Pharmacogenetics of antihypertensive drug responses.

The blood pressure (BP) response to any single antihypertensive drug is characterized by marked interindividual variation, and the known predictors of response are of limited value in identifying the optimum drug for an individual patient. Analysis of genetic variation has the potential to improve our understanding of determinants of antihypertensive drug response in order to individualize drug selection. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Classic pharmacogenetic investigations have identified variations in single genes that have a large effect on antihypertensive drug metabolism and are inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6 gene, encoding a cytochrome p450 family member involved in phase I drug metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these polymorphisms have major effects on the pharmacokinetic profiles of both commonly used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have not been shown to influence variation in the antihypertensive effect of these drugs at conventional doses. Interest is now focused on identifying genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Using a candidate gene approach, such polymorphisms have been identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone system (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE), beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1), angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful. New genome-wide scanning techniques may lead to the identification of genes previously unsuspected of influencing drug response. Additional requirements for pharmacogenetic approaches to become clinically useful are the characterization of the effects of haplotypes and multi-locus genotypes on drug response, and consideration of gene-by-environment interactions. Such studies will require huge sample sizes and novel statistical methods, but the theoretical and technical framework is in place to make this possible.