December SNPits Summary

In the December issue of UF Health Personalized Medicine Program's e-newsletter, SNPits, a recent study by Lee, et al. entitled "DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment" is reviewed.  The authors find a statistically significant association between DPYD*2A and rs67376798 (DPYD D949V) and increased toxicity in patients treated with 5-fluorouracil-based combination chemotherapy.  This large randomized phase III trial is important evidence supporting the clinical applicability of these variants.

CPIC's dosing recommendations for 5-FU dosing with DPYD variants is found on PharmGKB here.

CPIC Term Standardization

CPIC (Clinical Pharmacogenetics Implementation Consortium) is leading an effort to standardize terms for clinical pharmacogenetic tests.  The goal of the project is to create standardized terms to be used in CPIC guidelines (specifically Tables 1 and 2) and in the larger pharmacogenetics community.  A list of phenotype term options based on an extensive literature review and scanning of sample laboratory reports is being developed.  Refinement of the terms will be performed using a modified Delphi method in the context of expert opinions.

CPIC is actively engaging different constituencies including members of the PGRN, ClinGen, the CDC PGx nomenclature working group, clinical laboratories and the IOM PGx roundtable.  Further details about this project are described here. If you have questions or comments regarding this project, and/or if you are interested in participating in this process, please contact us at
cpic@pharmgkb.org.

Annotated PMDA drug labels now available on PharmGKB

PharmGKB now has annotated drug labels available from the Pharmaceutical and Medical Devices Agency (PMDA), Japan.

The PMDA is a regulatory agency responsible for scientific reviews for the approval of drugs or medical devices, as well as safety monitoring after approval. The PMDA website provides PDF copies of package inserts for approved drugs. However, these inserts are only available in Japanese, and until recently PharmGKB had been unable to search for or annotate PMDA package inserts containing relevant pharmacogenetic (PGx) information.

In a paper published in 2013 in the Journal of Clinical Pharmacy and Therapeutics, Shimazawa and Ikeda selected PMDA inserts to examine for PGx information based on the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling. In addition to a discussion of the differences in PGx biomarker information between labels from the United States, United Kingdom and Japan, the authors also provided a table in the supplementary information that gave translations of any PGx information present in the PMDA package inserts. Using these translations, PharmGKB was able to create annotated drug labels for the package inserts examined by Shimazawa and Ikeda that contained PGx information. As with the annotated FDA and EMA drug labels, PMDA labels are given a PGx level of evidence, and a PDF copy of the package insert with PGx information highlighted is available for each annotated label.

It is likely that there are other PMDA package inserts that contain PGx information, and PharmGKB welcomes any feedback regarding PGx information within PMDA package inserts or labels from other medicine agencies around the world.

See a list of drug labels available on PharmGKB:
PMDA labels on PharmGKB

Read the paper:
Differences in pharmacogenomic biomarker information in package inserts from the United States, the United Kingdom and Japan
Shimazawa R, Ikeda M. Journal of Clinical Pharmacy and Therapeutics 2013; 38(6): 468-75. PMID 23895776.

November SNPits Summary

The November issue of UF Health Personalized Medicine Program's e-newsletter, SNPits, is out.  This issue contains a summary of a recent paper by Nicholson and Formea in Clinical Chemistry that discusses implementing CPIC guidelines for CYP2D6 and codeine.  The authors highlight some of the difficulties that may arise in the clinic.  We are pleased that the larger clinical community is beginning to embrace PGx guidelines and practice.

PharmGKB VIP Summary for CYP4F2 published in Pharmacogenetics and Genomics

The PharmGKB Very Important Pharmacogene (VIP) summary describing important pharmacogenetic variants in CYP4F2 was recently published by Pharmacogenetics & Genomics. Cytochrome p450, family 2, subfamily F, polypeptide 2 (CYP4F2) catalyzes the oxidation of the terminal carbon of the side chains of vitamin K, vitamin E, arachidonic acid (AA), and leukotriene B4 (LTB 4). Thus, CYP4F2 plays a role in the regulation of the inflammation response, blood pressure as well as vitamin K and vitamin E bioavailability. A single genetic variant (rs2108622 C>T also known as CYP4F2 *3) has consistently demonstrated a small but significant effect on warfarin and acenocoumarol dosage and safety, particularly in Caucasian and Asian populations. 

View an interactive version: 

CYP4F2 VIP Summary on PharmGKB


Read the publication:


PharmGKB summary: very important pharmacogene information for CYP4F2 
Pharmacogenetics & Genomics. 2014 Nov 3. (Epub ahead of print)Alvarellos ML, Sangkuhl K, Daneshjou R, Whirl-Carrillo M, Altman RB, Klein TE.

