CP&T Issue Focuses on Personalized Medicine

The October 2012 issue of Clinical Pharmacology & Therapeutics focuses on individualized medicine including articles that discuss, reveal and tackle key issues in the field of PGx, and provides examples of current clinical implementation projects. Clinical Pharmacology & Therapeutics Volume 92, Issue 4 (October 2012)

Amongst these are articles by past and present members of the PGRN:

• Ready when you are: easing into preemptive pharmacogenetics.   He YJ, McLeod HL.
• Pharmacogenomics and individualized medicine: translating science into practice. Crews KR, Hicks JK, Pui CH, Relling MV, Evans WE.
• The relevance of "missing heritability " in pharmacogenomics. Sadee W.
• Strategies for personalized medicine-based research and implementation in the clinical workflow. Lieb W, Völzke H, Pulley JM, Roden DM, Kroemer HK.

and articles we have announced in previous blogs:

• 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.
  
• The 1200 Patients Project: Creating a New Medical Model System for Clinical Implementation of Pharmacogenomics. P H O'Donnell, A Bush, J Spitz, K Danahey, D Saner, S Das, N J Cox and M J Ratain.
  
• Implementing Personalized Medicine: Development of a Cost-Effective Customized Pharmacogenetics Genotyping Array. J A Johnson, B M Burkley, T Y Langaee, M J Clare-Salzler, T E Klein and R B Altman.

CPIC publishes guidelines on interpreting genetic test results for HLA-B*5801 when prescribing allopurinol therapy.

Allopurinol is an analog of the purine base hypoxanthine. It inhibits the conversion of hypoxanthine and xanthine to uric acid by XDH and is used in the treatment of gout.  Severe cutaneous adverse reaction, SCAR, also known as allopurinol hypersensitivity syndrome, is a rare serious and sometimes fatal side effect that occurs in an estimated 0.1 to 0.4% of allopurinol-treated patients.  SCAR is manifested by Stevens-Johnsons Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS). 

There is substantial evidence linking HLA-B*5801 with allopurinol-induced SCAR [see Articles: 15743917, 18192896, 19018717, 19696695, 21301380, 21393610, 21545408].  A recent meta-analysis pooling all the published studies gave the odds ratios for allopurinol induced SCAR in HLA-B*5801 carriers as 73 and 165 for studies using healthy controls and allopurinol tolerant controls, respectively [Article: 21906289]. 
A multinational team of rheumatologists, clinicians and pharmacogenomics researchers evaluated the evidence on HLA-B*5801 and allopurinol-induced SCAR. The CPIC guidelines recommend that allopurinol not be used in patients who are known carriers of HLA-B*5801.

To find out more:

Please click here to see excerpts from the guideline and access downloads of the article and supplement . 

Please click here for a complete list of CPIC publications.

European Medicines Agency Drug Labels

European Public Assessment Reports (EPARs) for drugs published by the European Medicines Agency (EMA) that include pgx information are now available to view on PharmGKB. We add any pgx-containing EMA or FDA drug labels that come to our attention.

Like our FDA drug label information, we provide a summary and excerpt from the EMA drug report. A PDF of the EPAR with pgx information highlighted by our curators is available to download.

View our complete list of drug labels with pgx information.

View newly added EMA drug labels and related genes:

• Abacavir and HLA-B
• Aripiprazole and CYP2D6, CYP3A4
• Arsenic trioxide and PML, RARA.
• Clopidogrel and CYP2C19
• Rasburicase and G6PD

New PGRN Featured Project and PI for the Month of December

The PGRN website is featuring a new project and investigator of the month from the NWAP (Pharmacogenetics in Rural and Underserved Populations) group.

For detailed information, please visit the PGRN website.

PharmGKB welcomes Julia Barbarino to the team

We are pleased to welcome scientific curator Julia Barbarino to the PharmGKB team. Julia recently completed her master's in Medical Molecular Genetics from the University of Aberdeen, Scotland, where her research focused on epigenetic modifications of the apolipoprotein E gene and their role in human longevity. While undertaking her degree, she had the opportunity to receive lectures in pharmacogenomics, and is excited to be working with PharmGKB in this area of genetics. In addition to her master's degree, Julia also holds a degree in Biochemistry from UCLA.

