SLCO1B1 Haplotypes updated on PharmGKB

The PharmGKB Haplotype table for SLCO1B1 has just been updated and  now contains information for alleles *1-*36.  The literature includes two different alleles which were both named *16 at the time of publication, and we are using the definition for the first *16 allele to be published.  References are listed at the top of the page, above the table.  We appreciate the help of Dr. Laura Ramsey from St. Jude Children's Research Hospital and of  Dr. Kathy Giacomini and the International Transporter Consortium (Polymorphism subgroup) !  Presumably in the future, the duplicate *16 allele will receive a later *allele designation and can then be added to this table.

Curators' Favorite Papers

Russ Altman’s recent commentary in Clinical Pharmacology & Therapeutics highlights the importance of integrating personal genomic information with traditional health information in order to use it for 'personalized medicine' [PMID: 23241835]. PharmGKB’s PI uses a hypothetical example to illustrate how general population-based data can be combined with individual genomic data to create an updated estimate of drug response. In his commentary, Altman concludes that, "We can use Bayesian reasoning to integrate prior knowledge and new sources of data to estimate key clinical probabilities. We then evaluate these in the context of the anticipated value of each outcome to make the best clinical decisions possible... we can make each individual patient a small experiment that contributes to better estimates of these probabilities—a rapid-learning paradigm. We will thus continuously improve our understanding of how to use these powerful new measurements for precise and accurate clinical decisions."

We have updated the pathway: Tamoxifen PK pathway.

Tamoxifen is a selective estrogen receptor modulator. It is used to treat estrogen receptor positive breast cancer, and has been shown to decrease disease recurrence and mortality rates by 50% and 30%, respectively.

PharmGKB's Tamoxifen PK pathway describes the metabolism of tamoxifen from what can be classified as a pro-drug, to a more potent estrogen receptor inhibitor, and finally to its inactivation.

View or download the pathway here: Tamoxifen PK pathway.

View all pathways at PharmGKB.

Personalized Medicine World Conference 2013

PharmGKB curators attended the PMWC this week, featuring talks covering different areas and aspects of personalized medicine, including pharmacogenetics, co-drug and diagnostics development, adaptation of clinical trials, systems medicine, wellness, sequencing technologies, and implementation.

CPIC guidelines for TPMT and Thiopurine dosing: Update 2013

The 2013 update of the CPIC guidelines for TPMT and Thiopurine dosing is now available online, as an accepted article preview. CPIC genotype-based dosing guidelines are reviewed and updated every two years in order to be clinically current - this is the first update to be released.

After an extensive literature review, CPIC concluded that there is no new evidence that would result in changes to the original guidelines, published in 2011 and available to read or download from PharmGKB.

Read the 2013 update:

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for thiopurine methyltransferase (TPMT) genotype and thiopurine dosing: 2013 update 

Mary V. Relling, Eric E. Gardner, William J. Sandborn, Kjeld Schmiegelow, Ching-Hon Pui, Sook Wah Yee, Charles M. Stein, Michelle Carrillo, William E. Evans, J. Kevin Hicks, Matthias Schwab and Teri E. Klein. 
Clin Pharmacol Ther doi:10.1038/clpt.2013.4; accepted article preview online January 17, 2013.

View the CPIC gene-drug pairs table with the current status of guidelines and updates.

Additional EMA drug labels released on PharmGKB

Our collection of drug labels containing pgx information from the European Medicines Agency has been extended:

Boceprevir and IL28

Brentuximab vedotin and CD30 (TNFRSF8)

Capecitabine and DYPD

Cetuximab and KRAS

Crizotinib and ALK

Dasatinib and the Philadelphia chromosome

Eltrombopag and F5, SERPINC1 

Everolimus and ERBB2 (HER2)

Fulvestrant and estrogen receptor

View a complete list of available FDA and EMA drug labels with highlighted pgx information.

Tailored therapy in asthma? ADRB2 genotype in the context of salmeterol therapy

In a recent trial, asthmatic children homozygous for the beta2-adrenergic receptor Arg16 variant (ADRB2 gene, rs1042713 genotype AA) were randomized and treated with either salmeterol (a beta2-adrenergic receptor agonist) or montelukast (a leukotriene receptor antagonist), both combined with fluticasone. Those in the montelukast treatment group displayed significantly better responses in several symptom categories, had fewer school absences, and overall had significantly higher quality of life scores over the 1 year period compared to those treated with salmeterol. [Click here for Further details]

Tailored second line therapy in asthmatic children with the arginine-16 genotype. Lipworth BJ, Basu K, Donald HP, Tavendale R, Macgregor DF, Ogston SA, Palmer CN, Mukhopadhyay S. Clinical Science (2013) 124, (517-519).

This trial was based on previous studies from the same group showing an increased risk of asthma exacerbations in children with daily exposure to beta2-adrenergic receptor agonists who have the ADRB2 Arg16 variant: 

• "Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol" Palmer et al, (2006). 
• "Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol" Basu et al, (2009).

These studies suggest that alternative treatments may be more beneficial in children with the Arg16/Arg16 genotype compared to using beta2 adrenergic receptor agonists.

Learn more about Beta-agonist action on ADRB2:

PharmGKB Beta-agonist/Beta-blocker Pathway, Pharmacodynamics

Learn more about the ADRB2 gene:

ADRB2 Very Important Pharmacogene summary