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

1 型糖尿病易感基因的克隆作为多因素疾病的模型案例

基本信息

批准号：
11470233
负责人：
IKEGAMI Hiroshi
金额：
$ 6.59万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470233/
关键词：
MULTIFACTORIAL DISEASE GENETICS DIABETES MELLITUS SUSCEPTIBILITY 自己免疫

项目摘要

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.

与单基因疾病不同，经典的连锁分析对于多因素疾病如糖尿病的遗传解剖是不可行的。因此，我们采用了一种新的策略，1型糖尿病的遗传解剖作为一个模型的情况下，多因素diseases.To使复杂的相互作用的遗传和环境因素在人类更简单，我们使用近交系动物模型的1型糖尿病（NOD小鼠）。为了将多基因遗传分解为单基因遗传，建立了与亲本有一条不同染色体的同源株系并进行了分析。通过使用与重组MHC同源的NOD菌株，其具有与NOD相同的II类MHC，但与NOD不同的侧翼标记，已经鉴定了与MHC连锁的1型糖尿病易感性的第二组分（Idd 16），并将其定位在II类区域中邻近但不同于Idd 1、A和E的候选基因。人类同源区的分析表明，MHC连锁的1型糖尿病易感性的第二个组成部分，影响疾病的发病年龄，也位于邻近，但不同于II类DQ和DR位点。这些数据表明，同源策略对于复杂性状（如1型糖尿病）的遗传解剖具有强大的作用。当同样的方法应用于3号染色体上的Idd 3时，发现与NOD具有相同序列的Il2基因（3号染色体上Idd 3的候选基因）但与NOD具有不同侧翼标记的同源NOD菌株具有与NOD亲本菌株不可区分的表型，强烈表明Il2的NOD等位基因负责Idd 3效应。