PGx: Truth, Hope, and Hype
Author: Dr. JP Canner, Ph.D., NRCC, MT(AAB)
Pharmacogenetics (PGx) is the practice of applying the knowledge of an individual’s genes to guide the best therapeutic options. Given the generality of this definition, there are numerous ways to implement PGx in practice. In this article, we’ll cover the basics of PGx, detailing what it is and more importantly, what it is not. Furthermore, we’ll highlight some classical drug-gene interactions and how those can improve patient outcomes.
PGx: Truth, Hope, and Hype
Starting with the hype, PGx will not perfectly match the dose of a medication to every single patient. The way an individual will respond to a medication depends on multiple factors, with genetics being one of those factors. The truth is PGx is the application of decades of research to determine which drug-gene interactions are important to consider. These drug-gene interactions are established through studies conducted as part of a medication’s FDA submission, retrospective outcome studies, and individual case-studies. The weight of evidence is considered by a consortium of experts and if the data from these various sources predict that understanding an individual’s genetics will improve treatment options, then a guidance document is drafted, reviewed, and published. The hope is PGx testing will allow a more targeted treatment approach that reduces unsuccessful outcomes and even avoids adverse drug reactions.
Statins – SLCO1B1
Statins are a class of medications that inhibit the hydroxymethylglutaryl-coenzyme A, resulting in the decrease of circulating cholesterol levels(1). It’s estimated that 92 million people are prescribed statins(2). Statins are a safe and effective medication, but do carry a risk of causing muscle degradation known as Statin-associated Myopathy (SAM)(1). The incidence of SAM has a strong correlation with increased serum concentration of statins(1). A reason some individuals have increased plasma levels of statins is due to a reduced functioning transporter that limits the amount of statin removed from the blood stream. The gene which encodes this transporter is SLCO1B1(3). There are well characterized alleles, or versions, of SLCO1B1 that can be identified through genetics testing, which will determine if the individual has a reduced function transporter(3). The results from these testing can then be used to guide the patient’s therapy to either include lower doses of statins or other alternates to lower their cholesterol. This is one example where PGx testing can provide insight to improving patient care.
5′-Fluorouracil – DPYD
5′-Fluorouracil (5-FU) is a fluoropyrimidine that inhibits the thymidylate synthase (TS) enzyme, preventing the production of the nucleotide thymidine(4). This inhibition leads to disruptions in DNA replication during cell division, which causes apoptosis (cell death) of highly proliferating cells, such as cancerous cells in tumors(4). 5-FU is a common chemotherapeutic used to treat a variety of solid tumors, including colorectal, gastric, and breast cancer(5). Given this mechanism of action, there is a tight therapeutic window for 5-FU with a limited range between an effective dose and toxicity(5). It’s estimated that 10-40% of patients given 5-FU develop severe and even life threatening toxicities(6). DPYD is the liver enzyme that metabolized 5-FU into an inactive substance. This gene has a number of alleles, including those which produce a reduced functional enzyme. Within individuals of European ancestry, the incidence of one decreased functional allele is estimate to be 7%, and in individuals with African ancestry the incidence is between 3-5%(5). Therefore, a large number of individuals can be identified as having an increase in 5-FU toxicity prior to chemotherapy initiation through DPYD.
Gravity’s PGx Services
Gravity Diagnostics offers PGx testing with our upcoming menu expansion to cover a total of 31 genes. These genes have consensus guidance documents on how they impact medications or are listed on FDA labels as important for prescribing medications. We built out our custom report to ensure all actionable information is clear to the provider. We continue to curate the literature and make semi-annual updates to ensure our testing matches best practices. Reach out today to learn more about our services and how we can help improve your patient outcomes.
References:
(1) Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circ Res. 2019 Jan 18;124(2):328-350. doi: 10.1161/CIRCRESAHA.118.312782. PMID: 30653440.
(2) Matyori A, Brown CP, Ali A, Sherbeny F. Statins utilization trends and expenditures in the U.S. before and after the implementation of the 2013 ACC/AHA guidelines. Saudi Pharm J. 2023 Jun;31(6):795-800. doi: 10.1016/j.jsps.2023.04.002. Epub 2023 Apr 11. PMID: 37228328; PMCID: PMC10203693.
(3) Cooper-DeHoff RM, Niemi M, Ramsey LB, Luzum JA, Tarkiainen EK, Straka RJ, Gong L, Tuteja S, Wilke RA, Wadelius M, Larson EA, Roden DM, Klein TE, Yee SW, Krauss RM, Turner RM, Palaniappan L, Gaedigk A, Giacomini KM, Caudle KE, Voora D. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. doi: 10.1002/cpt.2557. Epub 2022 Mar 11. PMID: 35152405; PMCID: PMC9035072.
(4) Zhang N, Yin Y, Xu SJ, Chen WS. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules. 2008 Aug 5;13(8):1551-69. doi: 10.3390/molecules13081551. PMID: 18794772; PMCID: PMC6244944.
(5) Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018 Feb;103(2):210-216. doi: 10.1002/cpt.911. Epub 2017 Nov 20. PMID: 29152729; PMCID: PMC5760397.