GENOME-WIDE SEARCH FOR THE SUSCEPTIBILITY GENES FOR OBESE DIABETES IN THE DOMINICAN REPUBLIC

我们以前报道过，多米尼加共和国人PC-1 121 Q等位基因的患病率极高，这是2型糖尿病的易感基因之一。在研究主题1中，我们通过分析人类线粒体DNA（mtDNA）D环区的核苷酸序列来表征其遗传背景。对包括美洲原住民、非洲人和欧洲人在内的mtDNA谱系进行系统发育分析，使我们能够评估祖先组分对多米尼加共和国群体的相对遗传贡献。在肥胖2型糖尿病（OD）组中，大多数（64.0%）mtDNA谱系来自非洲血统，而在健康组中，美洲原住民部分占主导地位（51.5%）。系统发育分析同样证明了这种差异。这些发现可能意味着种族特异性的易感性OD，一个可能的关联，从非洲血统与OD在Dominican Republic.在研究主题2，我们分析了Kir 6.2基因，这是从胰腺β细胞分泌胰岛素相关。我们发现23 K等位基因与胰岛素分泌水平降低相关，并且在多米尼加共和国易患非肥胖型糖尿病。在研究主题3中，我们调查了肥胖相关基因的变化以及血管紧张素II受体阻滞剂（ARB）在饮食诱导肥胖（DIO）小鼠中的作用，以分析肥胖糖尿病的候选基因。DIO小鼠表现出肥胖相关基因表达的各种变化。另一方面，ARB改善了体重增加和脂肪组织及肝脏基因表达的紊乱。由于脂联素、UCP 1和Apotin基因与肥胖及相关代谢紊乱的发生密切相关，因此这些基因是肥胖-糖尿病的良好候选基因。

We reported previously that people in the Dominican Republic have extremely high prevalence of PC-1 121Q allele, which is one of the susceptibility genes for type 2 diabetes. In the research theme 1, we characterized their genetic background by analyzing the nucleotide sequences of the D-loop region of human mitochondrial DNA (mtDNA). Phylogenetic analysis of mtDNA lineages including Native Americans, Africans, and Europeans enabled us to assess relative genetic contributions of the ancestral fractions to the groups in the Dominican Republic. In the obese type 2 diabetes (OD) group, the majority (64.0%) of the mtDNA lineages were from African ancestry, whereas the Native American fraction was predominant (51.5%) in the healthy group. This difference was similarly demonstrated by phylogenetic analysis. These findings may imply ethnic-specific predisposition to OD, a possible association of an unidentified factor from African ancestry with OD in the Dominican Republic.In the research theme 2, we analyzed the Kir 6.2 gene which is related to insulin secretion from pancreatic β cells. We showed that the 23K allele is associated with the decreased level of insulin secretion and predispose to non-obese diabetes in the Dominican Republic.In the research theme 3, we investigated the changes of obesity-related genes and the effect of an angiotensin II receptor blocker (ARB) in diet-induced obese (DIO) mice in order to analyze candidate genes for obese-diabetes. DIO mice exhibited various changes in the expression of obesity-related genes. On the other hand, ARB ameliorated the body weight gain and the disorder of gene expression in the adipose tissue and the liver. Since adiponectin, resistin and UCP1 genes are related closely to the development of obesity and related metabolic disorders, these genes are good candidate genes for obese-diabetes.