New VIP gene summary for CYP2E1

A new VIP summary is available for CYP2E1, a member of the cytochrome P450 family of drug metabolizing enzymes. CYP2E1 is constitutively expressed in the liver but makes up less than 1% of the total hepatic P450 isoforms [Article: 20100563]. It metabolizes relatively few prescription drugs (approximately 2%), however its important in the toxicity of acetaminophen, the antituberculosis drug isoniazid, and the probe drug and muscle relaxant chlorzoxazone [Article: 18695978]. Pathways for acetaminophen and isoniazid are in development and will be released soon ( NEW: Acetaminophen Pathway, Pharmacokinetics is released 1/16/2013). 

For more information on this VIP gene and its variants see the VIP tab for CYP2E1

PharmGKB welcomes Ugur Hodoglugil to the team

We are pleased to welcome scientific curator Ugur Hodoglugil to the PharmGKB team. Previously, Ugur has worked as research scientist on identifying the genetic determinants of complex traits (lipid and other metabolic phenotypes) and population structure at Gladstone Institutes, University of California San Francisco where he analyzed genome-wide scans data for quantitative trait locus analysis in families and studied the effects of variations of several candidate genes on lipid metabolism in unrelated individuals. He  performed different assays with transgenic/knockout mice and cell culture experiments to show functionality of the variants or the phenotype of gene(s) of interest. He has obtained his M.D. and Medical Pharmacology, Ph.D. degrees from Ankara, Turkey.

New PGRN Featured Project and PI for the Month of November

The PGRN website is featuring a new project and investigator of the month from the PAT (Pharmacogenomics of Arrhythmia Therapy) group.

For detailed information, please visit the PGRN website.

From Genomics & Informatics to Precision Medicine

Several PharmGKB curators plan to attend UCSF's Institute for Human Genetics 2012 Symposium on Monday 5th Nov, entitled "From Genomics and Informatics to Precision Medicine".

Speakers include those from Genentech, Kaiser Permanente and prominent universities in the USA.

We hope to see you there!

PharmGKB team celebrates Halloween

The PharmGKB team joined the Halloween celebrations this week - take a look at our pumpkin carving skills!

ASHG Annual Meeting 2012 (6th-10th Nov)

The PharmGKB curators will be attending the American Society of Human Genetics Annual Meeting in San Francisco next week and look forward to a week of interesting talks and posters.

On Thursday 8th November (2:15-3:15pm) we will be presenting two posters - one focusing on the pharmacogenomic research undertaken by PharmGKB consortia, and the other focusing on the clinical interpretation and implementation of pharmacogenomics knowledge.

We hope to see you there!

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.

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.

The 1200 Patients Project

"The 1200 Patients Project" is a pharmacogenetics (PGx) implementation project established by a team at the University of Chicago who recruited 12 physicians to participate. The project is prospectively recruiting 1200 adults taking 1-6 prescription drugs, who are under the care of one of the participating physicians, and who give consent for pre-emptive genotyping of a panel of clinically-relevant PGx variants.

A genomic prescribing system (GPS) on a web-based portal for physicians provides patient-specific clinically-relevant pharmacogenetic summaries for a drug, with stop light representations of level of risk for an adverse event or non-response. The physicians are monitored to examine whether they access the GPS during a patient's visit. The primary and secondary end points of the project are to assess whether they take the PGx information into consideration and whether this results in changes in prescriptions for patients who are at a high risk.

The aim is to assess the effectiveness of a model in which PGx information is provided to physicians in an accessible format from which they can make informed decisions when they are in consultation with a patient.

