CLONING OF SUSCEPTIBILITY GENES FOR NON-INSULIN-DEPENDENT DIABETES MELLITUS BY A NOVEL STRATEGY

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多因素疾病如糖尿病进行遗传解剖。本研究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，对于低Xs值的2型糖尿病的基因分离，需要有足够的把握度。为了提高遗传分析的能力，我们新建立了基因型和表型（包括数量性状）之间关联研究的荟萃分析。通过使用这种方法，我们在5000多名受试者中显示了ACE基因插入/缺失多态性与糖尿病肾病易感性之间的显著关联，在9000多名受试者中显示了定量表型、体重指数和β 3肾上腺素能受体基因突变之间的显著关联。我们使用近交系糖尿病动物模型（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C3 H/He小鼠杂交的F2代小鼠中进行了数量性状位点（QTL）定位，在小鼠11、14和6号染色体上定位了至少3个QTL（Nidd 1、NIdd 2、NIdd 3）。Nidd 1通过imapired胰岛素分泌影响葡萄糖耐量，而Nidd 2通过胰岛素抵抗影响葡萄糖耐量。nidd 3显著影响胰岛素抵抗和腹部脂肪积累以及葡萄糖耐量。目前正在对这些基因座的同源株系进行进一步的定位和功能分析。

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.For genetic dissection of type 2 diabetes with low Xs values, 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.To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type 1 diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (QTL) 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. Nidd1 appears to affect glucose tolerance through imapired insulin secretion, whereas Nidd2 through insulin resistance. Nidd3 singnificantly affects insulin resistance and abdominal fat accumulation as well as glucose tolerance. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.