Wednesday, February 14, 2018

CPIC Guideline Update: Carbamazepine, Oxcarbazepine and HLA genotype


The CPIC Guideline for carbamazepine, oxcarbazepine and HLA genotype is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB pages for carbamazepine and oxcarbazepine and on the CPIC website. 

Carbamazepine and oxcarbazepine are anticonvulsants which have been approved for treatment for epilepsy and, in the case of carbamazepine, trigeminal neuralgia. Patients with the HLA-A*31:01 and/or the HLA-B*15:02 allele have a significantly increased risk of carbamazepine-induced cutaneous adverse reactions, while patients with the HLA-B*15:02 allele have a significantly increased risk of oxcarbazepine-induced cutaneous adverse reactions.

The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for carbamazepine and oxcarbazepine based on HLA genotype. This guideline is and update of the 2013 guideline for carbamazepine and HLA-B genotype and now includes prescribing information for oxcarbazepine and HLA-B and new prescribing information for carbamazepine and HLA-A genotype.

For further details see the guidelines and supplement on CPIC
, or on the pages for carbamazepine and oxcarbazepine on PharmGKB.


Monday, February 12, 2018

Promote the study of Pharmacogenomics in the All of Us cohort


The NIH is collecting suggestions for what to study in a new large cohort of one million or more people living in the United States. The All of Us research program is part of the Precision Medicine Initiative and will recruit volunteers across the USA to share their data with researchers to look at big questions. NIH is seeking input from the public on what questions to address with the All of Us data and asks people to vote on the ideas they value the most.


PharmGKB has submitted some questions related to PGx that need your vote!

Idea # 363: Does collecting side-effect data directly from patients improve compliance, personalized drug choice and efficacy? After a drug has been approved, big ADRs are reported to MEDRA, but smaller side effects are not usually reported. While some may be known and in the drug label, novel side effects may occur in populations not included in the original trials. Small effects may lead to discontinuation or poor compliance. Collecting better data about side effects and combining with genomic data could give improved pharmacogenomic prediction of side effects and allow for better selection of drugs for a patient.

Idea #379: Do tailored educational materials for patient-participants undergoing pharmacogenetic testing promote patient engagement? We will assess and compare the level of understanding, engagement and satisfaction in patients who received pharmacogenetic results and are randomized to 1) a web-based portal with personalized educational content tailored to subject's results or 2)standard of care. Subjects will be surveyed to determine 1) understanding 2) engagement and 3) satisfaction. Educational content will be created by and housed at PharmGKB, in collaboration with genetic counselors and science education specialists.

There are also several more questions regarding PGx that are tagged and worth our comments and votes. Click on Pharmacogenomics in “What we are discussing” on the right hand panel.  

Thursday, February 1, 2018

Curators' Favorite Papers

The first paper (Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned) describes the process of implementing systemwide thiopurine methyltransferase (TPMT) testing at the University of Florida Health Personalized Medicine Program (UF PMP). After the successful implementation of CYP2C19 testing for patients undergoing percutaneous coronary intervention in an inpatient setting, researchers opted to analyze test ordering patterns for TPMT in a large and more diverse group of patients. Pharamacogenetic (PGx) test results were incorporated into Electronic Health Records (EHR) using Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines. Data came over a period of three years from 834 patients for whom TPMT testing was ordered (February 2014 to February 2017). In general, enzymatic testing was ordered far more frequently than genetic testing (83% vs. 17%) and rates differed significantly (P< 0.0001) between outpatient (580) and inpatient orders (293). Significant differences were discovered between specialties with regards to TPMT test orders - for example,  hematology/oncology service providers ordered genotype testing more frequently in the inpatient setting (95% of tests from hematology/oncology vs. 60% of tests from other specialties; P< 0.0001). The study also discusses differences in testing between populations and breaks down test alert notification preferences by specialties in detail. You may find more information on TPMT, azathioprine, thioguanine,  or mercaptopurine on PharmGKB and PGx-guided dosing guidelines on PharmGKB or CPICpgx.org.

