DEVELOPMENT OF A NOVEL STRATEGY FOR GENETIC ANALYSIS OF MULTIFACTORIAL TRAITS USING DIABETES AS A MODEL CASE

糖尿病是一种多因素疾病，由遗传和环境因素复杂相互作用引起。与单基因疾病不同，经典的连锁分析是不可行的，因此需要一种新的策略来分析糖尿病等多因素疾病的遗传。在这项研究中，我们构建了一种新的多因素疾病尤其是糖尿病的基因分离策略。为了使基因分析更简单，我们使用了糖尿病的近交系动物模型(1型糖尿病的NOD小鼠和2型糖尿病的NSY小鼠)。在NSY与对照C3H/He小鼠杂交的F2小鼠中，至少定位了3个QTL(NIdd1、NIdd2、NIdd3)，分别位于小鼠的11、14和6号染色体上。这些基因座的遗传和同源品系正在进行进一步的定位和功能分析。通过利用具有历史重组染色体的同源品系，我们定位了一个…NOD小鼠MHC连锁糖尿病基因(Idd1)的更多第二组分(Idd1 6)。在人类中，发现了一个与IDDM13连锁不平衡的标记，这将为寻找IDDM 13的致病基因提供极大的便利。对于IS值远低于1型糖尿病的2型糖尿病的基因解剖，需要有足够强大的方法。为了增加遗传分析的能力，我们新建立了Meta分析，用于研究基因型和表型之间的关联，包括数量性状。利用该方法，我们在5000多名受试者中发现了ACE基因插入/缺失多态与糖尿病肾病易感性之间的显著关联，在9000多名受试者中发现了数量表型、体重指数和β3肾上腺素能受体基因突变之间的显著关联。较少

Diabetes mellitus is a multifactorial disease, caused by a complex interaction of genetic and environmental factors. Unlike monogenic diseases, classical linkage analysis is not feasible and therefore a novel strategy is required for genetic dissection of multifactorial diseases such as diabetes mellitus. In this study we constructed a novel strategy for genetic dissection for multifactorial diseases in general and diabetes mellitus in particular.To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type I diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (0TL) mapping in F2 mice in crosses of NSY with contsol C3H/He mice mapped at least 3 QTL (NIdd1, NIdd2 NIdd3) on mouse chromosomes 11, 14 and 6. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.By using congenic strains with historical recombinant chromosomes within the MHC, we mapped a … More second component (Iddl 6) of MHC-linked diabetogenic gene (Iddl) in the NOD mouse. A new recombinant within the Iddl 6 interval was obtained and the incidence of diabetes in being monitored for fine mapping and positional cloning of Iddl 6.In humans, a marker in linkage disequilibrium with IDDM13 on chromosome 2q was identified, which will greatly facilitate the identification of responsible gene for IDDM 13. For genetic dissection of type 2 diabetes, whose Is is much lower than type 1 diabetes, methods with enough power are required. To increase the power of genetic analysis, we newly eatablished meta-analysis for association studies between genotypes and phenotypes, including quantitative traits. By using this method, we showes significant association between insertion/deletion polymorphism of the ACE gene and susuceptibility to diabetic nephropathy in more than 5000 subjects, and between a quantiative phenotype, body mass index, and mutation in beta 3 adrenergic receptor gene in more than 9000 subjects. Less