Watch the Pharmacogenomics and PharmGKB video tutorial

Dr. Katrin Sangkuhl is a scientific curator at PharmGKB, the online pharmacogenomics knowledge base (www.pharmgkb.org). In this tutorial, Dr. Sangkuhl gives an introduction to the topic of pharmacogenomics - the impact of genetics on drug response. She reviews several pharmacogenetics examples, including codeine/CYP2D6 and clopidogrel/CYP2C19, and provides an overview of the PharmGKB website. The tutorial ends with a description of the clinical relevance of pharmacogenomics testing.

To view the video click here.

Curators Favorite Papers

The current Curators Favorite Papers are about the pharmacogenetics of statins. The review by Postmus et al. discusses achievements, whole-genome analyses and future perspectives [PMID: 22594514]. Van der Baan et al. investigate the value of pharmacogenetic testing in predicting statin response using data from the REGRESS trail [PMID: 22547143]. The Clinical Pharmacogenomics Implementation Consortium published a guideline for SLCO1B1 and simvastatin-induced myopathy [PMID: 22617227].

CPIC publishes guideline for SLCO1B1 and simvastatin-induced myopathy

Statins are among the most commonly prescribed drugs in the world to treat hypercholesterolemia and prevent cardiovascular diseases. They effectively lower cholesterol levels by inhibiting the HMG-CoA reductase, the rate limiting enzyme involved in cholesterol formation. Though well tolerated in general, statins can lead to myopathy with symptoms ranging from mild muscle pain to fatal rhabdomyolysis, especially when they are administered at higher doses and with certain other medications. A common coding SNP, rs4149056, in SLCO1B1 gene has been significant associated with marked increase in systemic exposure to simvastatin and risk of muscle toxicity. The overall effect size and significance of this association were striking for simvastatin with an odds ratio for myopathy of 4.5 (95% CI, 2.6 to 7.7) per copy of the C allele and 16.9 (95% CI, 4.7 to 61.1) among CC homozygotes as compared with the TT genotype (PMID:18650507).
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The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published the clinical dosing guideline for SLCO1B1 genotype and simvastatin dosing in Journal Clinical pharmacology & Therapeutics. This guideline  explores the relationship between rs4149056 (c.521T>C, p.V174A, SLCO1B1*5) and clinical outcome for all statins. Given that the evidence linking myopathy to rs4149056 in SLCO1B1 is more compelling for simvastatin than for any other statin, this guideline presents dosing recommendations for simvastatin only. This guideline represents the 6th publication from CPIC. All CPIC guidelines are simultaneously published and updated on PharmGKB.

To find out more,

Please see here for article and supplement.

Please see here for a complete list of CPIC publications and here for CPIC Drug-Gene Pairs..

Vitamin D receptor (VDR) polymorphisms and treatment responses

The human VDR protein is trans-acting transcriptional factor. It binds the active form of vitamin D (1,25-dihydroxyvitamin D3) to modulate many biological activities of the neural, immune and endocrine systems. Poon et al. have recently written an updated Very Important Pharmacogene (VIP) Summary for VDR gene that is published in Journal Pharmacogenetics and Genomics.

Due to the pleiotropic effect exerted by the 1,25-dihydroxyvitamin D3–VDR complex, genetic variants in VDR have been found to be associated with a wide variety of diseases and phenotypes, including various cancer, asthma, calcium absorption, bone mineral density (BMD) and hyperparathyroidism. They have also been linked to therapeutic responses to vitamin D and calcium supplements, antiresorptive treatments, calcipotriol and dexamethasone.

Find out more...

View our new VDR VIP with links to important variants, associated drug responses, mapping and publications.

Read our new VDR VIP Summary publication.

SFSU Personalized Medicine Conference - the role of epigenetics

See you at the San Francisco State University Personalized Medicine Conference 5.0, which this year focuses on epigenetics with speakers from academia and industry.

Thursday 24th May, 8:00am-7:30pm
South San Francisco Conference Center

 

Bay Area Biotechnology Symposium - Pharmaceuticals for the Future

UCSF School of Pharmacy, Industry Outreach Program is hosting a Bay Area Biotechnology Symposium tomorrow discussing the problems and solutions of developing Pharmaceuticals for the Future.

It is open to all audiences...see you there!

Saturday 19th May 2012 9:00am to 1:00pm
Genentech Hall, Byers Auditorium, UCSF Mission Bay Campus, San Francisco. 

