Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait
Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait
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DOI：
10.2337/diabetes.48.5.1168
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发表时间：
1999-05-01
期刊：
影响因子：
7.7
通讯作者：
Ogihara, T
中科院分区：
文献类型：
--
作者：
Ueda, H;Ikegami, H;Ogihara, T
2型糖尿病是一种复杂的性状，基因和环境因素都有助于易感性。除了具有单基因遗传的罕见亚型外，由于疾病的复杂性和异质性，2型糖尿病的遗传基础尚不清楚。通过使用NSY小鼠，一种2型糖尿病的近交系小鼠模型，我们从遗传学上剖析了迟发性2型糖尿病，并证明了2型糖尿病遗传控制的年龄依赖性变化以及多基因遗传。Nidd 1 nsy、Nidd 2nsy、Nidd 3 nsy三个主效基因座分别定位于小鼠第11、14和6号染色体上。存在的第四个位点（Nidd 4 nsy）与年龄依赖性的影响，建议纵向，但不是横截面，连锁数据分析。Nidd 1 nsy和Nidd 4 nsy似乎影响胰岛素分泌，而Nidd 2nsy和Nidd 3 nsy似乎影响胰岛素敏感性。Chr 6上的一个位点与附睾脂肪重量显著相关。Chr 11上编码肝核因子-1 β的候选疾病基因（Tcf 2）在模型中的DNA结合域中显示出罕见的序列变异。我们使用的小鼠模型将作为一个有用的模型，为未来的研究晚发型多基因2型糖尿病的病因在人类。
Type 2 diabetes is a complex trait with both genes and environmental factors contributing to susceptibility. Except for rare subtypes with monogenic inheritance, the genetic basis of type 2 diabetes is unknown because of the complex and heterogeneous nature of the disease. By using the NSY mouse, an inbred mouse model of type 2 diabetes, we genetically dissected late-onset type 2 diabetes and demonstrated age-dependent changes in the genetic control of type 2 diabetes as well as polygenic inheritance. Three major loci (Nidd1nsy, Nidd2nsy, Nidd3nsy) were mapped on mouse chromosomes (Chr) 11, 14, and 6, respectively. The existence of a fourth locus (Nidd4nsy) with an age-dependent effect was suggested by longitudinal, but not cross-sectional, analysis of linkage data. Nidd1nsy and Nidd4nsy appear to affect insulin secretion, whereas Nidd2nsy and Nidd3nsy appear to affect insulin sensitivity. A locus on Chr 6 was significantly linked to epididymal fat weight. A candidate disease gene (Tcf2) on Chr 11, encoding hepatic nuclear factor-1 beta, was shown to have a rare sequence variant in the DNA binding domain in the model. The mouse model we used will serve as a useful model for future studies on the etiology of late-onset polygenic type 2 diabetes in humans.