Importance of quantitative genetic variations in the etiology of hypertension

Recent progress has been remarkable in identifying mutations which cause di seases (mostly uncommon) that are inherited simply. Unfortunately, the comm on diseases of humankind with a strong genetic component, such as those aff ecting 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 genet ic etiology of essential hypertension. After presenting the distribution of blood pressures in the population, we propose the hypothesis that essentia l hypertension is the consequence of different combinations of genetic Vari ations that are individually of little consequence. The candidate gene appr oach to finding relevant genes is exemplified by studies that identified po tentially causative Variations associated with quantitative differences in the expression of the angiotensinogen gene (AGT). Experiments to test causa tion directly are possible in mice, and we describe their use to establish that blood pressures are indeed altered by genetic changes in AGT expressio n. Tests of differences in expression of the genes coding for the angiotens in-converting enzyme (ACE) and for the natriuretic peptide receptor A are a lso considered, and we provide a tabulation of all comparable experiments i n mice. Computer simulations are presented that resolve the paradoxical fin ding that while ACE inhibitors are effective, genetic variations in the exp ression of the ACE gene do not affect blood pressure. We emphasize the usef ulness 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.