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reductase gene may experience signifi cantly smaller reductions in cholesterol when
treated with pravastatin. The absolute difference in total cholesterol reduction asso-
ciated with HMG-CoA reductase was signifi cant enough to affect health outcome.
Future studies should determine if this difference can be offset by adjustment of
dose or use of a non-statin cholesterol-lowering agent.
There is interindividual variation in low-density lipoprotein cholesterol (LDLc)
lowering by statins. An intronic SNP in ABCA1 and the APOE ε3 allele are associ-
ated with reduced LDLc lowering by statins and identify individuals who may be
resistant to maximal LDLc lowering by statins (Voora et al. 2008 ).
HMG-CoA reductase inhibitors are generally very well tolerated but there are
two uncommon but potentially serious adverse effects related to HMG-CoA reduc-
tase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhab-
domyolysis in patients treated with cerivastatin has prompted concern on the part of
physicians and patients regarding the tolerability of HMG-CoA reductase inhibi-
tors. CYP2D6 plays an important role in the metabolism of simvastatin. It has been
shown that the cholesterol-lowering effect as well as the effi cacy and tolerability of
simvastatin are infl uenced by CYP2D6 genetic polymorphism. Because the differ-
ent HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism
by the different CYP enzymes, genotyping may help to select the appropriate HMG-
CoA reductase inhibitor and the optimal dosage during the start of the treatment and
will allow for more effi cient individual therapy.
Role of eNOS Gene Polymorphisms
The eNOS gene harbors a common polymorphism in intron 4 (4a/b), and some
clinical studies have suggested an association of the rare a-allele with coronary
artery disease and myocardial infarction. However, contradictory results have also
been reported. One study has investigated the associations of eNOS polymorphism
with these diseases in two prospective autopsy series. In one, no signifi cant differ-
ences in areas of atherosclerotic lesions and coronary stenosis percentages were
found between men carrying the a-allele (ba + aa) compared with those homozygous
for the b-allele. Subjects with the a-allele had signifi cantly lower risk of myocardial
infarction compared with those carrying the bb genotype. Men with the a-allele also
tended to have coronary thrombosis less often. The eNOS gene 4a/b polymorphism
was not associated with the extent of coronary atherosclerosis, but the a-allele of the
variant seems to protect to some degree against the development of myocardial
infarction. In the second, a placebo-controlled study, adenosine-stimulated myocar-
dial perfusion, as determined by PET, improved after treatment with pravastatin in
subjects with the eNOS ba-genotype but not in those with the bb-genotype. This
effect is not dependent on the decrease of serum cholesterol.
However, the current clinical relevance of this knowledge is quite limited due to
the small effects observed for each of the genetic markers examined. Future prog-
ress in this area will be driven by studying gene-gene and gene-treatment interac-
tions in much larger patient populations.
14 Personalized Management of Cardiovascular Disorders