Thursday, March 5, 2015

ABCB5 and haloperidol-induced toxicity: Results from a new study

Approximately 50% of patients treated with the antipsychotic drug haloperidol will develop extrapyramidal symptoms, a category that includes tremors, parkinsonism and decreased spontaneous movement. However, studies looking into the genetic variations associated with the development of these symptoms have been limited.

In a study recently published in PLOS Medicine, Zheng et al. used murine models and a human genetic association study to show a link between the ABCB5 gene and haloperidol-induced extrapyramidal symptoms (referred to as haloperidol-induced toxicity (HIT), and indicated in the murine models by "latency", or the time required for a mouse to move all four paws after being placed on an inclined wire-mesh screen). In the human genetic association study, it was the missense SNP rs17143212 in particular that was associated with haloperidol toxicities during the first 7 days of treatment, both before and after correcting for multiple testing using a permutation test.

ABCB5 is a member of the ATP-binding cassette (ABC) transporter family, and is responsible for the movement of substrates across cell membranes. Zheng et al. also used murine models to show that ABCB5 mRNA is expressed in brain capillaries, the location of the blood-brain barrier. This provides a possible mechanistic explanation for the association between the gene and HIT in mice - mouse strains with genetic variations that result in reduced ABCB5 activity may be more susceptible to HIT due to increased haloperidol concentrations in the brain. Furthermore, the authors suggest that this toxicity may actually be due to a metabolite of haloperidol, HPP+, which can induce mitochondrial toxicity that results in Parkinsonian-like symptoms.

While the authors conclude the paper by noting that other genetic factors are likely involved in the development of HIT in humans, the results from this study shed further light on the pharmacogenetics behind haloperidol-induced toxicity.

Read the original article:
The role of abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.
Zheng M, Zhang H, Dill DL, Clark JB, Tu S, Yablonovitch AL, Tan MH, Zhang R, Rujescu D, Wu M, Tessarollo L, Vieira W, Gottesman MM, Deng S, Eberlin LS, Zare RN, Billard JM, Gillet JP, Li JB, Peltz G. PLoS Medicine. 2015 Feb 3;12(2):e1001782. PMID 25647612.

See the annotation for this paper on PharmGKB:
https://www.pharmgkb.org/pmid/25647612

Wednesday, February 25, 2015

Our 10-step guide to enabling your PGx study to be curated

At PharmGKB we manually curate pharmacogenetic (PGx) associations found in published articles and add them to our database. However, lack of information or clarity is unfortunately common in publications and these hurdles make it difficult or impossible to curate a particular association.

We have published a guideline in Clinical Pharmacology & Therapeutics of 10 simple rules to help your publication be curated:

[Citation]


1. Use standard gene nomenclature. 

2. Provide dbSNP rsIDs, a reference sequence and mapping information for genetic variants. 

3. Clearly state which allele/genotype of the variant is associated with the phenotype and the direction of the association.  

4. Clearly state population size, ethnicity, gender and drug regimen. 

5. State the minor allele for the variant in the given population/cohort.

6. Clearly state on which chromosomal strand the alleles are reported. 

7. State all genetic variants that were screened (including SNPs, indels, copy number variations and structural variations). 

8. Specify how * alleles or haplotypes were defined. 

9. Report which genotypes/diplotypes were found in the study population and map them to phenotype groups. 

10. State the statistical tests used for each association analysis. Include methods used for multiple hypothesis correction. 



Why follow these steps? 

Here are some benefits to you for enabling us to add your study findings to our public database:
  • Be part of the largest collection of curated PGx literatures, which is often used for identifying clinically relevant variants, interpreting genomes and used as a standard for evaluating methods and models for mining scientific literatures as well as drug discovery.
  • Your results and a link to your publication on PubMed become accessible to a broad audience, including students, bioinformaticians, researchers and clinicians.
  • By becoming part of our data set, your results may contribute to further research studies.
  • Your findings can aid in the clinical interpretation of a PGx association (whether the association you found was negative or positive) by contributing evidence to a Clinical Annotation.
  • These in turn may aid towards establishing a PGx-based dosing guideline for a particular drug.

    Wednesday, February 18, 2015

    PharmGKB VIP summary for CFTR published

    The PharmGKB summary describing CFTR as a pharmacogene has been published by Pharmacogenetics & Genomics. Genetic variants within the CFTR gene are the target of new Cystic Fibrosis therapies and drugs in development. The hope is that patients will be better treated with personalized medicines tailored to the underlying defects within CFTR. The VIP summary details these treatment strategies and clinically important variants within the CFTR gene.

