The current issue of Genome magazine includes the article "Determining a Drug Response", which provides a discussion of pharmacogenomics and contains interviews with multiple members of the Clinical Pharmacogenetics Implementation Consortium (CPIC), including Mark Dunnenberger (director of the pharmacogenomics program at NorthShore University HealthSystem), Stuart Scott (assistant professor of genetics and genomic sciences at Mt. Sinai's Icahn School of Medicine) and Mary Relling (chair of Pharmaceutical Sciences at St. Jude Children's Research Hospital and CoPI of CPIC). The article discusses several important genes within the field of pharmacogenetics, including CYP2D6, HLA-B, and G6PD; it also briefly covers CYP2C19 and its role in response to antidepressants and antipsychotics.
CYP2D6 is responsible for metabolizing a large number of commonly prescribed drugs. The Genome article focuses on its role in converting codeine into morphine: CYP2D6 poor metabolizers cannot effectively metabolize codeine, and therefore often do not experience sufficient pain relief, while CYP2D6 ultra-rapid metabolizers metabolize codeine into morphine too efficiently, increasing the risk for morphine intoxication. The CPIC guideline for CYP2D6 and codeine recommends use of an alternative agent in these two types of CYP2D6 metabolizers. Indeed, as Mark Dunnenberger notes in the article, there have been several reports of severe or fatal toxicity in breastfeeding infants whose CYP2D6 ultra-rapid metabolizer mothers received codeine; these instances prompted the FDA to place a warning on the codeine drug label regarding breastfeeding infants. The codeine drug label also contains a black box warning regarding potential respiratory depression and death in CYP2D6 ultrarapid metabolizer children who receive codeine following tonsillectomy or adenoidectomy.
Variants within the HLA-B gene have been strongly linked with adverse reactions to a variety of different drugs. Odds ratios in the double, triple or even quadruple digits have been seen for the risk of abacavir-induced hypersensitivity reactions in individuals with HLA-B*57:01, and allopurinol-induced Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN) in individuals with HLA-B*58:01. In fact, the association between abacavir hypersensitivity and HLA-B*57:01 is significant enough that the FDA-approved drug label for abacavir currently states that genetic testing for this variant must be performed prior to initiating treatment, and that abacavir is contraindicated in carriers of *57:01. No such recommendations currently exist on the allopurinol label. Other significant HLA-B pharmacogenetic associations include the risk for carbamazepine- or phenytoin-induced SJS/TEN in patients with HLA-B*15:02.
While alternative agents exist for codeine, abacavir and allopurinol, some drugs do not have safe or effective alternatives. Rasburicase, as the article notes, is one example: leukemia or lymphoma patients are treated with the drug for tumor lysis syndrome, a potentially life-threatening condition. However, individuals with a deficiency in glucose-6-phosphate dehydrogenase (G6PD) who receive rasburicase are at a high risk for experiencing hemolytic anemia, which is itself a life-threatening adverse reaction. As Mary Relling comments in the article, alternatives exist for rasburicase but they are not optimal, meaning clinicians need to carefully weigh the pros and cons of prescribing the drug.
The article concludes with a discussion of the present and future directions of pharmacogenetics. While strong, consistent and clinically relevant associations exist for a large number of genes and drugs, the healthcare system infrastructure has not caught up with research. Stuart Scott comments on the current difficulties of getting reimbursement for genetic tests and receiving genetic results in a timely manner. He also discusses the potential benefits of having patients' genetic information integrated into the electronic medical record, which would allow doctors and pharmacists to easily access genetic data and receive alerts on pharmacogenetic associations.
View the CPIC guideline for CYP2D6 and codeine
View the CPIC guidelines for HLA-B and abacavir and allopurinol
View the CPIC guideline for G6PD and rasburicase