Read more:
The 1200 Patients Project: Creating a New Medical Model System for Clinical Implementation of Pharmacogenomics. O'Donnell PH, Bush A, Spitz J, Danahey K, Saner D, Das S, Cox NJ, Ratain MJ. Clin Pharmacol Ther. 2012 Aug 29. doi: 10.1038/clpt.2012.117. [Epub ahead of print]

Development of a Customized PGx Genotyping Array using key variants in PharmGKB

The University of Florida and Stanford University are undertaking a joint pharmacogenetics implementation project funded by the NIH, piloted first at Florida and replicated at Stanford. Initially, CYP2C19 genotype will be used to guide clopidogrel therapy, however a customized array of SNPs from 120 genes involved in drug response was designed for preemptive genotyping. This enables a patient's genotype information to be available in the future if or when a drug is to be prescribed. Read more in the Clinical Pharmacology & Therapeutics article available online.

Selecting SNPs for the array included one or more the following:

1. There is a PharmGKB Clinical Annotation written between the SNP and a drug response, usually with high levels of evidence.
2. It is a functional SNP within a VIP
3. It is a known tag SNPs for an important PGx haplotype
4. It is a SNP of interest to the research groups

to give:
252 PGx SNPs (listed in the Supplementary Information) + 2 sex markers + 2 SNPs for quality control

Details of the genotyping array technology, validation, costs and turnaround times are outlined. Also discussed in the article are the current potential barriers to clinical implementation of pharmacogenetics, and how a preemptive genotyping approach can overcome some of these.

Article:

Implementing Personalized Medicine: Development of a Cost-Effective Customized Pharmacogenetics Genotyping Array

J A Johnson, B M Burkley, T Y Langaee, M J Clare-Salzler, T E Klein and R B Altman. Clinical Pharmacology & Therapeutics (2012); advance online publication 22 August 2012. doi:10.1038/clpt.2012.125

New sortable PGx Research tables on PharmGKB

Tables of our Variant Annotations found on the PGx Research tab (view on gene, drug, variant and haplotype pages) can now be sorted and filtered to allow you to see the most relevant information you want to see.

example: If you want to see all variant annotations between the genetic variant rs1800462 (TPMT*2) and the drug mercaptopurine.

• From our homepage search for 'rs1800462' and click on the PGx Research tab to see the table of Variant Annotations.  
• Add filter: select 'Drug'/ pick filter select 'contains'/ type mercaptopurine/ click add (pictured). 
• The list can then be sorted by each column e.g. significance, p value. 
• Click the configure icon (pictured) in the right hand corner above the table to add, remove or rearrange columns and save your desired settings to keep them for the next time you come to the website.  

 

New features on the PharmGKB website

Check out the new features we have launched at www.pharmgkb.org

• Information is now more readily available, including haplotypes listed in the PGx Research Tab on gene and drug pages, and sortable tables.
• Our Clinical Annotations and Variant Annotations have their own page and a new look 
• Variant Annotations from the published literature used by our curators to determine the level of evidence are listed with each Clinical Annotation (click 'Show Evidence' as pictured).

We hope these new features help our users view the information they want more easily - we encourage feedback and questions to feedback@pharmgkb.org

Mining the pharmacogenomics literature

Briefings in Bioinformatics Special Issue: Current Progress in Bioinformatics 2012 contains an editorial by Russ Altman discussing the current status of bioinformatics research.

Among the articles in this special issue is a review on the current status of techniques for mining of the pharmacogenomics literature and includes descriptions of studies that have utilized the corpus of human-curated pharmacogenetic (PGx) articles in PharmGKB to train or assess the accuracy of machine-learning methods.

"The PharmGKB repository comes perhaps closest to the vision of an all-embracing pharmacogenomics corpus. It represents a major step towards an interdisciplinary biomedical information store." quote from: 

Mining the pharmacogenomics literature -- a survey of the state of the art. Hahn U, Cohen KB, Garten Y, Shah NH. Brief Bioinform. 2012 Jul;13(4):460-94.

At the PharmGKB we are currently working on a natural language processing (NLP) pipeline that would assist in the identification of relevant PGx articles for our curators to then manually curate.  

