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

52 Applying Pharmacogenomics in Therapeutics
KEY CONCEPTS
• Individual response to therapeutics is likely a complex trait influenced by
both genetic and nongenetic factors.
• Pharmacogenomics aims to elucidate the relationships between therapeutic
phenotypes and various molecular targets, such as gene expression, genetic
variants, and epigenetic markers.
• Clinical implications of pharmacogenomic biomarkers hold the promise of
realizing personalized medicine by identifying patients who may benefit
most from a particular drug as well as those who may perform the worst
and with severe adverse side effects.
• Pharmacogenomic biomarkers, particularly genetic variants associated
with therapeutic phenotypes, have begun to be replicated and applied in
several common diseases, including cardiovascular diseases, cancers, and
psychiatric disorders.
• Future pharmacogenomic discovery will integrate genetic variants and
other critical molecular targets, such as epigenetic biomarkers, for a more
comprehensive understanding of drug response.
INTRODUCTION
Clinical responses to therapeutic treatments may vary significantly among individual
patients. For a particular drug, individual responses may range from beneficial
effects to no response to severe side effects, including even fatal adverse drug reactions
(ADRs). Side effects from therapeutic treatments represent leading causes
for hospital admissions and mortality. It is estimated that ADRs account for over
2.2 million hospitalization cases and more than 100,000 deaths annually in the
United States alone. 1
In particular, for drugs with a narrow therapeutic window (i.e., a narrow range
of doses between efficacy and side effects), identifying patients who may benefit
from treatment and/or predicting those who may exhibit severe ADRs prior to treatment
will substantially improve clinical practice, acting by providing precision and
personalized care for patients. For example, in oncology, anticancer chemotherapeutics
often have a narrow range of drug dose requirements between therapeutic
response and resistance, as well as between tumor response and cellular toxicities.
Chemotherapy-induced toxicities may affect vital organs such as heart (cardiotoxicity),
2 kidney (nephrotoxicity), 3 nervous system (neurotoxicity), 4 and liver (hepatotoxicity)
5 and may cause severe ADRs including fatalities. Another well-established
example of a drug with a narrow therapeutic index is warfarin, a commonly prescribed
anticoagulant for the prevention of thrombosis and thromboembolism, featuring
large interindividual variability in dose requirements, which, if not properly
monitored and managed, may increase either thrombosis risk if doses are too low,
or serious bleeding risk if doses are too high. 6
Concurrent with our great improvement of knowledge in human genetic
variations (linkage disequilibrium patterns between genetic variants) since the
launch of the Human Genome Project 7,8 and the advances in molecular profiling