Defining our lists of PGx information

With the increasing implementation of pharmacogenomics knowledge we are often asked "What is the difference between the CPIC gene list, VIP list and the Clinical Annotations list on PharmGKB?"

Here we clarify their contents:

VIP genes (purple layer of the PharmGKB Knowledge Pyramid)
This is a list of Very Important Pharmacogenes for which the PharmGKB curators have written a concise review about the gene from the published literature. These summaries are useful for research purposes and background knowledge. These are genes with a known role in the pharmacokinetics or pharmacodynamics of drugs but associations with VIP genes may not necessarily translate into therapeutic recommendations for the clinic. This list is added to as new VIP summaries are written and published, and VIP summaries are periodically reviewed and updated.

Clinical Annotations (blue layer of the PharmGKB Knowledge Pyramid)
The PharmGKB Clinical Annotations cover the full spectrum of pharmacogenetic associations between a particular genetic variant and a drug, from low levels of evidence (e.g. in vitro assays only) to those that are implemented in the clinic. The likely drug response is outlined for each genotype of the genetic variant. Clinical Annotations below Level 1A may not yet be clinically actionable.

CPIC Gene-Drug Pairs (top green layer of the PharmGKB Knowledge Pyramid)
This is a list of gene and drug combinations for which consensus genotype-based therapeutic recommendations for clinical practice can be made. CPIC guidelines are only written for pharmacogenetic associations that are clinically actionable. This list is updated as new CPIC guidelines are published or new suggestions for important gene-drug pairs are discussed by the CPIC group. Read more about CPIC and view the published CPIC genotype-based dosing guidelines.

Read more in the Overview of the PharmGKB
Read the recent PharmGKB publication

The PharmGKB Knowledge Pyramid

New pathway: Vemurafenib Pathway, Pharmacodynamics

We have added a new pathway: Vemurafenib PD pathway to our pathway collections. 

Vemurafenib (marketed as ZELBORAF) is an oral BRAF inhibitor used to treat late-stage melanoma.  It specifically targets the mutant BRAF protein (V600E isoform) that is found in approximately half of all cases of melanoma. Vemurafenib is a personalized targeted therapy and it is only designed to be used in patients with the BRAF V600E mutation, but not for use in patients with wild-type BRAF melanoma.

PharmGKB Vemurafenib PD pathway describes the mechanism of action of vemurafenib and how it blocks tumor cell proliferation and survival via targeting BRAF V600E to effectively inhibit the MAPK signaling pathway. 

View or download the pathway at Vemurafenib PD pathway.

View all pathways at PharmGKB.

PharmGKB welcomes Daniel Klein to the team

We are pleased to welcome curator Daniel Klein to the PharmGKB team. Daniel recently graduated from the University of California, San Diego. His background is physics (specializing in astrophysics) with minors in biology, chemistry, and psychology. During his senior year at UCSD, Daniel worked as a part-time curator for the PharmGKB. We thank UCSD for providing Daniel a broad introduction to pharmacogenomics during his graduate course which included lectures from such PGx notables including Darrell Abernethy and Richard Weinshilboum.

PGx Look Up Tables

The Translational Pharmacogenetics Project (TPP) is a PGRN-led initiative with the goal to operationalize the work of CPIC by translating widely accepted actionable pharmacogenetics discoveries into real-world clinical practice.

TPP creates "look up" tables by gene which contain phenotype and clinical decision support system information based on haplotypes and diplotypes. These tables are a work in progress and are offered on PharmGKB "as is" until the tables become formalized.

View the TPP lookup tables for:

• TPMT
• CYP2C19
• CYP2D6

Read more:
A Clinician-Driven Automated System for Integration of Pharmacogenetic Interpretations Into an Electronic Medical Record.

Hicks JK, Crews KR, Hoffman JM, Kornegay NM, Wilkinson MR, Lorier R, Stoddard A, Yang W, Smith C, Fernandez CA, Cross SJ, Haidar C, Baker DK, Howard SC, Evans WE, Broeckel U, Relling MV. Clin Pharmacol Ther. (2012) Sep 19. doi: 10.1038/clpt.2012.140.

