Pharmacogenetics of statin-induced muscle toxicity: exploration using the UK General Practice Research Database (G
Lead Research Organisation:
University of Liverpool
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Statins are associated with myotoxicity, but to date, studies investigating genetic predisposition have been small and inconclusive. In the application, we propose the first ever use of GPRD to conduct a pharmacogenetic study. We propose a case-control study design, with patients recruited via GPRD practices. Cases will be patients with a creatine phosphokinase (CPK) level of at least 2x upper limit of normal during statin exposure in presence or absence of muscle symptoms. Saliva sample and patient questionnaires will be collected from cases and controls. The patient questionnaire will include questions on risk factors for myopathy and also questions about the patients willingness to participate in this research. DNA will be analysed using a candidate gene approach, with relevant genes in pathways being assessed (pathway pharmacogentics). The candidate genes will be chosen on the basis of the known pharmacokinetic and pharmacodynamic characteristics of statins. The genes will be analysed for tag SNPs, functional variants and haplotypes, which will then be related to the change in CPK levels. The milestone for this study is to recruit 250 cases and 500 controls and analyse the data within 2 years of the start of the study.
Organisations
- University of Liverpool (Lead Research Organisation)
- Royal Liverpool University Hospital (Collaboration)
- Radboud University Nijmegen Medical Center (Collaboration)
- London School of Hygiene and Tropical Medicine (LSHTM) (Collaboration)
- Uppsala University (Collaboration)
- St Jude Children's Hospital (Collaboration)
- University of Washington (Collaboration)
- UNIVERSITY OF DUNDEE (Collaboration)
Publications
Pirmohamed M
(2010)
Pharmacogenetics of idiosyncratic adverse drug reactions.
in Handbook of experimental pharmacology
Chan A
(2011)
Pharmacogenomics in neurology: current state and future steps.
in Annals of neurology
Pirmohamed M
(2011)
Pharmacogenetics: past, present and future.
in Drug discovery today
Carr DF
(2013)
SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink.
in Clinical pharmacology and therapeutics
Alfirevic A
(2014)
Phenotype standardization for statin-induced myotoxicity.
in Clinical pharmacology and therapeutics
Carr DF
(2014)
GATM gene variants and statin myopathy risk.
in Nature
Van Staa TP
(2014)
Predictors and outcomes of increases in creatine phosphokinase concentrations or rhabdomyolysis risk during statin treatment.
in British journal of clinical pharmacology
Carr DF
(2014)
Pharmacogenomics: Current State-of-the-Art.
in Genes
O'Meara H
(2014)
Electronic health records for biological sample collection: feasibility study of statin-induced myopathy using the Clinical Practice Research Datalink.
in British journal of clinical pharmacology
März W
(2017)
Leucocyte immunoglobulin-like receptor subfamily-B5 (LILRB5) genetic variation and statin-associated muscle symptoms: another piece in a puzzling puzzle
in European Heart Journal
| Description | Report to the Academy of Medical Sciences Review on research governance |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| Description | FP7 EU funding award (Prediction ADR) |
| Amount | £647,547 (GBP) |
| Funding ID | 602108 |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 08/2013 |
| End | 08/2016 |
| Title | Statin myopathy biological archive |
| Description | We have stored DNA samples from almost 150 patients with statin myopathy, together with 500 controls (statin exposed tolerant patients). |
| Type Of Material | Biological samples |
| Year Produced | 2012 |
| Provided To Others? | Yes |
| Impact | 1. We have written 4 papers from this study illustrating the feasibility of using GPRD for recruitment, validation of case phenotype through genotyping, and epidemiological aspects of statin myopathy. 2. We have just undertaken a GWAS; the data from this will be published and also shared with other researchers to undertake a meta-analysis. 3. Exome sequencing has been undertaken in collaboration with University of Washington, the data from which will be published, and will also be made available for other researchers. |
| Description | Clinical Chemistry |
| Organisation | Royal Liverpool University Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Working jointly for patient identification and recruitment |
| Collaborator Contribution | Access to database, recruitment of a validation cohort and controls |
| Impact | Not yet |
| Start Year | 2010 |
| Description | EU-FP7 award: PREDICTION ADR |
| Organisation | Radboud University Nijmegen Medical Center |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | We have been succesful in receiving EU-FP7 funding to look at mechanisms of severe adverse drug reactions. This work forms part of the PREDICTION-ADR study Our workpackage will focus on statin myopathy. |
| Collaborator Contribution | All partners from Dundee Uppsala and Utrecht universities will contribute patient samples and analysis, |
| Impact | A combined EU FP7 grant of £3million euros was received for a 3 year study. |
| Start Year | 2012 |
| Description | EU-FP7 award: PREDICTION ADR |
| Organisation | University of Dundee |
