Genetics of hypertension. Therapeutic implications.

Abstract

Essential hypertension affects approximately 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. The understanding of the molecular basis of essential hypertension may provide us with new and more specific pharmacological agents, and perhaps the ability to individualise treatment and maximise the reduction in risk of morbidity and mortality from cardiovascular disease. Hypertension due to single gene abnormalities is very rare; however, it follows a Mendelian model of inheritance and therefore can be identified successfully using family linkage studies. Since clear Mendelian models of inheritance cannot readily be assigned in essential hypertension as there may be variable penetrance of susceptibility genes, other studies with designs based on affected sibling pairs, family-based association studies and case-control studies have been performed. The renin-angiotensin system (RAS) plays an integral part in the control of blood pressure, and genetic polymorphisms within this system and their effect on the response to antihypertensive therapy are now being studied. Polymorphisms of the angiotensin converting enzyme (ACE) gene, although associated with left ventricular hypertrophy, do not appear to have a clear association with hypertension. Studies on the association of genotype with response to antihypertensive therapy are less consistent for genetic polymorphisms of the RAS. Although some of the results are positive, patient numbers have been small in the studies completed to date. Genetic polymorphisms of the adrenergic receptors have been associated with blood pressure variation in African-Americans, White Americans and African-Caribbeans. A beta 2-adrenoceptor polymorphisms exhibits agonist-mediated receptor downregulation which may lead to enhanced peripheral vasoconstriction. Therapeutic studies have not yet been completed on patients with this genotype. A further polymorphism of the alpha-adducin gene has been associated with essential hypertension. This may influence blood pressure response to sodium loading/depletion and response to long term treatment with a thiazide diuretic, but further studies are needed to clarify this. Antisense oligonucleotides targeted against genes of the RAS, e.g. angiotensinogen and the angiotensin type 1 receptor, are being modified to improve targeting and thereby reduce toxicity. However, gene therapy is unlikely to replace pharmacological therapy in the foreseeable future. The immediate goal should be to enhance our understanding of the genetic nature of essential hypertension based on the interaction of genetic makeup with the environment, with a view to individualising antihypertensive therapy.