Genetic variation can affect drug response in multiple ways, though it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE-PGx data release includes sequence-derived data from ~5000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled CADD score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype-guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel-CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25–30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice-based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models.

Pharmacogenetic testing can help identify primary care patients at increased risk for medication toxicity, poor response or treatment failure and inform drug therapy. While testing availability is increasing, providers are unprepared to routinely use pharmacogenetic testing for clinical decision-making. Practice-based resources are needed to overcome implementation barriers for pharmacogenetic testing in primary care.The NHGRI’s IGNITE I Network (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) explored practice models, challenges and implementation barriers for clinical pharmacogenomics. Based on these experiences, we present a stepwise approach pharmacogenetic testing in primary care: patient identification; pharmacogenetic test ordering; interpretation and application of test results, and patient education. We present clinical factors to consider, test-ordering processes and resources, and provide guidance to apply test results and counsel patients. Practice-based resources such as this stepwise approach to clinical decision-making are important resources to equip primary care providers to use pharmacogenetic testing.

Introduction: Clopidogrel is bioactivated by CYP2C19, and the CYP2C19 loss-of-function (LOF) genotype leads to reduced clopidogrel effectiveness after percutaneous coronary intervention (PCI). We examined whether clinical implementation of CYP2C19 genotype-guided antiplatelet therapy (APT) reduces the risk for cardiovascular events after PCI. Methods: CYP2C19 genotyping post-PCI was implemented at UF Health Shands Hospital in July 2012, with alternative APT recommended for LOF allele carriers. Major adverse cardiovascular events (MACE, comprised of cardiovascular death, MI, stroke and stent thrombosis) over the 6 months after PCI were determined via medical record review. MACE was compared between LOF allele carriers switched to alternative APT (LOF-alternative) and both LOF allele carriers who remained on clopidogrel (LOF-clopidogrel) and non-LOF carriers (non-LOF) using Kaplan-Meier method with additional multivariable Cox regression analysis and propensity score adjustment in LOF groups. Results: Of 412 patients (80% with ACS) who underwent PCI and genotyping, 126 (31%) had a LOF allele and 68 (54%) of these received alternative APT (prasugrel n=57, ticagrelor n=8, triple dose clopidogrel n=3). On Kaplan-Meier analysis (Figure), there was a lower incidence of MACE in LOF-alternative vs. LOF-clopidogrel groups and no significant difference between the LOF-alternative and non-LOF groups. On multivariable Cox regression analysis with propensity score adjustment, there was reduced risk of MACE in LOF-alternative vs. LOF-clopidogrel patients (HR 0.09, 95% CI 0.01-0.84, p=0.035). In the LOF-clopidogrel group, the majority of events (83%) occurred within 30 days; all were in patients who presented with an ACS. Conclusion: Changing from clopidogrel to alternative APT after PCI in patients with the CYP2C19 LOF genotype reduces the risk for MACE. These data support CYP2C19 genotyping in patients undergoing PCI, especially in those with ACS.