This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Much evidence (reviewed below) has established a genetic basis for type 2 Diabetes Mellitus (T2DM). As part of our Veterans Administration Genetic epidemiology Study (VAGES), we have completed an initial genome - wide scan of Mexican American families who reside in San Antonio and who were identified as having a sibpair with T2DM and only one diabetic parent. All subjects were phenotyped for diabetes- and obesity- related traits and linkage analysis was performed using microsatellite markers spaced at ~10cM intervals. This analysis has identified several chromosomal regions (6q23, 11q23, 5p23, 4p15, 2p22) strongly linked to diabetes and a combined diabetes-obesity phenotype. Within these regions are a number of candidate genes which are known to influence insulin sensitivity in insulin target tissues. Since insulin resistance is a characteristic feature of T2DM in Mexican Americans and other ethnic groups, we propose to further explore the potential role of these candidate genes in the pathogenesis of T2DM. RESEARCH PLAN AND METHODS: To accomplish this goal, we first will expand our VAGES family data base by combining it with the San Antonio Family Diabetes Study (SAFADS) to substantially increase statistical power and to refine linkage at regions (6q23, 11q23, 5p23, 4p15, 2p22 and others) shown by us to be linked with diabetes, obesity, and diabetes-obesity (diabesity) phenotypes. We will perform saturation SNP mapping at the critical 6q23 region that contains 99% of the probability for linkage in our preliminary analyses. We also will perform saturation SNP mapping of key positional candidate genes at 11q23, 4p15, 2p22 and 5q23 regions. Several potentially important candidate genes already have been identified at these sites. For candidate genes that survive the linkage/QTN analyses described above, we will perform initial molecular screening (multitissue Northern blot analysis, Affymetrix DNA microarray analysis, quantitative RT-PCR) to evaluate the role of the candidate genes in the pathophysiology of T2DM. CLINICAL
If the genes responsible for T@DM can be identified and their function delineated, this will provide crucial insights that eventually could lead to a cure for this debilitating disease.
Showing the most recent 10 out of 600 publications
