Hypertension as a complex genetic trait.

Abstract

Pickering first showed that blood pressure distribution is unimodal and that the diagnosis of essential (primary) hypertension is an arbitrary quantitative trait. His family studies suggested that not 1, but many, perhaps 30 or more, gene variations are responsible for raising blood pressure. Two approaches have been used to address the genetics of essential hypertension. Candidate genes have been selected by virtue of their physiologic function, and case-control association studies have been performed. Numerous candidates have been evaluated, genes of the renin-angiotensin-aldosterone system, genes coding for adrenergic receptors, genes coding for proteins regulating endothelial function, and genes involved in signaling have been studied. True to Pickering's prediction, each gene tested thus far seems to exert, at best, a small effect and contradictory studies are common. Linkage studies have been performed to map the loci of genes regulating blood pressure or inducing hypertension. Studies of dizygotic twins and their parents have permitted an identity-by-decent linkage analysis. Studies of affected sibling pairs involve subjects whose parents are generally already dead. Identity-by-state analysis requires a far greater number of pairs for results. Nevertheless, some large linkage studies have now been performed including subjects from Framingham. Log odds (LOD) scores are far removed from actually cloning genes responsible for hypertension. Single nucleotide polymorphisms (SNPs) permit linkage dysequilibrium mapping, which may enable cloning new genes. Thus far, very few new genes have been cloned for any complex genetic disease. The task is daunting but not impossible.