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

96 Applying Pharmacogenomics in Therapeutics
• Genetic variants associated with pharmacogenomics include SNPs, mutations,
insertions, small deletions or duplications, large deletions or duplications,
and chromosome rearrangements.
• Pharmacogenomic testing for clinical applications should be performed by
CLIA-certified laboratories and handled by qualified personnel certified by
an appropriate accrediting agency.
• Cytochrome P450 (CYP) superfamily is a class of the important drugmetabolizing
enzymes. Polymorphisms of CYP genes are associated with
variable drug response.
• Thiopurine methyltransferase (TPMT) is an important enzyme responsible
for the metabolism of thiopurine drugs, such as 6-mercaptopurine (6-MP)
used for the treatment of acute lymphoblastic leukemia (ALL) of childhood.
• Polymorphisms of other drug-metabolizing enzymes, including
N-acetyltransferase (NAT) and uridine diphosphate glucuronosyltransferase
1A (UGT1A) are also associated with different drug responses among
individual patients.
• Drug transporters, such as ATP-binding cassette subfamily B member 1
(ABCB1), breast cancer resistance protein (BCRP), and organic aniontransporting
polypeptide (OATP), play important roles in transporting drugs
across the cell membrane, and therefore polymorphisms of these transporters
could be associated with variation in drug efficacy and adverse reactions.
• Pharmacodynamics studies the biochemical and physiological effects of the
drug. There are more than 25 examples of drug targets with sequence variants
associated with drug efficacy. One such example is the beta-2 adrenergic
receptor (β2 adrenoceptor, or ADRB2).
• Pharmacogenomics has identified some novel cancer therapy targets, such
as BCR/ABL in chronic myeloid leukemia (CML), HER2 in breast cancer,
and ALK and EGFR in lung cancer.
• In addition to treating disease, pharmacogenomics can also provide information
on disease prevention by genetic testing for inherited susceptibility
to cancer. For example, testing of BRCA1 and BRCA2 is used to assess risk
for developing breast cancer.
• Precision medicine through pharmacogenomics will revolutionize disease
treatment and health improvement in the near future.
INTRODUCTION
It has been long recognized that there are often significant differences in drug efficacy
and side effect profiles among patients. It is estimated that most drugs are effective
for only about 30–60% of individual patients (Spear et al. 2001), and about 7%
of patients receiving the same drugs suffer a serious adverse drug reaction (ADR)
(Lazarou et al. 1998). Interindividual variations in drug efficacy and safety can be
affected by either genetic or environmental factors, such as age, organ function, drug
interactions, and comorbidities. Genetics is estimated to account for 20–95% of differences
in drug disposition and effects (Kalow et al. 1998). Pharmacogenetics studies