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

Essential Pharmacogenomic Biomarkers in Clinical Practice
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technologies (genotyping using microarrays and sequencing) during the last 15 years,
the development of pharmacogenetic and pharmacogenomic research has begun to
pave the road to precision and personalized medicine by investigating the relationships
between human genetic variations and drug response variation in patients.
Significant progress has been made in elucidating the genetic basis of drug response
phenotypes. In particular, pharmacogenomic loci or biomarkers with clinical implications
have been identified for a variety of therapeutic treatments.
In this chapter, the general background of drug response as a complex trait as
well as human genetic variations as the foundation of pharmacogenomic discovery
will be introduced. The commonly used research strategy for identifying pharmacogenomic
biomarkers will be reviewed to provide an overview of the investigative
approaches utilized in pharmacogenomic discovery. The focus of this chapter is
some of the essential pharmacogenomic biomarkers with currently the strongest evidence
and known clinical implementations for drugs used to treat common diseases.
We also describe some potential pharmacogenomic biomarkers in development that
will likely have high clinical impact.
DRUG RESPONSE IS A COMPLEX TRAIT
An individual patient’s response to the drug is a complex phenotype that can
be influenced by a variety of genetic and nongenetic factors (diet, life style, and
environment) (Figure 3.1). Nongenetic factors may contribute to drug response variability
due to drug–drug or drug–diet interactions. Notably, concomitant administration
of statins with dietary compounds was found to alter statin pharmacokinetics or
pharmacodynamics, thus increasing the risk of statin-induced ADRs (myopathy or
rhabdomyolysis) or reducing their pharmacological action. 9 Mechanistically, grapefruit
juice components may inhibit CYP3A4 (cytochrome P450, family 3, subfamily
A, polypeptide 4), reducing the presystemic or first-pass metabolism of drugs, such
as simvastatin, lovastatin, and atorvastatin. 9
In contrast, drug response has been demonstrated to be an inheritable phenotype,
suggesting that an individual’s genetic make-up may contribute substantially to drug
response variability. For example, using linkage analysis based on a large pedigree
of human lymphoblastoid cell lines (LCLs) derived from individuals of European
ancestry, the heritability for cisplatin, a platinum-containing chemotherapeutic
agent used to treat various cancers, 10 was estimated to be approximately 47%. 11
Therefore, sensitivity to the cytotoxic effects of cisplatin is likely under appreciable
genetic influence. In addition, there is evidence that drug response phenotypes can
be due to multiple genomic loci or regions (polygenic traits), each of which may
only contribute a small proportion of the total variability. Shukla et al. identified
11 genomic regions on 6 chromosomes that may be significantly associated with
the susceptibility to cisplatin-induced cytotoxicity using an LCL model and linkage
analysis. 12
Given the complexity of potential contributions from both genetic and nongenetic
factors, therefore, it is often not a straightforward decision to determine
whether a patient will respond well to the drug or not. Elucidating the relationships
between genetic factors and drug response variability is crucial for a comprehensive