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

与单基因疾病不同，经典的连锁分析不适用于糖尿病等多因素疾病的遗传解剖。因此，我们应用了一种新的策略来进行1型糖尿病的基因解剖，作为一般多因素疾病的模型病例。为了简化人类遗传和环境因素的复杂交互作用，我们使用了1型糖尿病的近亲交配动物模型(NOD小鼠)。为了将多基因遗传分解为单基因遗传，建立了与亲本菌株具有单一不同染色体的同源菌株，并进行了分析。通过使用Nod株同源重组MHC，与Nod的II类MHC相同，但与Nod的侧翼标记不同，已经鉴定出MHC连锁的1型糖尿病易感性的第二组分(Idd16)，并定位于Idd1，A和E的候选基因，但不同于Idd1，A和E的候选基因。对人类同源区域的分析表明，影响疾病发病年龄的MHC关联1型糖尿病易感性的第二个成分也位于DQ和DR第二类基因座附近，但与II类DQ和DR基因座不同。这些数据表明了同源基因策略对复杂特征的遗传解剖的力量，例如1型糖尿病。对3号染色体上具有相同IL2基因序列的同源NOD株，即第3号染色体上Idd3的候选者，采用同样的方法作为NOD，但与NOD的侧翼标记不同，发现其表型与NOD亲本株难以区分，强烈表明IL2的NOD等位基因对Idd3效应起作用。

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.