New PGRN Featured Project and PI for the Month of August

The PGRN website is featuring a new project and investigator of the month from the PARC (Pharmacogenomics and Risk of Cardiovascular Disease) group.

For detailed information, please visit the PGRN website.

Curators' Favorite Papers

Current Curators' Favorite Papers: The review by Alfirevic and Pirmohamed discusses genetic factors associated with drug-induced liver injury with a special focus on HLA gene variation [PMID: 22850601].  Parvez et al. reports that a common SNP on chromosome 4q25, which is associated with atrial fibrillation, modulates response to antiarrhythmic drugs [PMID: 22726630]. Savonarola et al. reviews the role of mutational analysis in anti-cancer targeted therapy [PMID: 22760589].

A message about RFA-HG-12-016

RFA-HG-12-016 "Clinically relevant genetic variants resource:  a unified approach for identifying genetic variants for clinical use (U01)."  

The PharmGKB team is excited to see this RFA because clinical genomics has great potential to impact medicine. PharmGKB catalogs genetic variation of relevance to drug response (pharmacogenomics) and moves research data to guidelines for clinical action.  We do not intend to apply for this RFA and we look forward to working with the grantee(s) under this program, who we presume will primarily focus on clinically actionable variants relevant to disease risk.

New PGRN Featured Project and PI for the Month of July

The PGRN website is featuring a new project and investigator of the month from the PHAT (Pharmacogenetics of Asthma Treatment) group.

For detailed information, please visit the PGRN website.

Effect of a genetic variant associated with Multiple Sclerosis mirrors response to anti-TNF therapy

Though anti-TNF therapy can be effective in the treatment of many auto-immune diseases including Rheumatoid Arthritis (RA), drugs that block TNF can promote or exacerbate Multiple Sclerosis (MS).

A genetic variant (rs1800693) within the TNFRSF1A gene has been identified in multiple GWAS as being associated with MS but not associated with other auto-immune diseases, such as RA and Chrohn's disease. New findings show that allele G of rs1800693 (the risk allele for MS) alters exon splicing and results in a novel soluble TNFR1 protein that antagonizes TNF, mimicking the effect of anti-TNF therapeutics.    

Therefore, disease-associated genetic variants identified in GWAS may provide insight into mechanisms behind drugs that cause adverse effects associated with inducing or exacerbating disease symptoms, and may help inform treatment choice for common multifactorial diseases. 

Read the article in Nature Letters:

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Gregory, A.P. et al, Nature, Published online 08 July 2012


Find out more about the pharmacogenetics of anti-TNF therapies: 

• Variants within the TNF gene have been associated with response to anti-TNF therapy.

• Genetic variants have been associated with response to infliximab,  adalimumab,  and  etanercept.
• View a Clinical Annotation relevant to anti-TNF therapy response.

abbreviations 
GWAS = genome-wide association study

MS = Multiple Sclerosis   
RA = Rheumatoid Arthritis
TNF = tumor necrosis factor 
TNFR1 = tumor necrosis factor binding protein 1

TNFRSF1A = tumor necrosis factor receptor superfamily, member 1A

New pathways on PharmGKB: Sorafenib PK and PD

We have added two new pathways: Sorafenib PK and PD pathways to our pathway collections. 

Sorafenib (Nexavar, BAY 43-9006) is a cancer drug used to treat advanced renal cell carcinoma and unresectable hepatocellular carcinoma.  It blocks tumor cell proliferation and angiogenesis by targeting various types of serine/threonine and receptor tyrosine kinases.  PharmGKB sorafenib PD pathway describes its mechanism of action and PK pathway depicts candidate genes mediating the metabolism, transport of sorafenib and possible drug-drug interactions.

View or download the pathways at Sorafenib PK and PD.

View all pathways at PharmGKB.

New Relationships File Available

PharmGKB has a new relationships file available for download. This file catalogs all the current relationships between drugs, genes, diseases, variants, and haplotypes in PharmGKB. These relationships are based on annotations generated by our curators.