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.

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.

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 https://en.wikipedia.org/wiki/PharmGKB.

Email us suggestions for expanding our Wikipedia page at feedback@pharmgkb.org.

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: 

Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans.

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.

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




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

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

•  CYP2C19 poor metabolizers may need a four-fold dose increase for clopidogrel
•  CYP2D6  drug interactions may decrease response to hydrocodone and increase response to ondansetron
•  personalized medicine in cardiology and oncology in Europe.

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!

CPIC PEG interferon-alpha guideline now available on guideline.gov

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: 

• CYP2D6, CYP2C19 & tricyclic antidepressants
• CYP2D6 & codeine
• CYP2C19 & clopidogrel
• TPMT & thiopurines
• HLA-B & allopurinol
• HLA-B & abacavir
• HLA-B & carbamazepine
• SLCO1B1 & simvastatin
• DYPD & fluoropyrimidine
• IFNL3/IL28B & peginterferon alpha

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

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.

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. 

> View the PharmGKB Efavirenz Pathway, PK/PD

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:

Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties

Pharmacogenomics and personalized medicine (2014).

Dickinson Barry, D and Johansen Taber Katherine A. 

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. 

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.

New PharmGKB VIP Summary: HLA-B

Human leukocyte antigen B (HLA-B) is a cell-surface molecule responsible for the presentation of endogenous peptides to cytotoxic CD8+ T cells. This presentation of peptides allows for the recognition of pathogens, and leads to an immune reaction that destroys the infected cell. Variations within the HLA-B gene affect which peptides the molecule can present, but allelic changes have also been associated with susceptibility and resistance to numerous diseases and adverse reactions to a wide range of pharmaceuticals. Some of these pharmaceutical associations have been well-studied, such as HLA-B*57:01 and abacavir hypersensitivity, HLA-B*58:01 and allopurinol-induced severe cutaneous adverse reactions (SCARs), and HLA-B*15:02 and carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, many other variants within the HLA-B gene also show associations with drug phenotypes. 

The VIP summary posted on PharmGKB provides background on HLA-B and its role in the immune system, as well as discussing the roles of HLA-B alleles in diseases and pharmacogenetics, with a particular focus on the *57:01, *58:01 and *15:02 alleles. 

For more information, please read the entire HLA-B VIP summary and its associated variant summaries on PharmGKB.

View all VIP gene summaries at PharmGKB.

European approval of additional CFTR variants listed for ivacaftor use

The drug Ivacaftor (Kalydeco) was originally indicated for use in cystic fibrosis (CF) patients with one or two copies of the G551D variant (rs75527207) in the CFTR gene. The European Commission has approved the use of ivacaftor in patients with an expanded list of CFTR variants that all result in a defect in CFTR gating (announced in a press release by the company).

The additional variants are: G178R (rs80282562), S549N (rs121908755), S549R (rs121908757 and rs121909005), G551S (rs121909013), G1244E (rs267606723), S1251N (rs74503330), S1255P (rs121909041) and G1349D (rs193922525). 

These additional variants were approved by the FDA earlier this year, and added to the ivacaftor drug label indication section. In light of these changes, the CPIC therapeutic guidelines for ivacaftor were updated. 

The variants are listed in Table 2 of the PharmGKB CFTR VIP summary - view to read more about targeting CFTR variants to treat CF.

Praise for PharmGKB

PharmGKB is “the Holy Grail” for DNA STAT, a company that provides pharmacogenomics testing for patients. DNA STAT goes on to praise PharmGKB’s “accessibility and comprehensiveness” and highlights its “interactive SNP features and tools for education and clinical implementation of genetic data.”

Ifosfamide PK and PD pathways published in PG&G

Ifosfamide is a produg used in combination chemotherapy for the treatment of solid tumors. Around 20% of patients experience toxicity. Pathways depicting the genes involved in the pharmacokinetics and pharmacodynamics of ifosfamide have been published in PG&G. Variants in these genes that are associated with toxicity and drug resistance are discussed.

Click on the pictures to view the pathways:

Pharmacokinetics

Pharmacodynamics

Read the publication:

PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics.
Lowenberg D, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE.

Pharmacogenetics & Genomics. 2014 Feb;24(2):133-8.

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.

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:

• G551D
• S549N
• G1244E 
• G1349D
• G178R
• G551S
• S1251N
• S1255P
• S549R(A>C) and S549R(T>G)