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

为了明确糖尿病的遗传基础，更好地了解糖尿病发病的分子机制，为制定有效的预防和干预方法，我们在1型（NOD小鼠）和2型（NSY小鼠）糖尿病的近交动物模型中对1型和2型糖尿病进行了分子遗传学研究。对NSY衍生的致糖尿病染色体渗入对照C3H/He遗传背景的同体菌株和同源菌株的分析显示，小鼠11号染色体和14号染色体上分别存在致糖尿病基因。11号和14号染色体之间的基因-基因相互作用证明了肥胖。在饮用水中添加30%蔗糖后，11号和14号染色体上的致糖尿病基因表现出基因与环境的相互作用，表型显著恶化。亚同源分析表明，11号染色体上的致糖尿病基因由多个组分组成。对NOD小鼠17号染色体Iddl6区同源基因进行亚基因分析，发现Iddl6由多个组分组成，其中一个组分位于I类K区。多中心合作研究小组，被称为日本1型糖尿病遗传学研究小组的成立，使得对1型糖尿病候选基因进行大规模遗传关联研究成为可能。利用这些宝贵的资源，我们证实了INS、CTLA4、PTPN22和SUMO4在日本人1型糖尿病易感性中的作用。本研究的数据为糖尿病的遗传学研究提供了有价值的信息，为未来糖尿病治疗的量身定制药物的开发提供了依据。

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.