Wednesday, July 16, 2014

New PharmGKB VIP Summary: CYP4F2

Cytochrome p450, family 2, subfamily F, polypeptide 2 (CYP4F2) is known to catalyze multiple biological reactions.  It is predominantly expressed in the liver and kidneys, although there is evidence that it is also expressed in the intestines. Of specific interest in pharmacogenetics, hepatic CYP4F2 regulates the bioavailability of vitamin K and vitamin E and is currently studied to determine how polymorphisms in CYP4F2 affect warfarin dosing in patients. A single variant in CYP4F2 (rs2108622) is significantly associated with small, but significant alterations in warfarin dosage in Asian and Caucasian populations.

For more information on this VIP gene and variant, please see the VIP tab for CYP4F2.


Monday, July 7, 2014

Introducing CFTR as a Very Important Pharmacogene (VIP)

Variants within the CFTR gene underlie Cystic Fibrosis (CF). Traditionally, drugs used in the treatment of this disease have focused on ameliorating symptoms, fighting infection, thinning mucus and dampening inflammation. Now, drug development is focusing on pharmaceuticals that correct the underlying CFTR defect. The PharmGKB CFTR VIP summary describes potential treatment strategies that target defects conferred by particular classes of CFTR variants.

Read VIP information about these CFTR variants: 
  • F508del-CFTR is prematurely degraded, failing to reach the plasma membrane. 
          Variants resulting in CFTR gating defects:
                                                             

Tuesday, June 17, 2014

CPIC simvastatin & SLCO1B1 guideline 2014 update published

The 2014 update of CPIC guideline regarding SLCO1B1 and simvastatin-induced myopathy, has been published in Clinical Pharmacology and Therapeutics. CPIC extensively reviewed the literature from February 2011 to December 2013 and concluded that the dosing recommendations provided in the 2012 CPIC guideline for SLCO1B1 and simvastatin-induced myopathy have not changed.

The 2014 update includes the following additions:
  • Created comprehensive translation tables mapping SLCO1B1 genotypes to coded genotype/phenotype summaries, electronic health record (EHR) priority result notation and interpretation (consultation) text to facilitate incorporation of SLCO1B1 pharmacogenetics into EHR with clinical decision support.
  • Provided a brief review regarding SLCO1B1 genotype and risk of myopathy for other statins.
  • Updated SLCO1B1 * allele nomenclature and functional status (Supplemental Table S1 and S2)
  • Updated evidence linking SLCO1B1 genotype to phenotype (Supplemental Table S5).
  • Updated FDA dosing recommendations (Supplemental Table S7)
  • Added figure depicting clinical implementation workflow for EHR (Supplemental table S2)

View the interactive CPIC simvastatin dosing guideline based on SLCO1B1 genotypes, with the available full update and original published guidelines.


Read the article:
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for SLCO1B1 and simvasatin-induced myopathy: 2014 update. Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M.
Clinical Pharmacology & Therapeutics accepted article preview online 2014 Jun 11. doi: 10.1038/clpt.2014.125.

Thursday, June 12, 2014

New publication: PharmGKB Uric acid-lowering drugs pathway

Disorders involving uric acid levels are prevalent (e.g. gout, hyperuricemia and resultant kidney failure) and pharmaceuticals that reduce the generation, increase the removal or prevent the absorption of uric acid have been developed to treat these disorders.

Two PharmGKB pathways depicting the mechanism of action of these drugs and the genes involved in these pathways have been published in PG&G.

The article details the genetic associations behind severe adverse reactions induced by allopurinol (Stevens-Johnson syndrome and toxic epidermal necrolysis) and rasburicase (hemolysis).

Read the article:
PharmGKB summary: uric acid-lowering drugs pathway, pharmacodynamics.
McDonagh EM, Thorn CF, Callaghan JT, Altman RB, Klein TE.
Pharmacogenetics & Genomics. 2014 Jun 9. (Epub ahead of print)


https://www.pharmgkb.org/pathway/PA165980774https://www.pharmgkb.org/pathway/PA166114721

Click on each picture to view an interactive version of the pathway in PharmGKB

Saturday, June 7, 2014

Big Data Conference Videos

Videos of the talks at the Stanford Big Data Conference 2014 are now available to watch online (view agenda).

A selection of our favorite talks that are currently available to watch: 



New publication: NAT2 VIP Summary

The PharmGKB Very Important Pharmacogene (VIP) summary for NAT2 has been published in Pharmacogenetics & Genomics.  

The review summarizes the important role NAT2 plays in the metabolism and detoxification of many therapeutic drugs, and why genetic variants within the NAT2 gene are associated with drug-induced toxicity as well as cancer. Associations between drug responses and important NAT2 variants are detailed, and possible reasons behind a lack of consistency for some associations are discussed. 

> View an interactive version of the NAT2 VIP summary on PharmGKB.

> Read the article:
PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2.
McDonagh EM, Boukouvala S, Aklillu E, Hein DW, Altman RB, Klein TE.
Pharmacogenetics & Genomics. 2014 Jun 2. (Epub ahead of print)



NAT2 genetic variants have been linked to drug-induced hepatotoxicity

Wednesday, May 28, 2014

Tramadol pathway summary published in PG&G


Tramadol is a centrally acting opioid analgesic used to relieve moderate to severe pain.  It is administered as a racemic mixture of (+) and (-) enantiomers and exerts its analgesic effect via activating the µ-opioid receptor and inhibiting the neurotransmitter reuptake. Tramadol metabolism to its major active metabolite O-desmethyl tramadol (M1) is predominantly mediated via CYP2D6. Genetic variations of CYP2D6 have been shown to affect not only the pharmacokinetics of tramadol and M1, but also the analgesic efficacy as well as pharmacodynamic responses.

We have published the
PharmGKB summary: tramadol pathway in the Pharmacogenetics and Genomics Journal. This review summarizes the metabolism and transport of tramadol and discusses genetic variations affecting the pharmacokinetics, efficacy and toxicity of tramadol and their clinical significance.

Find out more...
View our Tramadol pathway on PharmGKB.

Read our new publication: 
PharmGKB summary:tramadol pathway
Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE.
Pharmacogenet Genomics. 2014 May 20. [Epub ahead of print]
PMID: 24849324

View all pathways on PharmGKB.