Saturday, November 21, 2015

Article on PGx by Dean Julie A. Johnson in The Conversation

Dean Julie A. Johnson, Dean of the College of Pharmacy, Distinguished Professor of Pharmacy and Medicine, and Director of the University of Florida Health Personalized Medicine Program at University of Florida published an article in The Conversation on November 20th, 2015 providing an overview of pharmacogenetics. Within the article, Dean Johnson explains the meaning of pharmacogenetics, and then provides two clinically relevant examples of pharmacogenetic associations.

The first example involving treatment of childhood leukemia is the TPMT gene and a class of chemotherapy drugs known as thiopurines. Dean Johnson notes that individuals whose TPMT enzyme does not work properly are given one-tenth the normal dosage of thiopurines, as recommended in guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC). These patients carry two copies of a non-functional TPMT allele, such as *2 or *3A, and are at a 100% risk of developing life-threatening myelosuppression if they receive a normal dose of thiopurines. CPIC also recommends thrice weekly as opposed to daily dosing of thiopurines for these patients, and recommends a dose reduction of 30-50% in individuals who carry one non-functional TPMT allele.

The second example is focused on the CYP2C19 gene and clopidogrel therapy. The CYP2C19 enzyme is the major enzyme responsible for the biotransformation of clopidogrel into its active metabolite. Approximately 25-30% of individuals have a CYP2C19 enzyme with reduced function due to the presence of CYP2C19 alleles such as *2 or *3. These individuals cannot fully convert clopidgrel to its active form, resulting in reduced efficacy of the drug. Dean Johnson cites the CPIC recommendations for clopidogrel, which suggest using an alternative drug in patients who carry CYP2C19 reduced function alleles. She also notes that a study undertaken at the University of Florida showed that when these types of patients were given an alternative drug, they had significantly fewer heart attacks and strokes, and were less likely to die as compared to patients who continued taking clopidogrel.

PharmGKB worked in partnership with the University of Florida Health Personalized Medicine Program on the implementation of pharmacogenetics in medicine, specifically on the creation of a customized genotyping panel for use within their personalized medicine program.

Read the article:

The Conversation - How your genes influence what medicines are right for you

The CPIC guidelines for thiopurine and clopidogrel therapy are available online at PharmGKB


Read the CPIC guidelines for thiopurine dosing and clopidogrel therapy:

Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE; Clinical Pharmacogenetics Implementation Consortium. Clin Pharmacol Ther. 2011 Dec;90(6):894. PMID: 21270794

Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-219 (CYP2C19) genotype and clopidogrel therapy. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR; Clinical Pharmacogenetics Implementation Consortium. Clin Pharmacol Ther. 2011 Aug;90(2):328-32. PMID: 21716271

Friday, November 13, 2015

Associate Director of PharmGKB Discussing Database Curation and Genetic Test Interpretation at FDA Workshop

The adoption of next generation sequencing (NGS) in research and clinical practice has led to a rapidly expanding catalog of novel and rare genetic variants. However, the lack of robust statistical evidence to link novel and rare variants to specific phenotypes makes variant interpretation difficult. This is critically important as manufacturers of in vitro diagnostic tests (IVD) must provide evidence that a test supports its claimed intended use to the Food and Drug Administration (FDA).

With the goal to adopt an adaptive regulatory approach to NGS tests the FDA is holding a Public Workshop today, November 13, to discuss the role of public genetic databases in establishing the clinical relevance of rare and novel variants. Michelle Whirl-Carrillo, Associate Director of PharmGKB, is on Panel 2 to discuss database curation and clinical interpretation of genetic test results at 11:00 am EST. 

For more information, including an agenda and a link to a webcast of the workshop, click on the link below:

Thursday, November 5, 2015

Concordance of Drug Labels and Clinical Annotations

Some drug labels have been identified by the FDA as containing pharmacogenetic biomarker information, but occasionally these variants are not listed in the Clinical Annotations on PharmGKB. The Clinical Annotations are based on literature available in peer reviewed journals and focus on germline variants. As a result, there are a few reasons why variants identified in drug labels may not be found in PharmGKB Clinical Annotations.

  1. Data used to create the drug labels are not publicly available. Research conducted by pharmaceutical companies, such as trials done for drug approval, may be proprietary information and/or not be published, but are used by the FDA. Only published literature is curated in PharmGKB.  

  1. FDA labels may be based on drug classes but Clinical Annotations are drug specific. For example, the label of Protriptyline contains information about CYP2D6 but it is unknown whether proprietary information or drug class generalizations were used for this associations. Protriptyline is a tricyclic antidepressant. While no literature is available in a PubMed search for pharmacogenetics of protriptyline itself, the protriptyline drug label has a precaution for all tricyclic antidepressants, warning that poor metabolizers via CYP2D6 have higher plasma concentrations of tricyclic antidepressants generally.

  1. Data are based on studies that do not identify specific variants or that are done on functional protein assays. Clinical Annotations are written about specific SNPs or haplotypes, not for genes or pathways generally. For example, Tetrabenazine is used to treat hyperkinetic movement disorder, such as in Huntington’s Disease, and CYP2D6 testing is required by the FDA. The study describing altered metabolism of tetrabenazine based on CYP2D6 metabolizer status (Mehanna, 2013) classifies CYP2D6 metabolizer status by phenotypes but does not include any specific genotyping information. As a result, there are no variants to annotate in the case of tetrabenazine, though altered CYP2D6 activity has been associated with tetrabenazine response. Another example is valproic acid, which is contraindicated in patients with Urea Cycle Disorders (UCD). Therefore, genetic variation in any of the genes involved in the urea cycle is actionable, but not specifically annotatable.

