Combinatorial Pharmacogenetics

Our paper with Dr. Russ Wilke on epistasis and pharmacogenetics has been published in the November issue of Nature Reviews Drug Discovery. We review our MDR method and introduce a flexible four-step framework for data mining and knowledge discovery in human genetics. A more detailed paper on the latter topic has been revised and is under review.

Wilke RA, Reif DM, Moore JH. Combinatorial pharmacogenetics. Nat Rev Drug Discov. 2005 Nov;4(11):911-8. [PubMed]

Abstract:

Combinatorial pharmacogenetics seeks to characterize genetic variations that affect reactions to potentially toxic agents within the complex metabolic networks of the human body. Polymorphic drug-metabolizing enzymes are likely to represent some of the most common inheritable risk factors associated with common 'disease' phenotypes, such as adverse drug reactions. The relatively high concordance between polymorphisms in drug-metabolizing enzymes and clinical phenotypes indicates that research into this class of polymorphisms could benefit patients in the near future. Characterization of other genes affecting drug disposition (absorption, distribution, metabolism and elimination) will further enhance this process. As with most questions concerning biological systems, the complexity arises out of the combinatorial magnitude of all the possible interactions and pathways. The high-dimensionality of the resulting analysis problem will often overwhelm traditional analysis methods. Novel analysis techniques, such as multifactor dimensionality reduction, offer viable options for evaluating such data.