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

234 Applying Pharmacogenomics in Therapeutics
complex traits, future pharmacogenomic applications would benefit more
from considering these potential effects. Similarly, future pharmacogenomic
approaches to considering both gene and environmental factors
(such as food intake) will be necessary to provide a more comprehensive
picture of the determinants for therapeutic response variation.
STUDY QUESTIONS
1. Why is drug response a complex trait or phenotype?
2. What are the general strategies for pharmacogenomic discovery?
3. Which gene is currently the most studied for pharmacogenomics of COPD?
4. Why are there overlapping pharmacogenomic loci between COPD and
asthma?
5. Are there any ongoing clinical trials for pharmacogenetics and pharmacogenomics
in pulmonary hypertension?
Answers
1. Drug response is likely affected by multiple factors including both genetic
and nongenetic factors (e.g., environment, food intake).
2. A candidate gene–based approach may be used if there is reasonable prior
knowledge. In contrast, an unbiased approach may be used for a genomewide
scan for associated loci.
3. To date, most studies have been focused on the roles of common genetic
variants in the ADRB2 gene (encoding β2-adrenergic receptor) on bronchodilator
responsiveness (BDR).
4. These two disorders share certain pathogenesis pathways. Many of the therapies
for asthma are also used for treating COPD.
5. Yes, for example, there are the Pharmacogenomics in Pulmonary Arterial
Hypertension Trial 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, and the PILGRIM Trial between
BMPR2 mutations and hemodynamic response by iloprost inhalation.
REFERENCES
1. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human
genome. Nature 2001;409:860–921.
2. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science
2001;291:1304–51.
3. Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution
to complex traits. Nature Reviews 2009;10:241–51.
4. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic and functional
implications of genome-wide association loci for human diseases and traits.
Proceedings of the National Academy of Sciences of the United States of America
2009;106:9362–7.