496
Pharmacogenomics of Diuretic Drugs
Diuretics are considered to be the fi rst-line drugs for HPN but their overall effi cacy
is not suffi cient. Many patients suffer adverse effects such as disturbances of serum
K + levels. Variations in effi cacy and susceptibility to adverse reactions of diuretics
may be partially caused by genetic polymorphisms of genes involved in the phar-
macodynamics and pharmacokinetics of diuretics. Genes with a role in the pharma-
cokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and
OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic
anhydrase (CA), CYP450 enzymes and sulfotransferases are relevant only for spe-
cifi c 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, e.g. GNB3,
α-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 α-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 benefi ted from the diuretic
and had a reduction in heart attack and stroke, while the other genotype group did
not. In the INVEST sub study, 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 benefi ted more from
diuretics, which help lower blood pressure by removing excess salt and water from
the body. The fi ndings of this study may enable patients to receive appropriate per-
sonalized medicine based on their genetic makeup.
Pharmacogenomics of ACE Inhibitors
Polymorphism of the ACE gene is known to infl uence the response to ACE inhibitor
fosinopril in hypertensive patients. Blacks with HPN, 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. HPN 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 fi rst line 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 β-blockers. Such a test enables the selection of the most effective
14 Personalized Management of Cardiovascular Disorders