Opportunities and limitations of genetic analysis of hypertensive rat strains

Abstract

Genetic influences contribute upto 30–50% to blood pressure variability in human essential hypertension [1]. Intense efforts have been dedicated to unraveling the role of genes in this disease, following two parallel and interacting tracks. Studies on human populations have mostly focused on the candidate gene linkage approach, associating single nucleotide polymorphic (SNP) markers with the hypertensive phenotype. In spite of some promising observations [2], most attempts to replicate association studies have not been encouraging [3]. There are calls for application of stricter quality criteria for genetic studies, including better definition of phenotype characteristics, increased attention to environmental factors, sharing and combining data resources and more emphasis on whole genome-linkage scans in the context of collaborative multidisciplinary approaches [4–17]. Recently, however, there has been impressive progress in designing studies, understanding the mechanisms of disease and genotyping technology [17]. The second parallel track is the development and study of rodent experimental models of disease. Genetically hypertensive rat strains have been developed over the past 60 years. The models were obtained from initial random rat populations by brother—sister mating selecting for a high blood pressure phenotype. The better characterized genetically hypertensive strains are the spontaneously hypertensive rat (SHR) [18], stroke-prone SHR (SPSHR) [19], Dahl saltsensitive [20], Milan hypertensive (MHS) [21], New Zealand genetically hypertensive [22], Sabra hypertensive (SBH) [23] and the Lyon hypertensive rats [24]. Comparisons are generally made with inbred normotensive strains derived from the original rat population and sharing most of the genetic background with the corresponding hypertensive strain. The most common normotensive strains are the Dahl salt-resistant, Wistar—Kyoto (WKY), Milan normotensive (MNS), genetically normotensive, Sabra normotensive (SBN) and Lyon normotensive and Lyon low blood pressure rats [18–24]. Physiological and pharmacological approaches to the study of these models have enhanced our understanding of many systems for blood pressure control. During the 1990s, technological advances allowed the use of quantitative trait locus (QTL) mapping to identify chromosomal regions with possible genetic variants affecting blood pressure. Many candidate genes for a role in human hypertension were identified as a consequence of findings in rodent animal models [25–30].