Genetics of hypertension: an assessment of progress in the spontaneously hypertensive rat

Abstract

The application of gene mapping methods to uncover the genetic basis of hypertension in the inbred spontaneously hypertensive rat (SHR) began over 25 yr ago. This animal provides a useful model of genetic high blood pressure, and some of its features are described. In particular, it appears to be a polygenic model of disease, and polygenes participate in human hypertension genetic risk. The SHR hypertension alleles were fixed rapidly by selective breeding in just a few generations and so are presumably common genetic variants present in the outbred Wistar strain from which SHR was created. This review provides a background to the origins and genesis of this rat line. It considers its usefulness as a model organism for a common cardiovascular disease. The progress and obstacles facing mapping are considered in depth, as are the emergence and application of other genome-wide genetic discovery approaches that have been applied to investigate this model. Candidate genes, their identification, and the evidence to support their potential role in blood pressure elevation are considered. The review assesses the progress that has arisen from this work has been limited. Consideration is given to some of the factors that have impeded progress, and prospects for advancing understanding of the genetic basis of hypertension in this model are discussed.

Keywords: SHR; blood pressure; genetics; mapping; review.

Fig. 1.

Summary of the breeding of spontaneously hypertensive rats (SHR) on the trait of elevated blood pressure from outbred Wistar stock in Kyoto (WKY). Incompletely inbred SHR animals were transferred to the National Institutes of Health (NIH) in the F13 generation and were subsequently fully inbred and distributed both from NIH (SHR/N) as well as from North American commercial breeders, e.g., SHR/NCrl, SHR/NHsd. Within the Kyoto colony at around the F21 generation, some animals in the A lineage were noted to experience cerebrovascular disease. Further selective breeding was performed to fix the trait of stroke susceptibility, leading to the stroke-prone, SHR-SP, line, of which SHR-A3 is the most widely distributed and studied. The lineages represented by green symbols experience severe hypertension, but resist stroke and other end-organ injury (hypertensive renal disease).

Fig. 2.

Logarithm of odds (LOD) plots of systolic and diastolic blood pressure mapping in an SHR-A3 × WKY0 F2 intercross (n = 173). The 95% confidence interval is achieved at a LOD score of 3.7. This level was exceeded only for the chr1:133 Mb peak for diastolic blood pressure.