Thursday, July 21, 2016

Standardized allele function and phenotype terms for clinical pharmacogenetic test results

In December 2014 and February 2015, we blogged about the CPIC term standardization project. CPIC (Clinical Pharmacogenetics Implementation Consortium) just published the results of this project in Genetics in Medicine.

Consensus terms for allele function and phenotype were determined by starting with a broad list of terms currently used by genetic testing laboratories and in the literature followed by a modified Delphi method surveying experts in the pharmacogenomics field. Ninety percent of the participants agreed on the final sets of pharmacogenetic terms.

Defining this standard vocabulary is an important step forward to reduce confusion across clinicians, laboratories, and patients.  Electronic health records with clinical decision support are essential for the implementation of pharmacogenetics, and wide use of these terms will facilitate sharing pharmacogenetic data across diverse electronic health record systems.

The terminology will be used in new and updated CPIC guidelines. Furthermore, Dr. James Hoffman, senior author of the study, told us: "We have already seen great interest in various organizations adopting these terms, and we hope this will only continue. For example, LOINC has already included the terms in a recent release, and the terms have been endorsed by the Association for Molecular Pathology."

Read the article on Genetics in Medicine: 

Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium. Kelly E. Caudle, Henry M. Dunnenberger, Robert R. Freimuth, Josh F. Peterson, Jonathan D. Burlison, Michelle Whirl-Carrillo, Stuart A. Scott, Heidi L. Rehm, Marc S. Williams, Teri E. Klein, Mary V. Relling, James M. Hoffman.

Monday, July 11, 2016

Improvements for Variant data in PharmGKB

PharmGKB is constantly improving the way we organize and annotate data in the field of pharmacogenomics. One of our recent improvements involves how we store and refer to Variants. Genetic variation is a very important part of what we do here at PharmGKB. That importance means we need a clear and effective way to store and use genetic variations throughout the site and services we offer.

The primary change is that Variant objects are now assigned PharmGKB Accession Identifiers (i.e. PA numbers). You’ve probably already seen that Genes and Chemicals have Accession Identifers (e.g. CYP2C19 has id PA124) and now that same system of identifiers is extended to the Variants that we annotate. This may not seem like a big change on the outside but it has big implications for how we can use Variants in our tools and through our API. One of these implications is that we’ll be able to more easily integrate rare variants and variations that aren’t tied to records in dbSNP.

The second change is that we will only store data on variants that we’ve annotated. It was previously possible to link to{rsid} and get a summary of the variant whether PharmGKB had annotated that dbSNP record or not. PharmGKB has a large amount of annotations on pharmacogenomic knowledge but that covers a very, very small percentage of the 153,953,962 variants cataloged in the current release of dbSNP. This method made our system bloated and more complex so we trimmed it down. PharmGKB curators now add Variant records as they annotate them and can update Variant information when necessary.

Other improvements to Variant records include:
  • Each variant gets a mandatory name and optional symbol (e.g. rs# if applicable)
  • Variants have a primary sequence location that we consider canonical for our annotations but this location is optional for variants that haven’t been located on a specific sequence yet.
  • Variants can also have alternate sequence locations. For example, our primary location for a variant is on GRCh37 but we may have an alternate sequence location for GRCh38.
  • We now have better support for tracking alternate names given to a Variant in publications
  • Variants will use the GRCh37 assembly for their primary location when possible
Existing URLs for Variant pages on PharmGKB remain in the same format (i.e.{rsid}) and we also support the new URL format of{PA#}. The layout of the Variant page has been updated slightly to add in the new information about sequence locations and other properties.

Keep an eye out for more changes to Variant pages and data as we take advantage of these new features.

Friday, July 8, 2016

Prediction of CYP2D6 phenotype from genotype across world populations

A. Gaedigk and S. Leeder together with PharmGKB published an article in Genetics in Medicine about the prediction of CYP2D6 phenotypes from genotype data across world populations (

In the supplemental materials of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines involving CYP2D6 ( and, allele frequencies across populations have been systematically captured and updated with each new guideline or update. Using this frequency table, the article describes the calculation of diplotype frequencies and the translation into phenotype based on the activity score system. The prevalence of genetically predicted poor, intermediate, normal, and ultrarapid metabolizer phenotypes are presented for major populations.

The article also includes a critical discussion highlighting the challenges of phenotype prediction from genotype data. This includes the overestimation of certain alleles in studies with minimal CYP2D6 genotyping and issues of grouping alleles and resulting diplotypes into functional and phenotype categories.

Thursday, July 7, 2016

Common variant found in populations of African descent linked with increased risk of venous thromboembolism

Roxana Daneshjou, along with co-authors Teri Klein and Russ Altman of PharmGKB, have published a paper describing a previously uncharacterized SNP in the Protein S (PROS1) gene that increases risk of venous thromboembolism (VTE).  VTE is more common in African American populations than in populations of European descent, yet the genetic risk factors identified previously are found predominantly in European populations. The V510M (rs138925964) variant in PROS1 described in Daneshjou, et al. was validated in a multi-center cohort and is expected to have a damaging effect on protein S function. This SNP was found at about 1% in populations of African descent but was found rarely in populations of European descent and is expected to confer an odds ratio of 4.61 (95% CI = 1.51- 15.20) for VTE. This finding highlights the importance of including diverse populations in genetic research. 