| Department | Biomedical Research Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have been succesful in receiving EU-FP7 funding to look at mechanisms of severe adverse drug reactions. This work forms part of the PREDICTION-ADR study Our workpackage will focus on statin myopathy. |
| Collaborator Contribution | All partners from Dundee Uppsala and Utrecht universities will contribute patient samples and analysis, |
| Impact | A combined EU FP7 grant of £3million euros was received for a 3 year study. |
| Start Year | 2012 |
| Description | EU-FP7 award: PREDICTION ADR |
| Organisation | Uppsala University |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | We have been succesful in receiving EU-FP7 funding to look at mechanisms of severe adverse drug reactions. This work forms part of the PREDICTION-ADR study Our workpackage will focus on statin myopathy. |
| Collaborator Contribution | All partners from Dundee Uppsala and Utrecht universities will contribute patient samples and analysis, |
| Impact | A combined EU FP7 grant of £3million euros was received for a 3 year study. |
| Start Year | 2012 |
| Description | Exome sequencing of statin myopathy patients |
| Organisation | University of Washington |
| Department | Cardiovascular Health Research Unit (CHRU) |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | The collaboration involves a large scale exome seuqncing project of cases of statin myopathy - we have contributed samples to this exercise and will be involved in the analysis, interpretation of the data when available, as well as in the submission of manuscripts. |
| Collaborator Contribution | Scientific consultation, and funding by the US NIH |
| Impact | n/a |
| Start Year | 2012 |
| Description | GWAS meta-analysis |
| Organisation | University of Washington |
| Department | Cardiovascular Health Research Unit (CHRU) |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We have undertaken a GWAS on our patient samples, and data from this will contribute to a meta-analysis. Analysis will be undertaken jointly as will interpretation. |
| Collaborator Contribution | GWAS data from their cohort will also be included. |
| Impact | Not yet |
| Start Year | 2012 |
| Description | St Judes Hospital |
| Organisation | St Jude Children's Hospital |
| Department | Pharmacogenomics (part of NIH Pharmacogenomics Research Network) |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Availability of unpublished data on rare variants in SLCO1B1 |
| Collaborator Contribution | Availability of unpublished data on novel and rare variants in SLCO1B1 |
| Impact | Not yet |
| Start Year | 2010 |
| Description | Statin Web-based Investigation of Side Effects Trial (Statin WISE trial) |
| Organisation | London School of Hygiene and Tropical Medicine (LSHTM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | University of Liverpool is providing genomics capability support for the trial. |
| Collaborator Contribution | The StatinWISE study is funded to and led by LSHTM and UoL is providing the capability to determine key genotypes which predispose study recruits to statin-induced myopathy |
| Impact | Multi-disciplinary: pharmacology, genetics, epidemiology, drug safety, medical informatics |
| Start Year | 2016 |
| Description | Statin myopathy genetic validation |
| Organisation | London School of Hygiene and Tropical Medicine (LSHTM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have genotyped statin myopathy cases provided by Mariam Molokhia as part of a validation analysis of our Genome Wide Association Study |
| Collaborator Contribution | They have provided blood/ DNA samples to act as a validation cohort of our GWAS findings. |
| Impact | This collaborations is likely to yield a jointly authored publication of the research. |
| Start Year | 2014 |
| Description | Association for Science Education |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | 30 science teachers attended to hear of latest developments in personalised medicine asked to go and present in shools |
| Year(s) Of Engagement Activity | 2012 |
| Description | Brighton Science Festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | over 100 people attended the presentation which was entitled: Personalised Medicines. it was held in The Sallis Benney Theatre, 58-67 Grand Parade, Brighton BN2 0JY. It was part of the DNA day at the Brighton Science Festival A group of medical translators have approached me to do a teaching presentation to their members. |
| Year(s) Of Engagement Activity | 2013 |
| Description | Play on Personalised Medicine |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | This involved a number of activities - (a) an initial workshop with 14-16 year olds and a presentation on personalised medicine to these students, and to a playwright; (b) helping the playwright to develop a play on personalised medicine; (c) commenting on the script; (d) meeting actors who acted in the play and undertaking a general Q&A session; (e) attending the play and taking part in a debate session with members of the general public. All these activities were undertaken with the Y-touring theatre company. Further details available on the website: http://www.theatreofdebate.com/Projects/Dayglo/Story.html The play was performed in many schools throughout the UK. it also ran for 1 week at the Royal Albert Hall. A DVD of the play which is called "Dayglo" has been made and was shown at the Edinburgh Science Festival, and will also be shown to medical students initially at Liverpool and eventually nationally. |
| Year(s) Of Engagement Activity | 2011,2012 |