Development of a Customized PGx Genotyping Array using key variants in PharmGKB

The University of Florida and Stanford University are undertaking a joint pharmacogenetics implementation project funded by the NIH, piloted first at Florida and replicated at Stanford. Initially, CYP2C19 genotype will be used to guide clopidogrel therapy, however a customized array of SNPs from 120 genes involved in drug response was designed for preemptive genotyping. This enables a patient's genotype information to be available in the future if or when a drug is to be prescribed. Read more in the Clinical Pharmacology & Therapeutics article available online.

Selecting SNPs for the array included one or more the following:

1. There is a PharmGKB Clinical Annotation written between the SNP and a drug response, usually with high levels of evidence.
2. It is a functional SNP within a VIP
3. It is a known tag SNPs for an important PGx haplotype
4. It is a SNP of interest to the research groups

to give:
252 PGx SNPs (listed in the Supplementary Information) + 2 sex markers + 2 SNPs for quality control

Details of the genotyping array technology, validation, costs and turnaround times are outlined. Also discussed in the article are the current potential barriers to clinical implementation of pharmacogenetics, and how a preemptive genotyping approach can overcome some of these.

Article:

Implementing Personalized Medicine: Development of a Cost-Effective Customized Pharmacogenetics Genotyping Array

J A Johnson, B M Burkley, T Y Langaee, M J Clare-Salzler, T E Klein and R B Altman. Clinical Pharmacology & Therapeutics (2012); advance online publication 22 August 2012. doi:10.1038/clpt.2012.125

New sortable PGx Research tables on PharmGKB

Tables of our Variant Annotations found on the PGx Research tab (view on gene, drug, variant and haplotype pages) can now be sorted and filtered to allow you to see the most relevant information you want to see.

example: If you want to see all variant annotations between the genetic variant rs1800462 (TPMT*2) and the drug mercaptopurine.

• From our homepage search for 'rs1800462' and click on the PGx Research tab to see the table of Variant Annotations.  
• Add filter: select 'Drug'/ pick filter select 'contains'/ type mercaptopurine/ click add (pictured). 
• The list can then be sorted by each column e.g. significance, p value. 
• Click the configure icon (pictured) in the right hand corner above the table to add, remove or rearrange columns and save your desired settings to keep them for the next time you come to the website.  

 

New features on the PharmGKB website

Check out the new features we have launched at www.pharmgkb.org

• Information is now more readily available, including haplotypes listed in the PGx Research Tab on gene and drug pages, and sortable tables.
• Our Clinical Annotations and Variant Annotations have their own page and a new look 
• Variant Annotations from the published literature used by our curators to determine the level of evidence are listed with each Clinical Annotation (click 'Show Evidence' as pictured).

We hope these new features help our users view the information they want more easily - we encourage feedback and questions to feedback@pharmgkb.org

Mining the pharmacogenomics literature

Briefings in Bioinformatics Special Issue: Current Progress in Bioinformatics 2012 contains an editorial by Russ Altman discussing the current status of bioinformatics research.

Among the articles in this special issue is a review on the current status of techniques for mining of the pharmacogenomics literature and includes descriptions of studies that have utilized the corpus of human-curated pharmacogenetic (PGx) articles in PharmGKB to train or assess the accuracy of machine-learning methods.

"The PharmGKB repository comes perhaps closest to the vision of an all-embracing pharmacogenomics corpus. It represents a major step towards an interdisciplinary biomedical information store." quote from: 

Mining the pharmacogenomics literature -- a survey of the state of the art. Hahn U, Cohen KB, Garten Y, Shah NH. Brief Bioinform. 2012 Jul;13(4):460-94.

At the PharmGKB we are currently working on a natural language processing (NLP) pipeline that would assist in the identification of relevant PGx articles for our curators to then manually curate.  

New PGRN Featured Project and PI for the Month of August

The PGRN website is featuring a new project and investigator of the month from the PARC (Pharmacogenomics and Risk of Cardiovascular Disease) group.

For detailed information, please visit the PGRN website.

Curators' Favorite Papers

Current Curators' Favorite Papers: The review by Alfirevic and Pirmohamed discusses genetic factors associated with drug-induced liver injury with a special focus on HLA gene variation [PMID: 22850601].  Parvez et al. reports that a common SNP on chromosome 4q25, which is associated with atrial fibrillation, modulates response to antiarrhythmic drugs [PMID: 22726630]. Savonarola et al. reviews the role of mutational analysis in anti-cancer targeted therapy [PMID: 22760589].

A message about RFA-HG-12-016

RFA-HG-12-016 "Clinically relevant genetic variants resource:  a unified approach for identifying genetic variants for clinical use (U01)."  

The PharmGKB team is excited to see this RFA because clinical genomics has great potential to impact medicine. PharmGKB catalogs genetic variation of relevance to drug response (pharmacogenomics) and moves research data to guidelines for clinical action.  We do not intend to apply for this RFA and we look forward to working with the grantee(s) under this program, who we presume will primarily focus on clinically actionable variants relevant to disease risk.