CLONING OF SUSCEPTIBILITY GENES FOR TYPE 1 DIABETES MELLITUS AS A MODEL CASE FOR MULTIFACTORIAL DISEASES

与单基因疾病不同，经典连锁分析对于糖尿病等多因素疾病的遗传解剖是不可行的。因此，我们应用了一种新的策略，将1型糖尿病作为多因素疾病的典型案例进行遗传解剖。为了简化人类遗传和环境因素的复杂相互作用，我们使用了近亲繁殖的1型糖尿病动物模型（NOD小鼠）。为了将多基因遗传分解为单基因遗传，建立了与亲本株染色体单异的同源菌株并进行了分析。通过使用NOD菌株同源重组MHC，与NOD具有相同的II类MHC，但与NOD不同的侧翼标记，已经确定了MHC- 1型糖尿病易感性的第二个成分（Idd16），并定位于II类区域邻近但不同于Idd1， a和E的候选基因。对人类同源区域的分析显示，影响发病年龄的mhc相关1型糖尿病易感性的第二个组成部分也位于II类DQ和DR位点附近，但与之不同。这些数据表明，先天性策略在复杂性状（如1型糖尿病）的遗传解剖中具有强大的作用。将相同的方法应用于3号染色体上的Idd3，发现一个具有相同Il2基因序列的同源NOD菌株（3号染色体上Idd3的候选基因）与NOD相同，但与NOD的侧翼标记不同，其表型与NOD亲本菌株没有区别，强烈提示Il2的NOD等位基因负责Idd3效应。

Unlike monogenic diseases, classical linkage analysis is not feasible for genetic dissection of multifactorial diseases such as diabetes mellitus. We therefore applied a novel strategy for genetic dissection of type 1 diabetes as a model case for multifactorial diseases in general.To make complex interaction of genetic and environmental factors in humans simpler, we used inbred animal models for type 1 diabetes mellitus (NOD mice). To dissect multigenic inheritance into monogenic inheritance, congenic strains with single different chromosome from parental strain were established and analyzed. By using NOD strain congenic for recombinant MHC with the same class II MHC as the NOD, but different flanking markers from the NOD, a second component (Idd16) of MHC-linked susceptibility for type 1 diabetes has been identified and localized adjacent to, but distinct from candidate genes for Idd1, A and E, in the class II region. Analysis of homologous region in humans revealed that a second component of MHC-linked susceptibility for type 1 diabetes, which affects age-at-onset of the disease, is also located adjacent to, but distinct from class II DQ and DR loci. These data suggest the power of congenic strategy for genetic dissection of complex traits, such as type 1 diabetes. When the same approach was applied for Idd3 on chromosome 3, a congenic NOD strain which possess the same sequence in the Il2 gene, a candidate for Idd3 on chromosome 3, as the NOD, but different flanking markers from the NOD, was found to have the phenotypes indistinguishable from the NOD parental strain, strongly suggesting that the NOD allele of Il2 is responsible for Idd3 effect.