Positional cloning represents a major challenge to researchers, particularly the identification of genes that influence complex, multigenic traits and that are common in the largely genetically heterogeneous, American population. With the advent of high-density cDNA microarray technology, a novel and powerful approach is now available for these types of genetic investigations. We hypothesize that candidate genes for pediatric type 2 diabetes genes can be identified by combining the power of microarray technology with the power of linkage = expression linkage mapping. We believe that this novel, expression linkage approach for identifying candidate genes at mapped diabetes loci will be most successfull if: 1) genetically homogeneous populations are utilized, and 2) the disease alleles exhibit a high penetrance (resulting in a high prevalence of both childhood obesity and pediatric type 2 diabetes). Certain of the genetic factors responsible for the familial aggregation of obesity and type 2 diabetes are thought to be shared with those that cause obesity. Epidemiological studies suggest that a subset of diabetes genes will be distinct from those that cause obesity. To identify diabetes genes that are separate from those that cause obesity, only obese subjects will be compared in this study (those with a similar childhood obesity history but a different glucose tolerance outcome). Due to the limitations of working with pediatric subjects, we propose to compare global gene expression in fibroblasts (basal and insulin-stimulated), as a surrogate for classical insulin-responsive tissues (muscle, adipose and liver), to uncover candidate genes for pediatric type 2 diabetes. This Exploratory/Development Research Grant (R21) will provide initial support to a new investigator interested in testing novel ideas for the study of type 2 diabetes in the pediatric population. Future funding for this new, expression linkage approach, utilizing genetically homogeneous populations with high levels of penetrance for pediatric t e 2 diabetes will be through the R01 grant program.
| Bittel, Douglas C; Kibiryeva, Nataliya; Sell, Susan M et al. (2007) Whole genome microarray analysis of gene expression in Prader-Willi syndrome. Am J Med Genet A 143:430-42 |
| Yoder, B; Sell, S M (2001) Jets: a modification to speed flexible oligonucleotide array construction. Pharmacogenomics J 1:163-5 |
