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

Applying Pharmacogenomics in the Therapeutics of Pulmonary Diseases
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relatively new area, so there has been little pharmacogenomic research on PAH.
However, there are ongoing clinical trials on the pharmacogenetics and pharmacogenomics
in PAH, such as the Pharmacogenomics in Pulmonary Arterial Hypertension
Trial (ClinicalTrials.gov Identifier: NCT00593905) with the goal to determine, clinically,
in PAH patients whether associations exist between the efficacy and toxicity
of sitaxsentan, bosentan, and ambrisentan and several gene polymorphisms in
several key disease- and therapy-specific genes. Another ongoing clinical trial is
the PILGRIM Trial (ClinicalTrials.gov Identifier: NCT01054105) between BMPR2
mutations and hemodynamic response by iloprost inhalation. Still, previous studies
have demonstrated that the presence of mutations in BMPR2 and ACVRL1 genes are
associated with a less-favorable clinical response to therapeutic therapies, and an
overall poorer prognosis. 147
CONCLUSIONS
Genetics is likely a contributor to complex traits, such as the risks for diseases and
altered responses to drug treatments. Advances in technologies have begun to allow
dissection of genetic factors contributing to various pulmonary diseases, including
COPD, asthma, and PH. A variety of drug treatments have been developed
to control the disease progression or exacerbation as well as relieve symptoms.
Pharmacogenetic and pharmacogenomic studies aim to associate genetic variants,
either from candidate genes/pathways or whole-genome unbiased scans, to
the variability of therapeutic response. During the past decade, progress has been
made to identify genetic variants linked to the therapeutic variation in patients
with these pulmonary diseases. Ongoing clinical trials will provide critical knowledge
of the clinical applications of pharmacogenomic approaches in managing
pulmonary diseases. Future incorporation of other genomic features such as various
epigenetic systems (e.g., DNA methylation) in pharmacogenomic discovery 148
has the promise to elucidate the complete genomic contributors to therapeutic
response, thus facilitating the ultimate goal of personalized care of patients with
pulmonary diseases.
THOUGHTS FOR FURTHER CONSIDERATION
1. Pharmacogenomic loci beyond genetic variants: The current pharmacogenomic
findings have been focused on genetic variants, especially those in
the form of SNPs. Since genetic variation can only explain part of the variability
in the phenotypes observed, including gene expression and therapeutic
response, it may be necessary to incorporate other genomic features
beyond genetic variation. For example, given the critical roles of epigenetic
factors, such as cytosine modifications (primarily DNA methylation) and
histone modifications in gene regulation, future pharmacogenomic studies
may need to consider and integrate these factors as well.
2. Gene × gene and gene × environment interactions: The current pharmacogenomic
studies have targeted the effects of individual genes. Since
genetic epistasis, that is, the interaction between SNP and SNP, may affect