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

连锁分析先前在利用OLETF （Otsuka Long Evans Tokushima Fatty）大鼠的2型糖尿病模型杂交中发现了一个高血糖数量性状位点（QTL） Nidd2/of。另一项独立的QTL研究将肥胖QTL Obs5定位到同一染色体区域。一个同源菌株在F344背景上放置了约38 cM的oletf衍生片段，包含Nidd2/of和Obs5，显示出轻度糖尿病和肥胖表型，这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，我们生成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Nidd2/of位点至少存在两个高血糖QTL。我们预测它们位于Nidd2/of区的两端。相比之下，Obs5 QTL进一步缩小到约10 cM片段的单个区域。更复杂的疾病不仅需要确定致病基因，还需要精确描述相关基因之间的相互作用。之前，我们在OLETF大鼠中发现了高血糖qtl，随后通过检查具有每个位点的遗传大鼠来验证。本研究构建了一株具有Nidd1/of和Nidd2/of基因的双同源菌株。OGTT分析显示，双基因大鼠出现急性血糖升高，可能是由于Nidd2/of的作用，随后通过Nidd1/of的作用出现持续高血糖。这表明这些位点之间存在特征差异。Nidd1/of在OGTT后期葡萄糖调节中起关键作用，而Nidd2/of在OGTT早期发挥更重要的作用。此外，它们在高血糖的表达中协同作用，表明存在上位性相互作用。因此，复杂疾病模型衍生的基因动物是研究常见病的重要资源。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