  1. Relevant variation is in tumor cells and not germline. Cancer drugs that target tumors may be active or inactive based on mutations in the tumor cells. These drugs include afatinib, which is used to treat non-small cell lung cancer with EGFR mutations. Because these mutations occur in the tumor cells and are not part of the germline DNA, they are not covered extensively in PharmGKB, though we are working on ways to expand coverage.

  1. PharmGKB does not have the resources to cover all the articles of PubMed, and some annotations may not be curated yet. For routine curation, we focus on journals with a high volume of pharmacogenetics articles. Articles published in other journals may lag behind in curation. If you know articles that you think should be added to curation, please send them to

Monday, October 26, 2015

International Workgroup Recommendations for Pharmacogenetic Test Result Reporting

Lack of standardization in gene nomenclature systems and inconsistencies between laboratory reports of genetic test results have been identified as significant barriers to the implementation of (PGx) information in the clinic.  PharmGKB members Teri Klein, Katrin Sangkuhl, and Michelle Whirl-Carrillo were part of an international workgroup of pharmacogenomic (PGx) experts that was organized by the Centers for Disease Control and Prevention (CDC) to make recommendations for the description and reporting of variants in PGx relevant genes. The workgroup consensus recommendations include standardizing PGx gene nomenclature by utilizing widely accepted nomenclature systems (e.g. use of HGNC gene symbols, HGVS nomenclature), as well as standardizing clinical reporting of genetic test results and genetic test descriptions (e.g. listing the variants that were observed in the test, and a publicly available description of the test). These recommendations were recently published in Clinical Pharmacology and Therapeutics.

Read the recommendations below:

Wednesday, October 21, 2015

Pharmacogenomics in the clinic: Review article in this week's Nature

In the most recent edition of Nature, Dr. Mary Relling and Dr. William Evans provide a review of pharmacogenomic implementation in the clinic. Within the article, they provide an overview of the history of pharmacogenomics (PGx), and then discuss the current state of diagnostic testing and clinical implementation of PGx. Within these latter two sections, Relling and Evans cover both the progress made and the difficulties that still exist with testing and then implementing PGx associations.

Relling and Evans bring up several interesting points in their review. With the falling cost of whole-genome sequencing, it is possible that in the near future, every individual will have their germline genome sequenced early in life. Relling and Evans suggest that there should therefore be a shift away from debate about whether a patient should be tested for genetic variants, and efforts focused instead on providing clinicians with informative guidelines on how to integrate genetic information into prescribing. They also highlight the fact that 7% of FDA-approved medications are affected by actionable pharmacogenes (as defined by the Clinical Pharmacogenetics Implementation Consortium (CPIC)), but that these drugs make up 18% of prescriptions within the United States; this data provides an incentive to improve clinical implementation of PGx. The authors also note the importance of considering multiple variants across one or more genes when analyzing PGx associations, as well as the growing importance and challenges of rare variants. In addition to these particular points of interest, the article also provides an excellent overview on the barriers to clinical implementation, and the complexity of determining the clinical actionability of gene-drug associations.

Read the article:

Pharmacogenomics in the clinic
Relling MV, Evans WE
Nature. 2015 Oct 15. 526(7573):343-50. doi: 10.1038/nature15817

Tuesday, October 13, 2015

Sequence to Medical Phenotypes, a Framework for Interpretation, Published in PLoS Genetics

As the cost of whole genome sequencing plummets and becomes more attractive for widespread application, utility depends on identifying and understanding the importance of specific genetic variants in disease risk and drug response. While tools do exist for interpretation of variants and for predicting phenotypes of novel variation, few are publicly available and are not integrated with each other. An open source framework for the interpretation of these data is presented in “Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data,” published in PLoS Genetics on October 8. The Sequence to Medical Phenotypes (STMP) framework integrates existing tools, including PharmGKB, for interpretation of variants related to Mendelian disease and drug response. It is customizable and includes both coding and noncoding variation. Its ability to identify clinically actionable and disease-causing variants has been validated in both large sets of unrelated individuals and in father-mother-child trios. It can also be used for genetic risk predictions and drug response predictions for an individual with exome, targeted resequencing, or whole genome DNA sequence data.

The STMP framework is available on the Ashley lab website:

Monday, October 12, 2015

PharmGKB succinylcholine PK/PD pathway published in Pharmacogenetics and Genomics

Succinylcholine (SCH) is a depolarizing neuromuscular blocking agent with a rapid onset of action and short half-life. SCH is commonly used in medical procedures requiring short-term skeletal muscle paralysis, such as intubation during surgery, or emergency medical procedures. The “PharmGKB summary: succinylcholine pathway, PK/PD” has been published in Pharmacogenetics and Genomics. The pathway summary describes the pharmacokinetic and pharmacodynamic pathways of SCH, and adverse reactions to SCH that are associated with variants in the genes BCHE, RYR1, and CACNA1S, as well as in patients with diagnosed with Duchenne or Becker muscular dystrophy. 

View the interactive online version of the pathway here.

See all pathways on PharmGKB.