Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Drug Therapy of Cardiovascular Diseases
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drug’s adverse effects, termed drug-induced LQTS (diLQTS). Antiarrhythmic drugs
that commonly cause LQTS are sotalol, dofetilide, or quinidine.
diLQTS is more likely associated with lower, rather than high doses of quinidine.
This could be in part due to mechanism of quinidine where at low doses it produces
arrhythmogenic effects on cardiac repolarization. However, quinidine inhibits
repolarization-related arrhythmias at higher doses. 58 The genes that cause patients to
be at a higher risk for diLQTS have not been fully identified. Some studies have associated
allele variants of IKs (slow rectifier potassium channels) 45 with an increased
susceptibility to drug-induced TdP. 39 Others have found women to be at a greater risk
for developing diLQTS due to the difference in modulation of IKr (rapid rectifier
potassium channels). 39
Clinical Application
Identifying patients at risk for long QT-related arrhythmias during drug therapy may
become possible as platforms to identify both common and rare variants are increasingly
deployed. Early studies suggest that available atrial fibrillation therapies may
be less effective in some genetically defined subsets, and these patients thus may be
candidates for alternate approaches.
N-ACETYLTRANSFERASE
The acetylation polymorphism elucidates another genetic polymorphism of a drugmetabolizing
enzyme studied in the early period of pharmacogenetics. NAT, a
phase II conjugating liver enzyme, catalyzes the N-acetylation and O-acetylation of
arylamine carcinogens and heterocyclic amines. The slow acetylator phenotype often
experiences toxicity from drugs such as procainamide and hydralazine, whereas
the fast acetylator phenotype may not respond to hydralazine. Slow acetylators are
also at risk for sulfonamide-induced toxicity and can suffer from idiopathic lupus
erythematosus while taking procainamide. 60 The slow acetylator phenotype is an
autosomal recessive trait. Studies have shown large variations of the slow acetylator
phenotype among ethnic groups. Allelic variation at the NAT2 gene locus accounts
for the polymorphism seen with acetylation of substrate drugs.
CONCLUSION AND FUTURE PERSPECTIVES
Translating fundamental discovery in genome science to individual patients and
populations is a challenge for the field, and genotyping for selection of appropriate
drug therapy is one of the first ways this is being accomplished. In oncology,
tumor genotyping is rapidly becoming standard of care to identify specific mutations
that then dictate selection of therapy. 61 Pre-prescription germline genotyping
is becoming standard of care to reduce the risk of serious adverse reactions
to carbamazepine and abacavir. 62 In cardiovascular therapy, a number of centers
are now deploying programs to use CYP2C19 genotypes to guide clopidogrel
therapy. The National Institutes of Health is making major investments in discovery
of new pharmacogenomic pathways and in how that information can be