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，是遗传和环境因素复杂相互作用的结果。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对糖尿病等多因素疾病进行遗传解剖。在这项研究中，我们构建了一种新的多因素疾病的遗传解剖策略，特别是糖尿病。为了简化遗传分析，我们使用了近交的糖尿病动物模型（NOD小鼠用于1型糖尿病，NSY小鼠用于2型糖尿病）。在NSY与对照C3H/He小鼠杂交的F2小鼠中，至少有3个QTL （NIdd1、NIdd2、NIdd3）定位在小鼠第11、14和6号染色体上。目前正在对这些位点的同源株和同源株进行进一步的定位和功能分析。利用在MHC内具有历史重组染色体的同源菌株，我们在NOD小鼠中定位了MHC-连锁糖尿病基因（Iddl）的第二个组分（Iddl 6）。在Iddl - 6区间内获得了一个新的重组蛋白，并监测了Iddl - 6的发病情况，进行了Iddl - 6的精细定位和克隆。在人类中，在染色体2q上发现了一个与IDDM13连锁不平衡的标记，这将极大地促进IDDM13致病基因的鉴定。对于i值远低于1型糖尿病的2型糖尿病的基因解剖，需要有足够功率的方法。为了增加遗传分析的能力，我们新建立了基因型和表型（包括数量性状）之间的关联研究的荟萃分析。通过这种方法，我们在5000多名受试者中发现了ACE基因的插入/缺失多态性与糖尿病肾病易感性之间的显著相关性，在9000多名受试者中发现了定量表型、体重指数和β 3肾上腺素能受体基因突变之间的显著相关性。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