Elucidation of susceptibility gene for type 1 diabetes mellitus using comparative chromosome map between human and animal model

虽然1型糖尿病的易感性由多种遗传成分决定，但主要组织相容性复合体（NHC）相关的遗传成分在人和NOD小鼠（1型糖尿病动物模型）中都是最强的因素。通过研究一个基因NOD。CTS- h -2系的基因间隔来源于与NOD小鼠具有相同MHC II类的CTS小鼠，我们已经证明小鼠强烈的MHC相关易感性是由于多个基因的联合作用，NOD在II类区域外具有易感性基因Idd16。在本项目中，我们明确了以下几点：通过从冷冻胚胎中扩增基因系，发现1型糖尿病在基因NOD中。CTS-H-2被NOD小鼠抑制约四分之一。2、我们通过选择性育种，在回交后代中发现了两个具有新的重组染色体的亚基因系（F17和F21），通过比较亚基因系之间糖尿病的发展，可以精确定位Idd16。3、作为Idd16的候选者，我们测定了NOD和CTS小鼠MHC I类K基因的基因组序列，并对K蛋白进行了研究。结果表明，CTS的K基因是独特的，提示K基因负责Idd16.4，由于小鼠SLC11A1基因被认为负责Idd5.2，因此研究了人类SLC11A1基因。我们通过关联研究和荟萃分析证明，SLC11A1基因启动子中Z-DNA形成基序的功能多态性与不同种族的1型糖尿病有关。

Whereas predisposition to type 1 diabetes mellitus is determined by multiple genetic components, major histocompatibility complex (NHC)-linked genetic component is the strongest factor both in human and NOD mouse, an animal model for type 1 diabetes. By investigating a congenic NOD. CTS-H-2 line whose congenic interval is derived from the CTS mouse that has the identical MHC class II to the NOD mouse, we have shown that the mouse strong MHC-linked susceptibility is due to a combined effect of multiple genes and NOD has susceptibility gene outside class II region, termed Idd16. In the present project, we have clarified the following points ;1, By expanding the congenic line from the frozen embryo, the type 1 diabetes in the congenic NOD. CTS-H-2 line was suppressed about one fourth to NOD mouse.2, We established, by selective breeding, two subcongenic lines with new recombinant chromosomes found in the backcross progenies (F17 and F21), allowing fine mapping of Idd16 by comparison of the development of diabetes among the subcongenic lines.3, As a candidate for Idd16, genome sequence of the MHC class I K gene of NOD and CTS mice was determined and K protein was investigated. The results indicated that K gene of the CTS was unique and suggested that K gene is responsible for Idd16.4, Human SLC11A1 gene was investigated since mouse Slc11a1 gene was suggested as responsible for Idd5.2. We demonstrated through association study and a meta-analysis that a functional polymorphism in the Z-DNA forming motif in the promoter of the SLC11A1 gene is associated with type 1 diabetes across the races.