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

66 Applying Pharmacogenomics in Therapeutics
variants (QTL), gene expression, and epigenetic systems such as microRNA 119 and
cytosine modification (primarily methylation at CpG dinucleotides) levels 120–123 have
been investigated using the HapMap LCL samples. Interestingly, in a recent pharmacogenomic
study, integrating CpG methylation has been shown to significantly
improve our understanding of the cytotoxicities induced by clofarabine, a purine
nucleoside analog used in the treatment of hematologic malignancies and as induction
therapy for stem cell transplantation, compared to genetic variants alone, 124
indicating the potential of epigenetic biomarkers of drug response phenotypes.
These advances in elucidating the complexity of human genome and gene regulation,
together with advances in high-throughput profiling technologies (NGS-based
approaches), suggest the promise of the next wave of pharmacogenomic discovery
that aims to integrate genetic variants with other molecular targets (epigenetic biomarkers)
in detecting pharmacogenomic biomarkers with clinical implications.
STUDY QUESTIONS
1. What is the major aim of pharmacogenetic and pharmacogenomic studies?
2. What is the clinical goal of applying pharmacogenomic biomarkers in
patients?
3. What is the major difference between pharmacogenetic and pharmacogenomic
studies?
4. Give an example for the current pharmacogenomic biomarkers with clinical
practice.
5. Besides genetic variants, what other genomic features and molecular targets
can be integrated into the next wave of pharmacogenomic discovery?
Answers
1. Pharmacogenetic and pharmacogenomic studies aim to elucidate the relationships
between genetic variations and therapeutic phenotypes.
2. Clinical applications of pharmacogenomic biomarkers in patients are used
to identify patients who may benefit most from a particular drug as well as
those who may perform the worst, with severe adverse side effects.
3. Pharmacogenetic studies usually focus on well-defined candidate genes
and/or pathways. In contrast, pharmacogenomic studies are intended to be
unbiased, genome-wide scans for pharmacogenomic discovery.
4. Currently, pharmacogenomic biomarkers are being implemented in clinical
practice in patients with several common, complex diseases, such as
cardiovascular diseases, cancers, and psychiatric disorders. For example,
extensive pharmacogenetic and pharmacogenomic studies have been carried
out for the phenotype of warfarin dosing, implicating genetic variants
in VKORC1 and CYP2C9 for determining interindividual variability of
dose requirements.
5. Given their critical roles in regulating gene expression, which is fundamental
to complex traits including drug response, epigenetic biomarkers, such
as CpG methylation; histone modifications; and microRNAs, can be a novel
class of pharmacogenomic biomarkers.