Development of the metabolic syndrome is detennined by a complex interaction of environmental and genetic factors and as with other complex human traits, disease gene identification is problematic due to a lack of statistical power and genetic heterogeneity in patients. Identifying genes' that underlie metabolic syndrome risk factors will allow better understanding and development of treatments which would decrease disease health burden. The spontaneously hypertensive rat (SHR) is a widely studied model of insulin resistance and hypertension and, as in humans, the hypertensive phenotype clusters with metabolic traits. SHR was crossed with nonnotensive Brown Norway rats to develop the BXHIHXB recombinant inbred (RI) strain panel. . In these studies this RI panel is being used to identify genomic regions influencing gene expression, tenned expression quantitative trait loci- (eQTL). Affymetrix microarray expression profiles from two tissues (fat and kidney) in the RI and parental strains were generated. Transcript abundance for each gene on the microarray was treated as a quantitative trait and these eQTL were defined as: cis-acting, and trans-acting. This work examines a subset of cis-acting eQTL (P<lO-4) to look for polymorphisms in the putative promoters of these genes. These polymorphisms may cause the differential expression detected in these strains and underlie the phenotypic variation seen. In silico comparative mapping was carried out to investigate the applicability of the detected rat cis-acting eQTL genes to human disease. This used human QTL for metabolic and cardiovascular phenotypes to identify rat cis-acting eQTL and their human orthologs as potential candidate genes. This analysis detected several genes with known involvement in human metabolic syndrome phenotypes and a large number of novel candidate genes that merit testing in human populations. The results demonstrate an integrated genome-wide expression profiling with linkage analysis approach and its use in identification of candidate genes which may underlie complex traits.Imperial Users onl
