Wednesday, September 24, 2014

SNP-its Study Summaries

The University of Florida Health Personalized Medicine Program has released "SNP-its" study summaries for pharmacogenomic articles with clinical relevance.    The editorial team reviews articles from multiple journals and writes summaries for the ones most relevant to practicing clinicians.  Those interested are welcome to subscribe to a monthly newsletter.  Online, readers can browse summaries by topic

In the first newsletter, SNP-its highlights articles about
They also provide an overview of the personalized medicine program at UF Health.

PharmGKB is pleased to work with the SNP-its initiative to highlight articles with these summaries on our website in the coming weeks.  Look for the SNP-its icon on PharmGKB!

Thursday, September 18, 2014

CPIC PEG interferon-alpha guideline now available on

More CPIC PGx-based dosing guidelines are now available on the National Guideline Clearinghouse (NGC) website.  NGC is a public resource for evidence-based clinical guidelines, an initiative of the Agency for Healthcare Research and Quality, US Department of Health Services.
The most recent CPIC guideline on NGC is:
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α–based regimens.

View 10 CPIC guidelines on the NGC website: 

Read more about CPIC and view all PGx-based dosing guidelines available on PharmGKB.

Friday, September 5, 2014

New CPIC Guideline: CYP2C9, HLA-B and Phenytoin

Guidelines regarding the use of pharmacogenomic tests for CYP2C9 and HLA-B in dosing phenytoin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Phenytoin is broadly used to treat epilepsy, but it has a narrow therapeutic index and wide inter-patient variability.  Much of this variability is due to genetic variations in CYP2C9 and dosing levels can be altered based on patient genotype.  Additionally, HLA-B*15:02 is associated with an increased risk of phenytoin-induced cutaneous adverse drug reactions, and it is recommended that patients with at least one copy of this variant allele receive an alternate drug.

For details, see the CPIC guideline on PharmGKB.
For other CPIC guidelines see the list of CPIC publications and guidelines in progress.

Tuesday, September 2, 2014

PGx of anti-HIV drug described in new PharmGKB pathway

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor used as part of a highly active anti-retroviral therapy (HAART) regimen against HIV-1 infection. Large variability in EFV plasma levels is observed between patients given the same dose. Genetic variants underlying EFV metabolism have been shown to contribute to this variability.

A new PharmGKB pathway depicts the inhibitory action of EFV on HIV replication in T cells and the genes involved in metabolism of the drug in human hepatocytes. Associations between variants in these genes and EFV exposure, toxicity and efficacy are discussed in the pathway description.

Friday, August 29, 2014

New study reveals PGx knowledge gaps among physicians

A recent study in the journal Pharmacogenomics and Personalized Medicine reveals clear pharmacogenomic “knowledge gaps” among physicians. Katherine A Johansen Taber and Barry D Dickinson of the American Medical Association surveyed 300 physicians across the United States to gauge their familiarity with pharmacogenomics as well as their knowledge of how to order and interpret pharmacogenomic tests.

Only 12.6% of physicians strongly or somewhat agreed with the question, “How familiar are you with pharmacogenomics?” even though nearly 20% of the physicians surveyed indicated that they had ordered a pharmacogenomic test within the past year. Of those respondents that had not ordered a pharmacogenomic test the most commonly cited reason was “Don't know which test to order” (69.7%). Almost half of all physicians anticipated ordering a pharmacogenomic test within the following year. Based on the results of the survey the authors conclude that physicians’ lack of understanding of pharmacogenomics remains a significant barrier to widespread implementation of pharmacogenomic testing. Thus, those of us in the PGx domain must do a better job of disseminating PGx information and educating physicians on the use of PGx knowledge. 

Read the full study and survey below:

Friday, August 22, 2014

PGx analysis of 482 whole genomes

Few studies have analyzed whole genomes for PGx-related variants - instead, many utilize genotyping platforms made up of known variants. A recent analysis of 482 whole genome sequences has revealed interesting findings for 231 ADMET*-related genes:
  • On average, each individual had a total of 17,733 variants in these genes.
  • 4% of these were not annotated in dbSNP and potentially have functional significance.
  • The percentage of novel variants identified was higher in ethnic populations under-represented by a DMET* genotyping platform coverage.
Focusing on CYP2C9, CYP2D6, VKORC1, UGT1A1 and TPMT pharmacogenes:
  • 2521 novel variants were found within these genes. 
  • 202 of these were in exons or proximal regulatory regions, and included novel missense, nonsense and frameshift variants.

Applying the analysis to a real-life clinical case, whole genomes of 7 Greek family members spanning 3 generations were annotated. Comparisons between two unrelated members of the family, who both undergo acenocoumarol treatment for atrial fibrillation (one of whom has responded well to treatment, the other has not), reveal clinical insights for these patients:
  • 1/3 variants in ADMET*-related genes are different between the two patients, and include novel putatively functional variants. 
  • The acenocoumarol non-responder is heterozygous for two variants in CYP2C9 (involved in acenocoumarol metabolism), whereas no CYP2C9 variants are found in the responder. 
  • The acenocoumarol non-responder has no sequence variants in genes involved in the pathways of other anti-coagulation therapies (such as clopidogrel), and so this patient could consider switching medication as this may be more efficacious compared to acenocoumarol. 
  • The acenocoumarol responder has known and novel variants within genes involved in the pathways of other anti-coagulation therapies and therefore should not modify their anticoagulation treatment, due to risk of adverse reactions or lack of efficacy.

Read the publication:
Personalized pharmacogenomics profiling using whole-genome sequencing.
Mizzi C, Peters B, Mitropoulou C, Mitropoulos K, Katsila T, Agarwal MR, van Schaik RH, Drmanac R, Borg J, Patrinos GP. Pharmacogenomics. 2014 Jun;15(9):1223-34. doi: 10.2217/pgs.14.102.

*ADMET = absorption, distribution, metabolism, excretion, toxicity.
    DMET = distribution, metabolism, excretion, toxicity. 

Tuesday, August 19, 2014

New PharmGKB pathway: Paroxetine

The paroxetine PK pathway is the newest addition to PharmGKB's pathway summaries.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of multiple psychiatric disorders including mood, panic, anxiety, and obsessive compulsive disorders. The pathway diagram depicts candidate genes mediating the transformation of paroxetine into its metabolites. The main enzyme responsible for the metabolism is cytochrome P450 2D6 (CYP2D6).

View the Paroxetine Pathway at PharmGKB for a summary of genetic variations in pharmacokinetic and pharmacodynamic genes that might affect paroxetine's metabolism and response. 

View all pathways at PharmGKB.