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

多米尼加共和国肥胖糖尿病易感基因的全基因组搜索

• 批准号: 15406035
• 负责人: YOSHIMATSU Hironobu
• 金额: $ 7.17万
• 依托单位: OITA UNIVERSITY (2004-2005)大分医科大学 (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15406035/
• 关键词: Dominican Republic; diabetes mellitus; obesity; insulin resistance; mitochondria; Kir 6.2; diet-induced obesity; antiotensin II receptor blocker; PC-1; 多型; 生活習慣病; SNP

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.

我们之前曾报道，多米尼加共和国人的PC-1121Q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描述它们的遗传背景。对包括美洲原住民、非洲人和欧洲人在内的mtDNA谱系的系统发育分析使我们能够评估祖先部分对多米尼加共和国群体的相对遗传贡献。在肥胖型2型糖尿病(OD)组中，大多数(64.0%)的mtDNA谱系来自非洲血统，而在健康组中，美洲原住民占主导地位(51.5%)。这一差异在系统发育分析中也得到了类似的证明。在研究主题2中，我们分析了与胰腺β细胞胰岛素分泌相关的KIR6.2基因。在研究主题3中，我们研究了饮食诱导肥胖(DIO)小鼠肥胖相关基因的变化以及血管紧张素II受体阻滞剂(ARB)的作用，以分析肥胖-糖尿病的候选基因。Dio小鼠在肥胖相关基因的表达上表现出不同的变化。另一方面，ARB改善了体重增加和脂肪组织和肝脏基因表达的紊乱。由于脂联素、抵抗素和UCP1基因与肥胖及相关代谢紊乱的发生发展密切相关，因此这些基因是肥胖-糖尿病的良好候选基因。

项目成果

Itateyama E., et al.: "Hypothalamic neuronal histamine in genetically obese animals : its implication of leptin action in the brain"Exp.Biol.Med.. 228. 1132-1137 (2003)

Itateyama E., et al.：“遗传性肥胖动物中的下丘脑神经元组胺：其对大脑中瘦素作用的影响”Exp.Biol.Med.. 228. 1132-1137 (2003)

Masaki T, et al.: "Neuronal histamine regulates food intake, adiposity and uncoupling Protein expression in agouti yellow (A^y/a) obese mice"Endocrinology. 144. 3547-3554 (2003)

Masaki T 等人：“神经组胺调节刺鼠黄 (A^y/a) 肥胖小鼠的食物摄入、肥胖和解偶联蛋白表达”内分泌学。

Yasuda T, et al.: "Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats"Neuroscience Lett.. 349. 75-78 (2003)

Yasuda T 等人：“集中施用生长素释放肽抑制大鼠棕色脂肪组织中的交感神经活动”Neuroscience Lett.. 349. 75-78 (2003)

The neuronal histamine H1 and pro-opiomelanocortin-melancortin 4 receptors independent regulation of food intake and energy expenditure.

神经元组胺 H1 和阿片黑皮质素原-黑皮质素 4 受体独立调节食物摄入和能量消耗。

• 发表时间: 2006
• 期刊: Peptides 27
• 作者: Homei Miyashita;Kazushi Nishimoto;Hajime Ishihara;Hajime Ishihara;H.Ishihara;H.Ishihara;Yoshimatsu H.
• 通讯作者: Yoshimatsu H.

Masaki T, et al.: "Chronic central leptin infusion restores hyperglycemia independently of food intake and insulin level in streptozotocin-induced diabetic rats"Endocrinology. 144. 2741-2748 (2003)

Masaki T 等人：“慢性中枢瘦素输注可独立于链脲佐菌素诱导的糖尿病大鼠的食物摄入和胰岛素水平恢复高血糖”内分泌学。