GENETICS OF HYPERTENSION - THERAPEUTIC IMPLICATIONS

Essential hypertension affects approximate to 20% of the adult populat ion, and has a multifactorial origin arising from an interaction betwe en;susceptibility genes and environmental factors. The understanding o f the molecular basis of essential hypertension may provide us with ne w and more specific pharmacological agents, and perhaps the ability to individualise treatment and maximise the reduction in risk of morbidi ty and mortality from cardiovascular disease. Hypertension due to sing le gene abnormalities is very rare; however, it follows a Mendelian mo del of inheritance and therefore can be identified successfully using family linkage studies. Since clear Mendelian models of inheritance ca nnot readily be assigned in essential hypertension as there may be var iable penetrance of susceptibility genes, other studies with designs b ased on affected sibling pairs, family-based association studies and c ase-control studies have been performed. The renin-angiotensin system (RAS) plays an integral part in the control of blood pressure, and gen etic polymorphisms within this system and their effect on the response to antihypertensive therapy are now being studied. Polymorphisms of t he angiotensin converting enzyme (ACE) gene, although associated with left ventricular hypertrophy, do not appear to have a clear associatio n with hypertension. Studies on the association of genotype with respo nse to antihypertensive therapy are less consistent for genetic polymo rphisms of the RAS. Although some of the results are positive, patient numbers have been small in the studies completed to date. Genetic pol ymorphisms of the adrenergic receptors have been associated with blood pressure variation in African-Americans, White Americans and African- Caribbeans. A beta(2)-adrenoceptol polymorphism exhibits agonist-media ted receptor downregulation which may lead to enhanced peripheral vaso constriction, Therapeutic studies have not yet been completed on patie nts with this genotype. A further polymorphism of the oc-adducin gene has been associated with essential hypertension. This may influence bl ood pressure response to sodium loading/depletion and response to long term treatment with a thiazide diuretic, but further studies are need ed to clarify this. Antisense oligonucleotides targeted against genes of the RAS, e.g. angioten-sinogen and the angiotensin type I receptor, are being modified to improve targeting and thereby reduce toxicity. However, gene therapy is unlikely to replace pharmacological therapy i n 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 t o individualising antihypertensive therapy.