Personalized Cardiology - Applications of Biotechnology in Cardiovascular Therapeutics - page 329

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 e3 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 reductase
inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomy-
olysis in patients treated with cerivastatin has prompted concern on the part of physi-
cians and patients regarding the tolerability of HMG-CoA reductase inhibitors.
CYP2D6 plays an important role in the metabolism of simvastatin. It has been shown
that the cholesterol-lowering effect as well as the efficacy and tolerability of simvas-
tatin are influenced by CYP2D6 genetic polymorphism. Because the different 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 efficient individual therapy (Vermes and Vermes 2004 ).
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 comprising altogether 700
Caucasian Finnish men who died suddenly (Kunnas et al. 2002a ). In ANCOVA, no
significant differences 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 significantly
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 a placebo-controlled study,
adenosine-stimulated myocardial perfusion, as determined by PET, improves after
treatment with pravastatin in subjects with the eNOS ba-genotype but not in those
with the bb-genotype (Kunnas et al. 2002b ). 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
progress in this area will be driven by studying gene-gene and gene-treatment
interactions in much larger patient populations (Ordovas and Shen 2002 ).