A video describing the study and findings can be found on Wiley's Youtube Channel and on the Molecular Genetics and Genomic Medicine website.

Wednesday, June 29, 2016

Wall Street Journal Discusses Predispositional Personal Genome Sequencing, PGx

A recent article by Laura Landro in the Wall Street Journal titled “Why Knowing Your Genetic Data Can Be a Tricky Proposition” discusses the benefits and complications of Predisposition Personal Genome Sequencing (PPGS) and the Personal Genome Sequencing Outcomes, or PeopleSeq consortium. PPGS is preemptive genome sequencing of apparently healthy patients, which contrasts with genome sequencing  for diagnosis of genetic disease. The article highlights the efforts of private companies, health care systems and academic research centers, some of which include members of the Clinical Pharmacogenetics Implementation Consortium (CPIC) that conduct PPGS in healthy patients. Although it emphasizes how PPGS may help patients discover genetic pre-disposition to disease, many institutions, including those that collaborated as part of the PeopleSeq consortium, returned pharmacogenomics results for health records or to patients if requested.  Of 258 adults surveyed from the three PeopleSeq sites (Harvard Personal Genome Project, Illumina Understand Your Genome program and Mount Sinai HealthSeq), 81% said it was “very” or “somewhat important” to learn about personal response to medications. In addition, 99 and 98% had a “personal interest in genetics in general” and “curiosity about my genetic make-up”, respectively, while “92% had a desire to participate in research to help others”. The favorable attitude of many participants towards genome sequencing and pharmacogenomics, demonstrates a growing understanding and awareness of genomics, which is an encouraging sign for genomics and pharmacogenomics research.

Friday, June 10, 2016

Congratulations to Dr. Rochelle Long in her new role at NIGMS

The PharmGKB team congratulates Dr. Rochelle Long, our program officer for the past 16 years, in her new role as Director of NIGMS Division of Pharmacology, Physiology, and Biological Chemistry.  Dr. Long’s vision, leadership, dedication, friendship and support have been instrumental in elevating and maturing the field of pharmacogenomics. Her friends and colleagues describe her by the words below:

We wish her great success in her new position, we look forward to her continued leadership, and, impact on and the facilitating of novel science

NIGMS has issued a press release detailing her new appointment.

Wednesday, June 8, 2016

Spring SNPits Summary

The Spring edition of UF Health Personalized Medicine Program's e-newsletter, SNPits is out now. This edition of SNPits summarizes and discusses publications in the American Journal of Health-System Pharmacy, Gastroenterology, and Genetics in Medicine. 

The first publication summary was of a retrospective study that analyzed the pharmacogenetic (PGx) and medication history data from over 20,000 male and female patients of various ethnicities who had been referred to Genelex for pharmacogenetic (PGx) testing. Some patients had genotype information for one CYP gene, while others had genotype information for CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5. The study reports that 93% of the individuals with genotype information for five SNPs were not “normal metabolizers” for at least one CYP isoenzyme, and that older patients were more likely to have potential drug-gene interactions (DGI) or drug-drug-gene interactions (DDGI) as compared to younger patients, likely due to polypharmacy. The authors of the study conclude that the relatively high prevalence of potential and actual DGIs and DDGIs (27.3% of all subjects were found to have at least one physician recommendation to change or consider changing medications due to DGI or DDGI) suggests that PGx testing benefits all patients, and that older patients on multiple drugs are at increased risk for harm. Read the SNPit here. 

The second publication summary was of a study in Dutch patients from 30 hospitals with inflammatory bowel disease (IBD). Thiopurines are standard treatment for IBD and variants in the TPMT gene (TPMT *2, *3A, *3C) are associated with increased hematological adverse reactions (ADRs) such as leukopenia or low platelet counts in patients administered thiopurines. Patients were randomized to receive a standard dose of thiopurines (controls) or TPMT genotype based dosing (intervention). Patients homozygous for the aforementioned TPMT variants received 0-10% of standard dose, and patients heterozygous for those variants received 50% of standard dose. Primary outcomes were the occurrence of a hematological ADR. In a twenty week follow-up the authors found no difference in the proportion of patients with hematological ADRs when comparing between the intervention and control groups (7.4% of the intervention vs 7.9% control; relative risk, 0.93; 95% CI 0.57-1.52). However, when looking exclusively at patients who carried TPMT variants, the proportion of patients that developed ADRs in the intervention was significantly lower (2.6%) as compared to the control group (22.9%) (relative risk, P= 0.11; 95% CI, 0.01-0.85). There was no significant difference in clinical outcome between groups. Read the SNPit here

Finally, the third publication summary is of a position statement from the American College of Medical Genetics Board of Directors regarding direct-to-consumer genetic testing, also known as DTC genetic testing. The publication is a revision statement from the ACMG Board of Directors on the use of DTC genetic testing. The revised position statement recognizes the utility of DTC genetic testing, but cautions that several conditions should be met for DTC genetic testing. Read the SNPit here

Genotype based dosing guidelines for CYP2D6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and TPMT are available at PharmGKB and CPIC