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

222 Applying Pharmacogenomics in Therapeutics
extensive genetic research, which provides the basis for pharmacogenetic
and pharmacogenomic discovery.
• Pharmacogenetic and pharmacogenomic studies in pulmonary diseases
are still in the early stage. Future integration of various “omics” data will
provide a more comprehensive picture of therapeutic responses in patients
with these diseases.
INTRODUCTION
The launch of the Human Genome Project in the 1990s and the completion of the
initial human genome reference sequences 1,2 in the early 21st century opened an era
of research efforts focusing on investigating genetic variations and their implications
for common, multifactorial diseases and phenotypes. Along with our much-improved
understanding of the genetic make-up of humans, advances in technologies of highthroughput
profiling of genetic variations during the past decade have allowed
extensive exploration of the genetic contributions to various complex traits, such
as genetic susceptibility to human complex diseases, and naturally occurring variations
in physiological traits (e.g., adult height, skin color, blood pressure) and in
responses to drugs. The availability of the genotypes of common genetic variants,
particularly those in the form of single nucleotide polymorphisms (SNPs), through
microarray-based genotyping platforms and more recently the next- generation
sequencing (NGS) technologies, has facilitated the widespread use of genome-wide
association study (GWAS) to assess common SNPs for statistical associations with
complex traits. 3 The unprecedented enhancement of our understanding of the genetic
contributions to complex traits can be evidenced by the substantial expansion of
the GWAS Catalog 4 maintained by the National Human Genome Research Institute
(NHGRI), which currently covers >15,000 associated genetic variants for more than
400 human complex traits.
Physicians prescribe drugs to treat diseases on the basis of their pharmacological
characteristics and based on the probability that a patient may respond with reliable
and reproducible clinical outcomes. However, the variability in response of
the patient to the drug, likely ranging from beneficial therapeutic effects to serious
adverse effects—even fatality—has long been demonstrated from clinical observations.
Furthermore, drug response differences are common among patients, therefore
presenting challenges that require the right drug and right dose for the right
patient. Of particular interest are those drugs with a narrow therapeutic window,
such as the oral anticoagulant warfarin, the overdose of which may cause severe
bleeding in 1–3% of treated patients. 5
In patient care, variability in response to the drug is the result of the interaction
of genetic and nongenetic factors. Of them, the common nongenetic (or environmental)
factors include smoking status, food intake, concomitant drug therapy,
alcohol use, compliance, psychological status, and pregnancy and lactation status
for females. The genetic factors refer to the patient’s genetic make-up, specifically
the states of common SNPs in the human genome, which may contribute substantially
to the variability of clinical outcomes from the drug. For example, a patient’s