    • Read the article: 
    McDonagh EM, Clancy JP, Altman RB, Klein TE.   
    Pharmacogenetics & Genomics. 2014 Dec 15. (Epub ahead of print)

    Sunday, February 8, 2015

    FDA Proposed Regulation of Laboratory Developed Tests (LDTs)

    Dear Colleagues,

    As you may know, the FDA is considering regulating laboratory developed tests (LDTs) and had an open comment period that ended February 2, 2015.  We would like to share with you a response that we wrote from our perspective at PharmGKB, working with the Stanford Law School “IP and Innovation Clinic” directed by Prof. Phil Malone.   Several law students worked on this with us on a very tight schedule since their clinic just started in January.  We anticipate other opportunities to comment on this important issue, and would be interested if any of you filed comments that you are willing to share.  This is a confusing situation and not directly in our expertise, but we saw an opportunity to get some things about PGx on the record.

    Thanks,
    Russ & Teri

    Friday, February 6, 2015

    Genomic CDS Sandbox

    A multidisciplinary team of genomics experts is planning to create and distribute a freely available, open source genomic clinical decision support (CDS) sandbox that experts could use to create and evaluate genomic CDS knowledge and novel approaches. This resource will be preconfigured with many open source health IT applications on a easily distributable virtual machine.

    At this point, they are assessing the level of interest among potential users and determining desired features. They have created a short survey (< 10 min) for genomic and CDS domain experts to assess this important information.


    They would appreciate your time completing this survey and look forward to your input. The survey will close February 28th, so a prompt response is appreciated.

    For more information, contact Brandon M Welch, MS, PhD (welchbm@musc.edu).

    Wednesday, February 4, 2015

    Pathways of acetaminophen metabolism at therapeutic versus toxic doses



    We have updated the acetaminophen pharmacokinetic pathway, which depicts the metabolism at therapeutic doses. In addition we added a new pathway illustrating the metabolism of acetaminophen at toxic doses.

    Acetaminophen (paracetamol) is widely used for its analgesic and antipyretic properties. Acetaminophen is mostly converted by glucuronidation and sulfation. A minor fraction of acetaminophen is oxidized to a reactive metabolite NAPQI, which is primarily responsible for acetaminophen-induced hepatotoxicity. A higher proportion of the drug gets oxidized at toxic doses leading to an increased risk of hepatotoxicity. 

    For more information on differences in the PK of acetaminophen between therapeutic vs toxic doses go to Acetaminophen Pathway (therapeutic doses), Pharmacokinetics and Acetaminophen Pathway (toxic doses), Pharmacokinetics.


    View all pathways at PharmGKB.

    Tuesday, February 3, 2015

    CPIC Term Standardization Survey Has Been Released

    In December 2014, we wrote a blog entry about the CPIC term standardization project. CPIC (Clinical Pharmacogenetics Implementation Consortium) is leading an effort to standardize terms for clinical pharmacogenetic tests, and the terms will be used in future CPIC guidelines. The hope is for the terminology to be adopted by the larger pharmacogenetics community as well.  CPIC will use a modified Delphi method in order to refine the term list based on expert opinions.

    The initial survey has been released and is available at: https://www.surveymonkey.com/r/Q8VZKYP

    The survey is to be completed by February 20th.  CPIC has prepared webinars to assist participants taking the survey.

    There are two upcoming live webinars:

    February 11th at 1:00 pm ET/12:00 pm CT/10:00 am PT 
    Live Webinar link
    https://stjude.webex.com/stjude/j.php?MTID=me7fe449ede0d5daf8ecb7f4695e00cf4

    February 19th at 3:00 pm ET/ 2:00 pm CT/ 12:00 pm PT
    Live Webinar link
    https://stjude.webex.com/stjude/j.php?MTID=m447451a04b34db2dc5e89097821ef39d
    If those are not convenient, you can access a streaming version and downloadable version of the webinar at any time:

    Streaming recording link
    https://stjude.webex.com/stjude/ldr.php?RCID=414f044f245c4aac12247582dbfc02b4

    Download recording link
    https://stjude.webex.com/stjude/lsr.php?RCID=22843f1e544a77db41d45b1f32ba1584

    If you have questions or comments regarding this project, please contact us at cpic@pharmgkb.org.