Friday, October 31, 2014

Clinical evidence support for biomarkers on FDA-approved drug labels

A recent article by Wang et al. in JAMA Internal Medicine reviews the clinical evidence support found on FDA-approved drug labels that are listed on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling.  The authors found that many labels on the list did not contain, or reference, "convincing evidence" of the biomarker's clinical validity or utility.  The authors used published guidelines from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group to grade the evidence.

October's SNPits summary from the University of Florida's Personalized Medicine Program highlights this article and provides a discussion about the clinical implications and some limitations of the paper.  They note that post-market label updates regarding safety decisions will often depend on retrospective data that will fall short of proving clinical utility. Additionally, the clinical evidence provided on labels may not reflect the totality of the available evidence because it is difficult for label revisions to keep up with the pace of emerging literature.

Almost a year ago, PharmGKB blogged about lack of clarity regarding the actionability of pharmacogenomic information on FDA-approved drug labels.  This is a separate issue from that of clinical evidence support for biomarker information on the labels discussed in the JAMA Internal Medicine article.  Both issues suggest the need for clearer language and guidance for clinicians on labels. 

As the SNPits summary points out, resources do exist for clinicians to gather information outside of what is provided on the label.  "Prescribers frequently rely on data sources other than the package insert in clinical decision making, including drug databases, published information in guidelines, journal articles, and others." Though there is room for improvement on FDA-approved drug labels, the provided pharmacogenomic information can be integrated with other information clinicians use while making prescribing decisions.

Monday, October 27, 2014

ClinGen's GenomeConnect Patient Portal Launches

The NIH-funded Clinical Genome Resource (ClinGen) project has launched its patient portal at GenomeConnect.  This site provides a patient registry for those who have already had or are contemplating genetic testing, or have family members who have been tested.  It is open to the public for enrollment.  Once a personal account is created, participants are asked to provide health history information through a survey, and upload genetic test results if available.

De-identified health and genetic information from participants in GenomeConnect will be shared with researchers and clinicians studying genetic associations with health outcomes.  Participants will also be able to connect with other patients through the registry based on genetic variants and diagnosis.  Personal information such as name, address and other personal identifiers will NOT be shared without express permission from participants.  By freely sharing de-identified genetic and medical information, participants become a part of a potentially huge study to further understanding of the impact of genetics on health.  The more participants, the greater the chance of medical discoveries that can influence future health care.

Thursday, October 16, 2014

New pathway: Ibuprofen Pharmacodynamics

We have added a new pathway: ibuprofen PD pathway  to PharmGKB's pathway collections.

Ibuprofen is a traditional non-steroidal anti-inflammatory drug (NSAID) widely used for its analgesic, anti-inflammatory, and anti-pyretic properties. The main mechanism of action of  ibuprofen is the non-selective, reversible inhibition of the cyclooxygenase enzymes COX-1 and COX-2 (encoded by genes PTGS1 and PTGS2, respectively). The ibuprofen PD pathway depicts the mechanisms of action of the drug and highlights genes mediating the diverse biological effects triggered by ibuprofen.

View  ibuprofen PD pathway on PharmGKB.

View all pathways at PharmGKB.

PharmGKB Wikipedia page

PharmGKB now has a Wikipedia page. The page provides an overview of our purpose, as well as the types of content available on the website.

PharmGKB would like to invite the community to add to the page, or email us suggestions for what you think would be useful to include.

Visit our new Wikipedia page at

Email us suggestions for expanding our Wikipedia page at

Wednesday, October 15, 2014

The genetics of warfarin dose: focus on African Americans

Warfarin has a narrow therapeutic window, therefore it is important to get the dosage for a patient correct - too low or too high a dose can have dangerous consequences. However, there is large interindividual variability in dose. Incorporation of a patient's genotypes at the polymorphisms CYP2C9*2 (C>T at rs1799853), CYP2C9*3 (A>C at rs1057910) and VKORC1 (G>A at rs9923231) into a dosing algorithm can help better predict the warfarin dose required by an individual (see the CPIC dosing guideline).

These three variants are rare in African American and African populations, and thus a larger percentage of variability in warfarin dosage remains unexplained in these patients compared to White individuals (see commentary below). There is therefore a need to identify genetic variants found in African Americans and Africans that could be used to enhance prediction of dosage in these patients.

A study in this month's issue of Blood outlines an exome sequencing project in African Americans that revealed a novel variant in the FPGS gene associated with warfarin dose. The G allele of rs7856096 was significantly associated with lower warfarin dose in both the discovery and independent replication cohorts of African American patients. This allele was shown to be most prevalent in populations on the African continent, and found at a frequency of around 0.2 in the discovery and replication cohorts. Adding this variant to the IWPC dosing algorithm helped to explain an additional 3.3% of dose variability in the combined cohort of African Americans. Preliminary functional analysis showed that the G allele may result in reduced FPGS expression. FPGS encodes an enzyme involved in folate homeostasis - though the biological mechanism behind the association with warfarin dose has yet to be investigated, the authors discuss that folate can affect warfarin metabolism and coagulation status.

Read the commentary:
Warfarin pharmacogenetics: it matters if you're black or white
Wadelius M. Blood. 2014 Oct 2;124(14):2171.

Read the article: 
Daneshjou R, Gamazon ER, Burkley B, Cavallari LH, Johnson JA, Klein TE, Limdi N, Hillenmeyer S, Percha B, Karczewski KJ, Langaee T, Patel SR, Bustamante CD, Altman RB, Perera MA. Blood. 2014 Oct 2;124(14):2298-305.

Thursday, October 2, 2014

Gemcitabine pathway published in Pharmacogenetics and Genomics

Gemcitabine is a cancer drug used to treat solid tumors as well as certain blood cancers. It can be administered alone or in combination with other drugs as part of a chemotherapy regimen. The genetic variants hypothesized to play a role in the variability of patient response to gemcitabine as well as those genetic variants that may influence severity of adverse events are summarized.

Click on the picture to view the pathway

Photo of a big bunny rabbit!

Read the publication: PharmGKB summary: gemcitabine pathway

Alvarellos ML, Lamba J, Sangkuhl K, Thorn CF, Wang L, Klein DJ, Altman RB, Klein TE.
Pharmacogenetics and Genomics.  Advanced online publication. 2014 August 26 doi: 10.1097/FPC.0000000000000086