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