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.

Curators' Favorite Papers

The current Curators' Favorite Papers highlight articles about the translation of pharmacogenomics into practice.  The article by Johnson et al. describes the design of a customized pharmacogenetics genotyping array. This broad pharmacogenetics panel is built for the personalized medicine programs of the University of Florida and Stanford University [PMID: 22910441]. The publication by O'Donnell et al. introduces the "The 1200 Patients Project", a pharmacogenetics implementation project established by a team at the University of Chicago [PMID: 22929923]. Chua and Kennedy review current state and future prospects of direct-to-consumer pharmacogenetics [PMID: 22934000].

New PGRN Featured Project and PI for the Month of September

The PGRN website is featuring a new project and investigator of the month from the PNAT (Pharmacogenomics of Nicotine Addiction Treatment) group.

For detailed information, please visit the PGRN website.