New Haplotype features on PharmGKB

New features on the Haplotype tab (example: CYP2A6):

• Details of the resources used to determine our curated haplotype maps and any important notes regarding the haplotypes are added by our curators. 
• Previously we only displayed dbSNP rsIDs within haplotypes - now you can view other genetic variants that currently have no known rsID.
• Different colors denote the reference sequence, positions that differ from the reference and tag SNPs.   

Haplotypes now also appear on gene and drug pages in the PGx Research table (example: CYP2A6 as pictured), with information including tag alleles and drugs that have been associated with the haplotype in our database.

• To view individual haplotype pages: search for a gene or drug, click on the PGx Research tab, click on the haplotype name.
• Individual haplotype pages now have extra tabs - Overview, PGx Research and VIP tab
• PGx Research tab will appear if there are variant annotations for this haplotype  
• VIP tab will appear if there is a very important pharmacogene summary with a summary for this haplotype 

PharmGKB Clinical Annotations Update and New Levels of Evidence

We have launched an update of our Clinical Annotations, assessing new evidence available for each gene variant - drug association. Each Clinical Annotation is written by a PharmGKB curator and assigned a level of evidence. We have recently revised our criteria to provide 6 levels of evidence, from the highest (1A) to the lowest (4), detailed below:

Level 1A - Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.

Level 1B - Annotation for a variant-drug combination where the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant p-values, and preferably will have a strong effect size.

Level 2A - Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.

Level 2B - Annotation for a variant-drug combination with moderate evidence of an association. The association must be replicated but there may be some studies that do not show statistical significance, and/or the effect size may be small.

Level 3 - Annotation for a variant-drug combination based on a single significant (not yet replicated) association or annotation for a variant-drug combination evaluated in multiple studies but lacking clear evidence of an association.

Level 4 - Annotation based on a case report, non-significant study or in vitro, molecular or functional assay evidence only.

Clinical Annotations can be found on PharmGKB:

• on our homepage by clicking "Clinically relevant PGx summaries'
• on gene, drug and variant pages under the 'Clinical PGx' tab
• made available as a download under the PharmGKB Data Usage Agreement 

We describe these new level of evidence criteria in the new published article:

Pharmacogenomics Knowledge for Personalized Medicine 

M Whirl-Carrillo, E M McDonagh, J M Hebert, L Gong, K Sangkuhl, C F Thorn, R B Altman and T E Klein. Clinical Pharmacology & Therapeutics (2012) 92: 414-417; doi:10.1038/clpt.2012.96

Click here to download the PDF

Zidovudine Pathway Publication

Zidovudine (ZDV, also known as azidothymidine (AZT)) is an important drug used for treatment of HIV infection. Belonging to the family of nucleoside analog reverse transcriptase inhibitor (NRTI), it is structurally related to the endogenous nucleoside thymidine. ZDV is a prodrug and must be activated by phosphorylation to exert its antiviral action.

ZDV has three important pathways of clearance: 1) phosphorylation through cellular kinases to zidovudine triphosphate; 2) inactivation by glucouronidation; 3) reduction of the azido moiety.
Zidovudine triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the endogenous nucleotide thymidine triphosphate for incorporation into newly synthesized viral DNA, which leads to DNA chain termination.

Few studies have evaluated pharmacogenomics with respect to zidovudine and antivirals overall. To find out more about how genetic variations in genes involved in the ZDV metabolism might influence efficacy and toxicity of zidovudine therapy read our publication PharmGKB summary: Zidovudine Pathway and visit the interactive pathway diagram at PharmGKB.

PharmGKB summary: Zidovudine Pathway. Y. Ghodke, P. L. Anderson, K. Sangkuhl, J. Lamba, R. B. Altman, T. E. Klein. Pharmacogenet Genomics 2012. PMID: 22960662.

View all pathways on PharmGKB.