Pharmacogenomics and Pharmacogenetics of Hypertension

Abstract

There is a growing literature on the potential prospective use of genome information to enhance success in finding new medicines. An example of a prospective efficacy of pharmacogenetic and pharmacogenomics is the detection and impact of adducin polymorphism on hypertension. Adducin is a heterodimeric cytoskeleton protein, the three subunits of which are encoded by genes (ADD1, ADD2, and ADD3) that map to three different chromosomes. A long series of parallel studies in the Milan hypertensive rat strain model of hypertension and humans indicated that an altered adducin function might cause hypertension through an enhanced constitutive tubular sodium reabsorption. In particular, six linkage studies, 18 of 20 association studies, and four of five follow-up studies that measured organ damage in hypertensive patients support the clinical impact of adducing polymorphism. As many modulatory genes and environment affect the adducin activity, the context must be taken into account to measure the clinical effect size of adducins. Pharmacogenomics is giving an important contribution to this end. In particular, the selective advantages of diuretics in preventing myocardial infarction and stroke over other antihypertensive therapies that produce a similar BP reduction in carriers of the mutated adducin may support new strategies that aim to optimize the use of antihypertensive agents for the prevention of hypertension-associated organ damage.

Upregulation of Na+/Ca2+exchanger and TRPC6 contributes to abnormal Ca2+homeostasis in arterial smooth muscle cells from Milan hypertensive rats

“…In the chronic phase, however, plasma volume and cardiac output are usually normal, and the elevated BP is the result of a blood flow-induced compensatory shift (whole body autoregulation) to increased vasoconstriction and total peripheral vascular resistance (17,34). A relationship between the alteration in the adducin genes and renal dysfunction has been extensively studied (8,18,46,64,78), but the mechanisms involved in cardiovascular functional abnormalities in MHS rats are still unclear.Chronic hypertension is typically associated with increased peripheral vascular resistance (65). This is due, in part, to enhanced arterial smooth muscle contractility, which is regulated by intracellular Ca 2ϩ (39,65,81).…”

Epithelial Sodium Channel

“…The adducin gene nicely illustrates the power of such approach. 69 Members of the metabolizing cytochrome P450 family (CYP3A5 and CYP4A10) have been involved in saltsensitive hypertension. 70,71 One way to test the role of such a candidate gene is obviously to inactivate it in a transgenic mouse model.…”

Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet?

“…A single drug is commonly used for disorders such as seizures and hypertension, and such disorders may lend themselves to pharmacogenetic study analyzing one, or a small number of, genetic variants. [22][23][24][25] In contrast, cancer, and in particular leukemia, is treated with multiple drugs with multiple different mechanisms of action, and many different genes are involved in response, each of which has the potential for gene-gene interactions. Rocha et al 26 genotyped 16 polymorphic loci in 246 children with ALL, including 116 children with low risk (LR) and 130 with higher risk (HR) disease.…”