Identification of blood pressure genes in the Dahl salt-sensitive hypertension model

Hypertension afflicts 21% of the Canadian population and is a leading cause of death as it is associated with an increased risk of cardiovascular diseases. Blood pressure (BP) regulation is a complex trait controlled by multiple genes and influenced by environment. Little is known about the genes responsible for BP regulation. Inbred rats genetically predisposed to hypertension have been developed to facilitate the study of the genetic basis to this disease. Preliminary linkage and congenic experiments have shown the presence of at least one BP quantitative trait loci (QTL) in a 80cM region of rat chromosome (chr) 2. The objective of the present thesis was to identify and characterize the rat chr 2 regions involved in the genetic control of hypertension. We are using congenic strains in which various segments from the Dahl salt-sensitive (DSS) rat chr 2 are replaced by the homologous segments coming from the Milan normotensive rat (MNS). This model has allowed to narrow down the rat chr 2 BP QTL to three non-overlapping regions each containing at least one distinct BP QTL: C2QTL1 (5.7cM), C2QTL2 (3.5cM) and C2QTL3 (1.5cM). These closely linked BP QTL showed epsitatic and additive interactions. We also identified a QTL for vascular smooth muscle cell (VSMC) number acting independently of BP. The gene coding for the angiotensin receptor 1b (Agtr1b) is located in the region containing the QTL for SMCN. Agtr1b is a candidate for the SMCN QTL because (1) two non-synonymous mutations were found in the coding region between DSS and MNS rats, and (2) contractile responses to Ang II are reduced in rats harbouring the MNS allele of the gene compared with DSS rats. The current work provide new insights about the genetic determination of hypertension and of vascular remodelling disorders. In the future, these knowledge may be useful in the development of new therapeutic targets, genetic diagnostic tools and pharmacogenomics.; Keywords. genetics of hypertension, Dahl salt-sensitive rat, quantitative trait loci, aortic hyperplasia, vasoreactivity.