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

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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.