Pharmacogenetics of statin-induced muscle toxicity: exploration using the UK General Practice Research Database (G

Lead Research Organisation: University of Liverpool

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.

Publications

10 25 50
 
Description Report to the Academy of Medical Sciences Review on research governance
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description FP7 EU funding award (Prediction ADR)
Amount £647,547 (GBP)
Funding ID 602108 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2013 
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 Public 
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