The new relationships file replaces and improves on the old relationships file. The entries in the old relationships file were based on co-occurence of gene, drug, and disease names within literature (primarily abstracts) and did not necessarily represent direct, curated relationships between entities.

The relationships file has quite a few new features.

• Includes relationships from our new annotations like clinical annotations, dosing guidelines, and drug label annotations
• Each relationship indicates what types of annotation it comes from in the “Evidence” field.
• PMIDs are now listed for relationships when available in the “PMIDs” field. This is a semi-colon(;) delimited list of PMIDs used to support the annotation.
• The “Association” field gives a sense of whether an association is positive, negative, or ambiguous. Please see note below regarding associations in disease relationships.
• Haplotype annotations are now included.
• PK/PD flags for pharmacokinetic or pharmacodynamic relationships have been added back in.

To get a copy of this file please sign into the site, agree to the PharmGKB Relationship Agreement on the Downloads page, and a copy of the file with supporting documentation will be sent to you.

NOTE: Disease associations derived from a VariantAnnotation or ClinicalAnnotation are really referring to a variant that has an annotation with that “Disease” tag. These associations can be misleading because they are not necessarily indications that a variant is directly associated with a disease phenotype.

PharmGKB has an opening for a scientific curator

PharmGKB is looking to fill a Curator position in the Department of Genetics at Stanford University.  We are specifically looking for someone with a clinical or pharmacology background to add to the curation team. 

This position works with a group of curators to collect and analyze information from the scientific literature as well as through direct submissions, abstracting this information in the required format(s), verifying for accuracy, compiling educated summaries of the literature, discovering new facts by analyzing the collected data and refining the submitted data.

Qualifications required:

PharmD, PhD, MD
Three - five years relevant experience
In-depth training and knowledge of pharmacology, genetics, molecular biology, and/or bioinformatics
In-depth training and knowledge of pharmaceuticals including dosing, interactions and use.
Familiar with disease areas including cancer, cardiovascular disease and asthma as well as publicly available biological databases
Strong analytical, organization and communication (English written and oral) skills
Detail oriented
Desired Qualifications:
Seven years relevant experience
Experience with relational databases, data integration and statistics preferred
Enjoys public speaking

Please apply here if you are interested in this position.

Genetic contribution of response to opioids

Opioids  are commonly prescribed for pain relief, yet many individuals suffer adverse side effects such as nausea, dizziness and sedation.

A study published in this month's Anesthesiology set out to establish the relative contribution of genetic and environmental factors in opioid response. 114 monozygotic and dizygotic twin pairs were recruited, and were given either alfentanil then placebo, or placebo then alfentanil. Significant heritability was shown for respiratory depression, nausea and disliking of the drug. Almost 60% of the variation in nausea response was attributed to genetic effects. Genetic effects also accounted for around 25% of the variance in disliking of the drug, and 30% of the variance in respiratory depression decreases. Genetic and/or environmental effects were attributed to liking of the drug, sedation, dizziness and pruritus.

Aversive and Reinforcing Opioid Effects: A Pharmacogenomic Twin Study. Angst M.S. et al. Anesthesiology. 2012 Jul;117(1):22-37. Read the article

  
PGx of opioids
Discovering the specific genetic variants behind these side effects may help identify patients most at risk before prescribing opioids...

Variants within the CYP3A5 and OPRM1 gene have been associated with alfentanil drug metabolism and dosage, respectively; view these variant annotations on PharmGKB.

To avoid toxicity, CPIC have published therapeutic dosing guidelines for codeine based on an individual's CYP2D6 genotype; view these dosing guidelines on PharmGKB.

Numerous genetic variants in many different genes have been associated with response to or dosage of methadone; view these variant annotations on PharmGKB.

Helix Group & PharmGKB Retreat

Much fun and team-building was had at the Stanford Helix Group & PharmGKB retreat in San Diego last week - including sea kayaking, insightful talks and a lively discussion with guest speaker Philip Bourne. 

Helix Group & PharmGKB team members kayaking in San Diego