Considerations for rare variants in drug metabolism genes and the clinical implications

Introduction: Large-scale whole genome and exome resequencing studies have revealed that humans have a high level of deleterious rare variation, which has important implications for the design of future pharmacogenetics studies.

Areas covered: Current pharmacogenetic guidelines focus on the implementation of common variation into dosing guidelines. However, it is becoming apparent that rare variation may also play an important role in differential drug response. Current sequencing technologies offer the opportunity to examine rare variation, but there are many challenges associated with such analyses. Nonetheless, if a comprehensive picture of the role that genetic variants play in treatment outcomes is to be obtained, it will be necessary to include the entire spectrum of variation, including rare variants, into pharmacogenetic research.

Expert opinion: In order to implement pharmacogenetics in the clinic, patients should be genotyped for clinically actionable pharmacogenetic variants and patients responding unfavourably to treatment after pharmacogenetics-based dosing should be identified and resequenced to identify additional functionally relevant variants, including rare variants. All derived information should be added to a central database to allow for the updating of existing dosing guidelines. By routinely implementing such strategies, pharmacogenetics-based treatment guidelines will continue to improve.