New VIP Summary for CYP2C8

A new VIP summary is available for CYP2C8, a member of the cytochrome P450 family of drug metabolizing enzymes. CYP2C8 accounts for 7% of CYP content in the liver, and is expressed to a lesser extent in the kidney, adrenal gland, mammary gland, brain, ovary, uterus, and duodenum.  CYP2C8 plays a major role in the metabolism of many commonly used drugs [Article:15900280]. Several CYP2C8 SNPs have functional consequences [Article: 20459297] and have been associated with variability in CYP2C8-mediated metabolism and altered disposition and response for many commonly used drugs such as repaglinide, rosiglitazone, pioglitazone,paclitaxel, bisphosphonates, amiodarone and amodiaquine [Articles:12429347, 11668219, 17361129, 23536207, 11767116, 12530467, 18769365]. As a result, CYP2C8 has emerged as a significant pharmacogene. 

For more information on this VIP gene and its variants see the VIP tab for CYP2C8.

For all VIP gene summaries on pharmgkb, see here.

CPIC guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 Update

The 2013 update of the CPIC guidelines for CYP2C19 and clopidogrel dosing is now available online, as an accepted article preview.

This updated guideline refines the recommendations for specific CYP2C19 alleles, with emphasis on the appropriate indication for CYP2C19 genotype-directed antiplatelet therapy, and, an expanded literature review to include recent published evidence.

Read the accepted article preview version:

Clinical PharmacogeneticsImplementation Consortium (CPIC) guidelines for cytochrome P450-2C19 (CYP2C19)genotype and clopidogrel therapy: 2013 Update.

Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR.

Clin Pharmacol Ther. 2013 May 22. doi: 10.1038/clpt.2013.105. [Epub ahead of print]

See excerpts from the guideline update:

Please click here to see excerpts from the guideline update and access downloads of the updated and original article and supplements. 

Please click here for a complete list of CPIC publications.

Big Data in Biomedicine

PharmGKB Developers and Curators attended the Big Data in Biomedicine conference this week, organized by Stanford University and the University of Oxford. The talks and panels raised a plethora of issues surrounding storing, sharing, analyzing, validating, visualizing and utilizing Big Data for improving healthcare and to drive change. Among the challenges is the need to integrate multiple big data sources together (genomic, metabolome, transcriptome, medical records, behavioural, environmental). Empowering patients, reproducible statistical analyses, and bioinformatics education were also discussed.

New name for IL28B gene = IFNL3

PharmGKB has updated our gene names that comply with The Human Genome Nomenclature Committee (HGNC) approved symbol, approved name, and synonyms.

One particular name change we would like to highlight with this update:
The HGNC-approved gene symbol for IL28B is now IFNL3 (interferon lambda 3) - a gene with variants that are associated with response to peginterferon alfa-2a, alfa-2b and ribavirin.

IFNL3 PGx information:

• FDA and EMA drug labels
• Level 1 Clinical Annotations
• Genetic tests
• Variant annotations

View the full IFN gene family in HGNC.

Curators' Favorite Papers

The current Curators' Favorite Papers' highlights the higher frequency of genetic variants conferring increased risk for adverse drug reactions (ADRs) for many commonly used drugs in persons of African descent. Differences in drug response, cure rates and survival outcomes between different ethnic populations exist. To assess this, Aminkeng et al. genotyped 1330 individuals of African and European descent over 4,000 SNPs in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Publicly available databases including PharmGKB were utilized to prioritize the selection of functional SNPs. The distribution of many variants were significantly different between African and European populations. These results were presented in the context of clinical annotations (toxicity, efficacy, ADR and drug response pathway) that were curated from PharmGKB and published studies. Important differences among the African populations were also observed in the frequency of variants. Results presented in this paper may translate to significant differences in drug efficacy and safety profiles in different populations.

Updated UGT1A1 VIP Summary

We have updated the UGT1A1 VIP summary to provide more in-depth information on this important pharmacogene. UGT1A1 is a member of the uridine diphosphate glucuronosyltransferase (UGT) enzyme family, and is responsible for the glucuronidation of target substrates. The transfer of glucuronic acid renders xenobiotics and other endogenous compounds water soluble, allowing for their biliary or renal elimination. Pharmaceutical drugs are a common substrate of UGT1A1, making this enzyme relevant to pharmacogenetic research.

The VIP summary posted on PharmGKB gives background on the UGT family and summarizes the function of UGT1A1, as well as the roles of UGT1A1 alleles in diseases and pharmacogenetics. In particular, certain genetic variants of UGT1A1 have been implicated in adverse reactions to irinotecan. For more information, please read the entire UGT1A1 VIP summary at PharmGKB.

View all VIP gene summaries at PharmGKB. 

The PGRN Translational Pharmacogenetics Program (TPP) publishes paper on overcoming challenges of real-world implementation

The Translational Pharmacogenetics Program (TPP) is a Pharmacogenomics Research Network (PGRN)-led initiative with the goal to identify barriers and develop real-world solutions to implement evidence-based pharmacogenetic tests in diverse health care settings. The participating sites include 6 implementation institutions (Universityof Maryland, University of Florida, St. Jude Children's Research Hospital, Vanderbilt University, Mayo Clinic, and Ohio State University),  as well as PharmGKB which serves a coordination and knowledge sharing and dissemination role and  Pharmacogenomic Ontology (PHONT) at the Mayo Clinic which provides data harmonization and standardization support.

The TPP investigators has published the design manuscript in Clin Pharmacol Ther this month. This paper discusses challenges and implementation barriers to translation of pharmacogenomics in clinical practice. Each implementation site institutes CLIA-based pharmacogenomics testing, reports results in EHR for clinical decision and tracks summary descriptions and implementation metrics to objectively evaluate the effectiveness of implementation. TPP also creates "look up" tables (posted on PharmGKB) which contain phenotype and clinical decision support system information based on haplotypes and diplotypes. These tables “complement the existing CPIC guidelines by providing therapy recommendations for a more comprehensive coverage of pharmacogenetic test results. They represent the current state of knowledge and demonstrate the range of observed results and recommended actions across sites”.

Read more:

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-World Implementation.

Shuldiner AR, Relling MV, Peterson JF, Hicks K, Freimuth RR, Sadee W, Pereira NL, Roden DM, Johnson JA, Klein TE. Clin Pharmacol Ther. 2013 Mar 19. doi: 10.1038/clpt.2013.59.