Genetics of hypertension: from experimental animals to humans

Abstract

Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.

Fig. 1

Selected analytical tools in rat genetics. A) The construction of recombinant inbred animals which are genetic mosaics of the two founding strains, consomic (chromosome substitution), congenic strains. B) An alternative method for fine-mapping small-effect QTLs uses outbred rats of known ancestry, genetically heterogeneous stock (HS). HS rats are generated by intercrossing several inbred progenitor strains followed by cross breeding for more than 50 generations.