Identification of type 2 diabetes genes using congenic rat strains introgressed Niddm locus

连锁分析先前确定了一个高血糖的数量性状位点（QTL），Nidd 2/的，在大鼠染色体14上的杂交利用OLETF（大冢长埃文斯德岛脂肪）大鼠，2型糖尿病的模型。一项单独的QTL研究将肥胖QTL Obs 5定位到相同的染色体区域。一个同类菌株放置约。在F344背景上含有Nidd 2/of和Obs 5的38 cM OLETF衍生片段显示具有轻度糖尿病和肥胖表型，表明存在影响葡萄糖代谢和脂肪积累的突变。为了更精确地定位位点，我们产生了一系列缺失亚同源菌株，其中OLETF片段从两端缩短。我们发现在Nidd 2/of位点上至少存在两个高血糖QTL。我们预测，他们是本地化的Nidd 2/区域的两端。而Obs 5 QTL则进一步缩小到了ca. 10 cM的片段。了解 关于我们 复杂疾病不仅需要鉴定致病基因，而且需要精确描述相关基因之间的相互作用。以前，我们确定了高血糖的QTL在OLETF大鼠，随后通过检查拥有每个位点的同类大鼠单独验证。本研究构建了Nidd 1/of和Nidd 2/of基因渗入的双同源菌株。OGTT分析显示，双同源大鼠表现出急性血糖升高，推测是由于Nidd 2/of的作用，随后通过Nidd 1/of的作用持续高血糖。这表明这些位点之间存在特征性差异。Nidd 1/of在OGTT晚期血糖调节中起重要作用，而Nidd 2/of在早期血糖调节中起更重要的作用。此外，它们相互作用协同高血糖症的表达，表明上位相互作用。因此，由复杂疾病模型衍生的同类动物是研究常见疾病的巨大资源。少

Linkage analysis previously identified a hyperglycemic quantitative trait locus (QTL), Nidd2/of, on rat Chromosome 14 in crosses utilizing OLETF (Otsuka Long Evans Tokushima Fatty) rat, a model for type2 diabetes. A separate QTL study mapped an obesity QTL, Obs5, to the same chromosomal region. A congenic strain placing ca. 38 cM OLETF-derived segments containing both Nidd2/of and Obs5 on the F344 background was shown to possess mild diabetic and obese phenotypes, suggesting the presence of mutations affecting the glucose metabolism and fat accumulation. In order to localize the loci more precisely, we generated a series of deletion-subcongenic strains in which OLETF-segments were shortened from either ends. We found that there are at least two hyperglycemic QTL within the Nidd2/of locus. We predict that they are localized towards both ends of the Nidd2/of region. In contrast, Obs5 QTL was further narrowed down to a single region of ca. 10 cM fragment.Understanding the genetic bases of … More complex disease requires not only the identification of disease causative genes, but also the precise description of interactions among genes involved. Previously we identified hyperglyceamic QTLs in OLETF rats, which were subsequently verified by examining congenic rats possessing each locus individually. In this study, we constructed a double congenic strain introgressing Nidd1/of and Nidd2/of loci. OGTT analysis revealed that the double congenic rats showed acute glucose elevation presumably due to the effect of Nidd2/of followed by sustained hyperglycemia via the effect of Nidd1/of. This suggested that there was a characteristic difference between these loci. Nidd1/of was critical for late-phase glucose regulation during OGTT, while Nidd2/of played a more important role in early-phase. Furthermore, they interacted synergistically for the expression of hyperglycemia, indicating an epistatic interaction. Therefore congenic animals derived from complex disease model are tremendous resources for the study of common diseases. Less