Functional genomics in rat models of hypertension: using differential expression and congenic strains to identify and evaluate candidate genes.

Abstract

Hypertension is a leading contributor to cardiovascular diseases such as heart attack and stroke. Genetic and environmental factors contribute to the development of hypertension. Animal models have been developed to study the genetic contributions to blood pressure (BP) regulation and to identify chromosomal regions harboring candidate genes causative of differences in BP regulation (i.e., BP quantitative trait loci [QTL]). Advances in both mammalian genome projects and global gene expression analysis present opportunities to study functional genomics in these animal models. In this article, novel approaches for designing experiments and interpreting global gene expression data using the Dahl salt-sensitive hypertension rat model are presented. We describe two-step screening protocols that can be used to identify BP QTL candidate genes. Genetically determined expression differences are identified in the target organs of inbred strains of contrasting phenotype in the first screen. Expression patterns in a panel of congenic strains or expression differences stemming from gene x environment interactions are examined in the second screen. Chromosomal locations of these genes can then be examined to determine whether they map to BP QTL-containing regions. Another approach is to study the expression of genes identified from public databases to be located within BP QTL-containing congenic regions. Several candidate genes have been identified using these strategies.