Genetic contribution of response to opioids

Opioids  are commonly prescribed for pain relief, yet many individuals suffer adverse side effects such as nausea, dizziness and sedation.

A study published in this month's Anesthesiology set out to establish the relative contribution of genetic and environmental factors in opioid response. 114 monozygotic and dizygotic twin pairs were recruited, and were given either alfentanil then placebo, or placebo then alfentanil. Significant heritability was shown for respiratory depression, nausea and disliking of the drug. Almost 60% of the variation in nausea response was attributed to genetic effects. Genetic effects also accounted for around 25% of the variance in disliking of the drug, and 30% of the variance in respiratory depression decreases. Genetic and/or environmental effects were attributed to liking of the drug, sedation, dizziness and pruritus.

Aversive and Reinforcing Opioid Effects: A Pharmacogenomic Twin Study. Angst M.S. et al. Anesthesiology. 2012 Jul;117(1):22-37. Read the article

  
PGx of opioids
Discovering the specific genetic variants behind these side effects may help identify patients most at risk before prescribing opioids...

Variants within the CYP3A5 and OPRM1 gene have been associated with alfentanil drug metabolism and dosage, respectively; view these variant annotations on PharmGKB.

To avoid toxicity, CPIC have published therapeutic dosing guidelines for codeine based on an individual's CYP2D6 genotype; view these dosing guidelines on PharmGKB.

Numerous genetic variants in many different genes have been associated with response to or dosage of methadone; view these variant annotations on PharmGKB.

Helix Group & PharmGKB Retreat

Much fun and team-building was had at the Stanford Helix Group & PharmGKB retreat in San Diego last week - including sea kayaking, insightful talks and a lively discussion with guest speaker Philip Bourne. 

Helix Group & PharmGKB team members kayaking in San Diego

Curators' Favorite Papers

The current Curators' Favorite Papers are about pharmacogenomics of antidepressant drugs. Narasimhan and Lohoff review recent findings on the pharmacogenetics of antidepressant drugs and discuss possible future clinical implementations [PMID: 22380000]. The study by de Klerk et al. investigates the association of ABCB1 variants with adverse effects of antidepressants in a large cohort of patients with major depressive disorder. The authors report a significant association between the number of selective serotonin reuptake inhibitors-related adverse drug effects and two ABCB1 SNPs (rs2032583 and rs2235040) [PMID: 22641028]. Sasayama et al. present evidence that polymorphisms in the CUX1 gene (rs365836 and rs201522) may be associated with response to antidepressant treatment based on a genome-wide approach followed by a candidate SNP analysis [PMID: 22584459].

Metformin Pharmacogenomics

Metformin is a first line therapy for type 2 diabetes, and is one of the most commonly prescribed drugs worldwide.   We have recently written a Metformin Pathways Summary that is published in Journal Pharmacogenetics and Genomics.

Metformin effectively lowers both basal and postprandial plasma glucose. However, the glycemic response to metformin is quite variable. Some patients respond extremely well while others show no benefit to therapy. The role of genetics in predicting response to metformin has been the subject of much research. Multiple studies have reported associations between genomic variations of metformin transporters and its pharmacokinetics (PK) and response, and a few have explored the role of pharmacodynamic (PD) genes/variants in drug efficacy. This summary briefly reviews the pharmacokinetics of metformin and highlights genes and variants modulating the diverse pharmacological responses to metformin treatment. Knowledge of the PK and PD pathways of the drug may help identify genetic markers predicting variation in response as well as aid the personalization of metformin therapy.

Find out more...

View our Metformin PK and PD Pathways on PharmGKB.

Read our new Metformin Pathways: Pharmacokinetics and Pharmacodynamics publication.
Metformin Pathways: Pharmacokinetics and Pharmacodynamics, Gong L and Goswami S (co-first authors), Giacomini  KM, Altman RB, Klein TE. Pharmacogenet Genomics. 2012

View all pathways on PharmGKB.

New haplotypes available on PharmGKB

Haplotypes for the UGT1A3, CYP2F1 and CHRNA5 genes are now available on www.pharmgkb.org


View a list of all the genes with haplotypes available on PharmGKB.

CYP2C19 and clopidogrel therapy CPIC guideline endorsed by the ASHP

The American Society of Health-System Pharmacists (ASHP) has endorsed the CPIC guidelines for CYP2C19 genotype and clopidogrel therapy, published in Clinical Pharmacology and Therapeutics.

In their report, they highlight that the guidelines address an important need for information on the clinical application of pharmacogenomic testing and appreciate that the recommendations are based on interpretation of genetic test results and not whether a genetic test should be carried out or not.

Read the CYP2C19-clopidogrel CPIC therapeutic guidelines on PharmGKB

See more pharmacogenetic-based drug dosing guidelines published by CPIC

Read the ASHP reports on the ASHP website

Curators' Favorite Papers

The current Curators' Favorite Papers are about rare variants, which are part of the genetic diversity within and among populations. Keinan and Clark explain how the recent explosive human population growth has resulted in an excess of rare genetic variants [PMID: 22582263]. The article by Nelson et al. focuses on rare functional variants in drug target genes [PMID: 22604722]. Ramirez et al. concluded that novel rare non-synonymous variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes [PMID: 22584458].

FDA approves new ERBB2 targeted drug

The FDA approved a new drug for HER2 (ERBB2) positive breast cancer (June 8, 2012). Pertuzumab (Perjeta) is an antibody that targets a different epitope than trastuzumab (Herceptin), the first HER2 targeted antibody drug. The two drugs can therefore be combined to improve efficacy, and this was shown quite successfully in the CLEOPATRA clinical trial [PMID: 21147694]. Pertuzumab is approved for use in combination with trastuzumab and docetaxel for metastatic breast cancer.
 
Last week at the annual meeting for the American Society for Clinical Oncology (ASCO), there were also reports about the promising new anti-HER2 antibody drug conjugate in development, trastuzumab emantidine. Trastuzumab emtansine (T-DM1) is trastuzumab covalently bound to DM1, a microtubule polymerization inhibitor.

For more details see the FDA release.

New PGRN Featured Project and PI for the Month of June

The PGRN website is featuring a new project and investigator of the month from the PPII (Pharmacogenetics of Phase II Drug Metabolizing Enzymes) group.

For detailed information, please visit the PGRN website.

CYP2C8 haplotype table available

The most recent addition to the PharmGKB set of haplotype tables is  for CYP2C8 (cytochrome P450, family 2, subfamily C, polypeptide 8 ).  The main source for this table was the The Human Cytochrome P450 (CYP) Allele Nomenclature Database .


The PharmGKB haplotype tables, each located on a tab of the relevant gene page, list star alleles and the (positive strand) nucleotides found at each position included in the table.  The tables contain only SNPs for which we have an rsID or UCSC Golden Path Position.


View or download this table from the Haplotype tab of the CYP2C8 gene page.