Nature Outlook: Precision Medicine on Pharmacogenetics highlights its status, promise, and burdens

An outlook on precision medicine in Nature discusses the status, promise, and burdens of the implementation of pharmacogenetic knowledge into clinical care. It highlights the PGEN4Kids program at St Jude, which is implementing CPIC recommendations in a preemptive genetic testing program for pediatric patients. As discussed in the article, CPIC has published recommendations for genotype-guided therapy of 33 drugs, with more guidelines being released each year. CPIC guidelines can be read and downloaded here: https://cpicpgx.org/guidelines/.

The article reports successful implementation of using TPMT genotypes to adjust thiopurine treatment and of screening for HLA-B genotype to avoid hypersensitivity reactions to abacavir in treatment for HIV. Moving the field forward, we agree with Drew’s emphasis on the increased value of preemptive genetic testing compared to reactionary testing, on the need for sustainable program funding, and on the importance of developing strong infrastructure to support clinical decision making in response to test results.

The article points out the struggles of the pharmacogenetics field, citing the failure of clinical trials to show improved warfarin dosing when using a genotype-guided dosing algorithm compared to a clinical algorithm. However, as Daneshjou, et al. pointed out in NEJM in their 2014 letter to the editor, the finding that the genotype-guided dosing algorithm is inferior to a clinical-dosing algorithm may be biased by different important variants and different frequencies of the variants included in the algorithm in different populations globally. For example, the apparent ineffectiveness of a genotype-guided dosing algorithm for warfarin for people of African descent may be affected by low population frequencies of the CYP2C9*2 and *3 variants that are included in this algorithm. As a result, “the authors’ ability to draw appropriate conclusions about the usefulness of genetics when determining dosages of warfarin for patients of African descent is thus very limited, and the benefits for this population have not been adequately tested.” Furthermore, if a minority of patients receive altered drug treatment as a result of genetic test results in a clinical trial, these benefits may not appear in overall summary statistics. However, the improved personalized treatment for this subset of patients should not be undervalued.

Integrating pharmacogenetics in a conservative medical system seems subject to a genetic exceptionalism resulting in a high burden of proof. Drugs thought to be affected by pharmacogenetic variability comprise 18% of the US drug market, suggesting far-reaching benefits of preemptive testing programs. We see great power in implementing the information we have now, and recognize the need for additional research to expand knowledge of variation globally and of the impacts of variants on drug response so that the benefits of pharmacogenetic testing can continue to grow.