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:

Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations for Test Result Reporting

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

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: http://ashleylab.stanford.edu/tools/stmp.html.

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.

Successful implementation of widespread pharmacogenetic testing discussed this week in The Atlantic

An article this week in The Atlantic presents the story of widespread testing for HLA genotypes in some Southeast Asian countries. Simple pharmacogenetic ID cards are issued to inform physicians of a patient’s risk for developing Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) hypersensitivity reactions if prescribed carbamazepine, allopurinol, abacavir, and other drugs. Despite a drop in the incidence of SJS as a result of the cards, better integration with electronic medical records is needed if cases are to be eliminated entirely.

This type of translation of pharmacogenetic research to improve patient outcomes is the goal of the PharmacogenomicsResearch Network (PGRN), supported by the NIH since 2000 under the leadership of Dr. Rochelle Long. Specific PGRN groups address questions ranging from basic science to clinical trials and implementation. In 2009, the Clinical Pharmacogenomics Implementation Consortium (CPIC), led by Dr. Mary Relling of St. Jude Children’s Research Hospital and Dr. Teri Klein of PharmGKB, was established to develop guidelines for and to address barriers to implementation of pharmacogenetic research. The CPIC guidelines for testing of HLA variants in relation to carbamazepine (HLA-B*15:02), allopurinol (HLA-B*58:01), and abacavir (HLA-B:57:01) treatment were published in Clinical Pharmacology and Therapeutics. Each guideline summarizes the relationship of specific HLA variants with hypersensitivity reactions to each drug and recommendations of how to alter care in response. All CPIC guidelines are freely available to the public.

July/August SNPits Summary

The July/August issue of UF Health Personalized Medicine Program's e-newsletter, SNPits, reviews a recent article in the Journal of the American Medical Informatics Association focused on genomic information in the electronic health record (EHR).  The authors of the study looked at how EHRs currently display genomic and genetic information, and how to optimize and improve upon it.  They concluded that the way that genomic information is stored and displayed affects the usefulness of the information, and made several recommendations, including development of clinical decision support (CDS) for genetic results.  Read more.

PharmGKB welcomes Alie Fohner to the team

We are pleased to welcome scientific curator Alison (Alie) Fohner to the PharmGKB team. Alie recently earned her PhD in Public Health Genetics at the University of Washington, where she worked with the Pharmacogenomics Research Network group that focuses on rural and underserved populations. Her dissertation included an analysis of genetic and environmental drivers of variation in cytochrome P450 expression in Alaska Native people, and a recommendation for reconciling conflicting ethical and statistical demands in conducting research with historically marginalized populations.  She is excited to be starting with PharmGKB, 10 years after attending a lecture by Russ Altman that inspired her interest in pharmacogenetics, and to be back at Stanford, where she received both a BS and MS in Biology.

New CPIC Guideline- UGT1A1 and atazanavir

Guidelines regarding the use of pharmacogenetic tests of UGT1A1 for atazanavir prescribing decisions have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Atazanavir is an antiretroviral protease inhibitor administered to patients infected with the human immunodeficiency virus (HIV). Atazanavir, often co-administered with low-dose ritonavir (atazanavir/r), specifically inhibits UGT1A1-mediated glucoronidation of bilirubin, leading to elevations in concentrations of plasma indirect bilirubin (hyperbilirubinemia). The resulting hyperbilirubinemia is not indicative of hepatic injury, but may result in jaundice in patients with genetic variants that negatively impact UGT1A1 function. Patient stigma due to jaundice may be of particular concern to individuals whose line of work requires them to interact frequently with the public, and may also cause individuals with visible jaundice to prematurely discontinue atazanavir. 

In the newly published guidelines, CPIC recommends advising patients with two decreased function UGT1A1 alleles about their increased chances of developing jaundice if prescribed atazanavir/r. The CPIC recommendations suggest that clinicians avoid prescribing atazanavir to such individuals, unless a patient does not consider jaundice to be a concern, or unless a strong argument exists in favor of prescribing atazanavir.  For patients carrying one, or no decreased function UGT1A1 alleles, CPIC deems the likelihood of bilirubin-related discontinuation of atazanavir to be low, and very low, respectively. 

For details, see the CPIC guideline on PharmGKB.