Curators Favorite Papers

The current Curators Favorite Papers are selected around pharmacogenetics of smoking cessation and nicotine metabolism. The review by Gold & Lerman [PMID: 22290489] discusses evidence for the association of cholinergic and nicotine metabolism gene variations with smoking cessation and therapeutic response. The article by Binnington et al. [PMID: 22569203] studied variants in the CYP2A6 and CYP2B6 gene in association with nicotine metabolism in Alaska Native people. The role of the CYP2A6 gene and its variation in the metabolism of several drugs is summarized in the review by McDonagh et al. [PMID: 22547082].
The PharmGKB Pharmacokinetic and Pharmacodynamic Nicotine Pathways illustrate where the above mentioned gene are involved in nicotine metabolism and action.

NAT1 Haplotype table now available on PharmGKB

Haplotype tables are useful recent additions to PharmGKB, and the latest addition to the set is for NAT1 (N-acetyltransferase 1).  The main source for this table was the University of Louisville School of Medicine Arylamine N-acetyltransferase Gene Nomenclature Committee  website.

The PharmGKB haplotype tables, located on tabs of Gene pages, list star alleles and the (positive strand) nucleotides found at each position included in the table.  The tables contain only SNPs for which we have an rsID or UCSC Golden Path Position.

View or download this table from the Haplotype tab of NAT1.

Understanding the effect of protein structure variation on drug response

Understanding how genetic variants translate into variability in phenotype is important in the field of personalized medicine.
 

In this review, Lahti et al discuss combining knowledge of pharmacogenetics, the impact of genetic variation on protein structure, and the molecular mechanisms of how a drug works (pharmacodynamics), to provide a greater understanding of an individual's drug response. This may also aid in the development of drugs with increased efficacy and reduced toxicity.

They outline structural characteristics of drug targets, common mechanisms of protein-drug interaction and drug action, effects of genetic variation on protein structure and the impact of this structural variation on drug response. They also review the bioinformatic tools and databases available to study such effects.


Read the review:

Bioinformatics and variability in drug response: a protein structural perspective.

Lahti JL, Tang GW, Capriotti E, Liu T, Altman RB.
J R Soc Interface. 2012 May 2. [Epub ahead of print]

Review of Translational Bioinformatics

Russ Altman has published a review of translational bioinformatics based on his annual reviews at the 2012 Summit on Translational Bioinformatics (TBI) held by AMIA (American Medical Informatics Association).  Read the article online at Clinical Pharmacology & Therapeutics.

How might genetic variants of a single gene affect addiction to cigarettes and response to anti-cancer therapy?

Nicotine - one of the many substrates of CYP2A6

The human CYP2A6 enzyme is involved in the metabolism of many different compounds - including  those found in our diet and therapeutic drugs. We have recently written an updated Very Important Pharmacogene (VIP) Summary that is published in Pharmacogenetics and Genomics.

CYP2A6 has a major role in the metabolism of nicotine, and variants of the CYP2A6 gene have been associated with extent of nicotine metabolism and cigarette smoking behaviors. Individuals who have the CYP2A6*2, *4, *9 and *12 alleles, show reduced metabolism of nicotine (they are "slow metabolizers" of nicotine) and smoke fewer cigarettes per day, take smaller puffs, and find it easier to quit smoking than individuals who have normal metabolism of nicotine (see the CYP2A6 VIP summary for references and more details).

CYP2A6 also has a role in the conversion of the prodrug tegafur into 5-fluorouracil (5 FU), a compound that is broken down to metabolites that have anti-cancer properties (see the Pharmacokinetic and Pharmacodynamic pathways). Several CYP2A6 variants (such as *4, *7, *9 alleles) that have been shown to result in reduced metabolism of tegafur, have separately been associated with lower anti-cancer therapy response rates and increased risk of disease progression (see the CYP2A6 VIP summary for references and more details).

Find out more...
View our new CYP2A6 VIP Summary www.pharmgkb/vip/PA121 with links to variants, haplotypes, drugs and publications.

Read our new CYP2A6 VIP Summary publication.
PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. McDonagh EM and Wassenaar C (co-first authors), David SP, Tyndale RF, Altman RB, Whirl-Carrillo M, Klein TE. Pharmacogenet Genomics. 2012 Apr 26 (Epub ahead of print).

New PGRN Featured Project and PI for the Month of May

The PGRN website is featuring a new project and investigator of the month from the PHONT (Pharmacogenomics Ontology Network Resource) group. Learn about the informatics efforts applied to pharmacogenomics and how this data is integrated into EMRs and its translation into clinical practice.

For detailed information, please visit the PGRN website