Personalized Cardiology - Applications of Biotechnology in Cardiovascular Therapeutics - page 325

of serum K + levels. Variations in efficacy and susceptibility to adverse reactions of
diuretics may be partially caused by genetic polymorphisms of genes involved in the
pharmacodynamics and pharmacokinetics of diuretics. Genes with a role in the
pharmacokinetics of most diuretics are renal drug transporters, especially OAT1,
OAT3, and OCT2 (genes SLC22A6, SLC22A8, and SLC22A2) whereas variants in
carbonic anhydrase (CA), cytochrome P450 enzymes, and sulfotransferases are rel-
evant only for specific substances. Genes on the pharmacodynamic side include the
primary targets of thiazide, loop, K + -sparing, and aldosterone antagonistic diuretics:
NCC, NKCC2, ENaC, and the mineralocorticoid receptor (genes SLC12A3,
SLC12A1, SCNN1A, B, G, and NR3C2). Polymorphisms in these and in associated
proteins such as GNB3, a-adducin and ACE seem to be clinically relevant.
A particular genetic alteration in hypertensive patients dramatically increases
the risk of heart attack, stroke, or death, and may explain why some hypertensive
patients fare worse than others, even if they take the same medication. Patients car-
rying a-adducin gene are less likely to suffer a heart attack or stroke if they were
taking a diuretic. Data from the International Verapamil SR-Trandolapril study
(INVEST-GENES) suggested that one genotype group benefited from the diuretic
and had a reduction in heart attack and stroke, while the other genotype group did
not. In the INVEST substudy, nearly a third of the participants were carriers of the
tryptophan version of the alpha-adducin gene, a protein associated with the move-
ment of ions, especially sodium, across cells. In these individuals, the amino acid
glycine has been swapped with the amino acid tryptophan. Up to 40% of the popu-
lation carries at least one copy of the tryptophan form of the gene. Patients with this
version had a 43% higher risk of heart attack, stroke, or death than those with the
glycine form in the 2½ years after the study began. But unlike previous research,
the UF study did not show that patients with the glycine form benefited more from
diuretics, which help lower blood pressure by removing excess salt and water from
the body. The findings of this study may enable patients to receive appropriate
personalized medicine based on their genetic makeup.
Pharmacogenomics of ACE Inhibitors
Polymorphism of the ACE gene is known to influence the response to ACE inhibi-
tor fosinopril in hypertensive patients. Blacks with hypertension, as a group, have
lower plasma renin activity and are less likely than hypertensive whites to achieve
adequate blood pressure reductions with ACE inhibitor monotherapy. Hypertension
is considered to be a good model for development of personalized medicine
because it is a multifactorial disease.
It is now possible to identify a subgroup of hypertensive patients (30%) that
should be treated with ACE-inhibitors as first line of treatment, since they will
show a much better response than the remaining population. This test has been
expanded to cover a panel of different classes of antihypertensive treatments, such
as angiotensin II antagonists and b-blockers. Such a test enables the selection of the