Pharmacogenomics and pharmacogenetics of hypertension: update and perspectives--the adducin paradigm.
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.
Division of Nephrology, Dialysis, and Hypertension, University Vita-Salute San Raffale, Via Olgettina 60, 20131 Milan, Italy. manunta.paolo@hsr.it
Paolo
P
Manunta
Giuseppe
G
Bianchi
D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D051381:Rats; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D000099291:Adducins