Importance of quantitative genetic variations in the etiology of hypertension

Recent progress has been remarkable in identifying mutations which cause diseases (mostly uncommon) that are inherited simply. Unfortunately, the common diseases of humankind with a strong genetic component, such as those affecting cardiovascular function, have proved less tractable. Their etiology is complex with substantial environmental components and strong indications that multiple genes are implicated. In this article, we consider the genetic etiology of essential hypertension. After presenting the distribution of blood pressures in the population, we propose the hypothesis that essential hypertension is the consequence of different combinations of genetic variations that are individually of little consequence. The candidate gene approach to finding relevant genes is exemplified by studies that identified potentially causative variations associated with quantitative differences in the expression of the angiotensinogen gene (AGT). Experiments to test causation directly are possible in mice, and we describe their use to establish that blood pressures are indeed altered by genetic changes in AGT expression. Tests of differences in expression of the genes coding for the angiotensin-converting enzyme (ACE) and for the natriuretic peptide receptor A are also considered, and we provide a tabulation of all comparable experiments in mice. Computer simulations are presented that resolve the paradoxical finding that while ACE inhibitors are effective, genetic variations in the expression of the ACE gene do not affect blood pressure. We emphasize the usefulness of studying animals heterozygous for an inactivating mutation and a wild-type allele, and briefly discuss a way of establishing causative links between complex phenotypes and single nucleotide polymorphisms.