genetic association studies with sufficient power on candidate genes for type 1 diabetes. Taking advantage of these valuable resources, contribution of INS, CTLA4, PTPN22 and SUMO4 on susceptibility to type 1 diabetes in Japanese was confirmed. The data generated from the present study provides valuable information on genetics of diabetes for future development of tailored medicine in the treatment of diabetes mellitus.