The second paper (Patient understanding of, satisfaction with, and perceived utility of whole-genome sequencing: findings from the MedSeq Project) examines patient-subject understanding of informed consent, satisfaction with disclosure of results, and perception of whole genome sequencing utility (WGS) in cardiology and primary care patients. Patient-subjects were recruited by their cardiologists (already diagnosed with hypertrophic cardiomyopathy or dilated cardiomyopathy) or primary care physicians (PCP) (healthy adults) and were randomized to give family health history (FH) alone or undergo WGS too (FH + WGS). Results were discussed with their respective physicians, who had been counseled in genetics. A majority of subjects (N = 203) were White, non-Hispanic, had completed college and had annual household incomes of over $100K. Most subjects were able to adequately describe the study and demonstrated high genetics and health literacy, as well as an understanding of informed consent and experienced a high level of satisfaction. However, some differences emerged between the FH and the FH + WGS groups: subjects in the FH + WGS group were more likely to report feeling that they had received too much information, and subjects in the FH group reported less satisfaction and more decisional regret than the FH + WGS group. The authors suspect that FH subjects may have been disappointed at not having been randomized to receive WGS results. The primary care group was also more likely to feel that they had received too much information relative to the cardiology group. The authors note that the results are encouraging but suggest that similar efforts in future studies should aim to temper subjects’ expectations regarding WGS and that studies in more diverse cohorts will be necessary.



Wednesday, January 31, 2018

New CPIC Guideline: CYP2D6 and tamoxifen

The CPIC Guideline for tamoxifen and CYP2D6 is now published in Clinical Pharmacology and Therapeutics. The accepted article can be viewed on the PharmGKB page for tamoxifen, and the CPIC website. 

Tamoxifen is a selective estrogen receptor modulator (SERM) and is utilized in breast cancer treatment. Tamoxifen is extensively metabolized, in part by CYP2D6. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer.


The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

For further details see the guidelines and supplement on CPIC, or on the pages for tamoxifen on PharmGKB

Researchers interested in a highly curated genotype-phenotype data set for women treated with tamoxifen, please see the International Tamoxifen Pharmacogenetics Consortia (ITPC) paper published in Clin Pharmacol Ther (2014; PMID 24060820) with the associated data set at PharmGKB.

Friday, January 19, 2018

2018 Precision Medicine Conference

UF Precision Medicine Conference is focused on implementing PGx and genomic medicine, happening March 2018 in Orlando, Florida. See the website for registration and more information. 

Thursday, December 28, 2017

Curators' Favorite Papers

The first paper from Genetics in Medicine by Khoury et al. (From Public Health Genomics to Precision Public Health: a 20-Year Journey) reviews developments in the field of public health genomics over the last twenty years. Public health genomics deals with the “effective and responsible translation of genomic research into population health benefit” through assessment, policy, and assurance. It summarizes current research projects in the field and describes the role of organizations, including the Centers for Disease Control and Prevention (CDC) in the development and implementation of evidence-based guidelines for genetic testing. The authors recognize that genomics cannot be isolated from other determinants of health including behaviors or socioeconomic factors such as housing, education, and access to care and the need for subsequent developments in “precision public health” to integrate genomics data with other health determinants to improve public health outcomes.


Despite the fact that over 100 GPCRs are targeted by approximately 34% of FDA-approved drugs, the frequency of genetic variation of GPCRs is not known according to a study by Hauser et al. from the December issue of Cell (Pharmacogenomics of GPCR Drug Targets). The study evaluates pharmacogenetic (PGx) variation in 108 G-protein coupled receptors (GPCRs) using datasets from the exome aggregation consortium (ExAC) and the 1000 Genomes Project that include over 60,000 individuals and estimates that there is an average of 128 rare and 3.7 common variants per receptor and that 25% of all positions in each GPCR contains a missense variant. In addition approximately 120 of the 60,706 individuals from the dataset harbored loss of function mutations in a GPCR drug target and each GPCR had approximately two duplications and three deletions. The authors support their findings with an analysis of the molecular literature, including data from PharmGKB Clinical Annotations, functional PGx studies of GPCRs on drug response and efficacy and an economic analysis of how incorporation of GPCR PGx could decrease the UKs National Health Service (NHS) financial burden.

Friday, December 1, 2017

PharmCAT commentary in Clinical Pharmacology & Therapeutics

A commentary about the Pharmacogenomics Clinical Annotation Tool (PharmCAT) was recently published in Clinical Pharmacology & Therapeutics.  PharmCAT is developed in a collaboration between the former PGRN Statistical Analysis Resource (P-STAR) and the Pharmacogenomics Knowledgebase (PharmGKB) with input from other groups (click here for a list of participants). PharmCAT will extract PGx variants, beginning with variants in genes with CPIC guideline recommendations, from VCF files, infer diplotypes/genotypes, and generate an interpretation report containing the relevant CPIC recommendations.

In the article, Teri Klein and Marylyn Ritchie highlight challenges in the field and describe the rationale for PharmCAT. The tool's workflow is depicted graphically and the different components are briefly introduced.

For more information about PharmCAT read the complete commentary at Clinical Pharmacology & Therapeutics.