Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

Abstract

Disease, drugs and the placebos used as comparators are inextricably linked in the methodology of the double-blind, randomized controlled trial. Nonetheless, pharmacogenomics, the study of how individuals respond to drugs based on genetic substrate, focuses primarily on the link between genes and drugs, while the link between genes and disease is often overlooked and the link between genes and placebos is largely ignored. Herein, we use the example of the enzyme catechol-O-methyltransferase to examine the hypothesis that genes can function as pharmacogenomic hubs across system-wide regulatory processes that, if perturbed in randomized controlled trials, can have primary and combinatorial effects on drug and placebo responses.

Financial & competing interests disclosure

The authors have no competing interests to declare. KH is funded by NIH grant # 1K01HL130625 and TJK is funded by # NIH/NCCIH grant R01AT008573 and grant #R33AT009306. JL is supported by AHA grant D700382 and NIH grants HG006790, HL061795, HL119145 and GM107618. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Acknowledgements

The authors thank Kenneth Mukamal and Daniel Chasman for insightful discussions.

Additional information

Funding

The authors have no competing interests to declare. KH is funded by NIH grant # 1K01HL130625 and TJK is funded by # NIH/NCCIH grant R01AT008573 and grant #R33AT009306. JL is supported by American Heart Association AHA grant D700382 and NIH grants HG006790, HL061795, HL119145 and GM107618. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.