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

利用OLETF(Otsuka Long Evans Tokushima Fatty)大鼠(一种2型糖尿病模型)进行连锁分析，在大鼠14号染色体上发现了一个高血糖数量性状基因座(QTL)Nidd2/Of。另一项独立的QTL研究将肥胖QTL Obs5定位到相同的染色体区域。在F344背景上放置了约38 cM的含有Nidd2/Of和Obs5的OLETF衍生片段的同源菌株被证明具有轻度糖尿病和肥胖的表型，这表明存在影响葡萄糖代谢和脂肪积累的突变。为了更准确地定位基因座，我们产生了一系列缺失的亚基因菌株，其中OLETF片段两端都被缩短了。我们发现在Nidd2/OF基因座上至少存在两个高血糖QTL。我们预测它们定位于Nidd2/OF区的两端。相反，Obs5QTL被进一步缩小到一个约10 cM的片段区域。了解…的遗传基础更复杂的疾病不仅需要识别致病基因，还需要精确描述所涉及的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，随后通过单独检查拥有每个基因座的同源基因大鼠来验证这些QTL。在本研究中，我们构建了一个导入Nidd1/Of和Nidd2/Of基因座的双等位基因品系。OGTT分析显示，双同基因大鼠表现出急性血糖升高，可能是由于Nidd2/OF的作用，随后通过Nidd1/OF的作用而持续高血糖。这表明这些基因座之间存在特征差异。在OGTT中，Nidd1/Of在晚期血糖调节中起关键作用，而Nidd2/Of在OGTT的早期阶段起更重要的作用。此外，它们在高血糖的表达上存在协同作用，表明是上位性相互作用。因此，从复杂疾病模型衍生的同源动物是研究常见病的巨大资源。较少

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