Study of the interplay of genetic, biochemical, and lifestyle factors on coronary heart disease incidence

Lead Research Organisation: University of Cambridge
Department Name: Public Health and Primary Care

Abstract

Heart disease is the single leading killer in the UK and globally, is responsible for considerable disability, and involves several important modifiable risk factors, such as smoking, diabetes, and elevated levels of cholesterol and blood pressure.

The occurrence of heart attacks depends on the complex interplay of genetic make-up, environmental factors and chance. Understanding the interplay of ?nature? and ?nurture? in heart disease should contribute to important advances in: (i) explaining the biological chain of events that leads to a heart attack, (ii) effectively targeting existing measures to prevent disease, and (iii) developing lifestyle programmes for people to counteract disadvantageous genetic profiles.

Until recently, it has been difficult to study the interplay of genes, biochemical factors and lifestyles (eg, dietary habits and physical activity) in CHD. Medical surveys have tended to be too small, insufficiently detailed, inappropriately designed, or had some combination of these limitations. Also, it is only in the past few years that genetic research has identified a reasonably large number of genetic factors related to heart disease and relevant characteristics (such as levels of blood fats, obesity and diabetes).

The current research project seeks to conduct a large and detailed study of genetic, biochemical and lifestyle factors in heart disease by using an existing survey of over 500,000 middle-aged Europeans living in ten countries. Starting in the early 1990s, initially healthy participants gave blood, replied to questionnaires (eg, about lifestyles, habits) and provided physical measurements. These individuals have now been monitored for over a decade on average, during which time more than 10,000 people have had heart attacks. It is proposed to conduct genetic and biochemical tests in the stored samples of 10,000 patients with confirmed heart disease and in 10,000 controls who have remained free of heart disease.

Genetic and biochemical information assessed in these individuals will then be collated with information on smoking habits, diet, physical activity and other characteristics previously recorded at the initial visit to create a rich and powerful database. This database will be carefully harvested to yield a series of immediate and longer-term findings of major international importance for the understanding, prediction and prevention of heart disease.

Technical Summary

A strategic award is sought, jointly from the MRC and BHF, to enable large-scale investigation of the separate and combined influences of genetic, biochemical and major lifestyle factors (notably diet) on the incidence of coronary heart disease (CHD) in an existing large population-based prospective study across Europe. Reliable evaluation of the interplay of these factors should substantially advance understanding of the aetiology of CHD and contribute to prevention strategies, such as optimum targeting of interventions and identification of novel therapeutic targets. EPIC-Heart is in an excellent position to provide rapid, reliable and cost-effective studies of the combination of genetic, biochemical, and lifestyle factors because it has already:

1) recorded, in a standardised and prospective manner, information on diet, physical activity and other lifestyle characteristics in almost 520,000 mostly middle-aged Europeans from 10 countries (with over ?100M invested to date to establish and maintain this cohort)
2) collected and stored biological material to enable analyses of DNA, plasma and red cells
3) accrued over 10,000 cases of incident CHD during over 5 million person-years of follow-up
4) verified in a substudy that almost 90% of the patients in EPIC with suspected CHD fulfil standard criteria, and
5) agreed and published a scientific plan and study management arrangements.

EPIC-Heart will achieve further efficiency by utilising the 10,000 controls in the EPIC-InterAct case-cohort study of gene-lifestyle interactions in type 2 diabetes. InterAct has already been funded and will assay some risk markers of potential shared relevance to diabetes and CHD. Strategic support is sought, therefore, to enable an efficient case-cohort study of genetic, biochemical and lifestyle factors in CHD involving about 10,000 confirmed incident cases and 10,000 controls. This will entail: ascertainment and verification of CHD cases; retrieval of stored samples; extraction and preparation of DNA; focused genetic and biochemical assays; statistical analyses; and studies of implications of findings for clinical practice and population health. In addition to generating a series of exceptionally informative findings that address major current hypotheses in CHD, this initiative will create a unique resource for future investigations.

Publications

10 25 50

 
Description INTERVAL study
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact The INTERVAL study provided NHS Blood and Transplant with the first data from a randomised trial of the effects of different blood donation intervals. The quantitative data produced from INTERVAL (and published in The Lancet) include data on the amount of blood collected from donors and the health and well being of blood donors and will inform NHSBT policy on blood donation strategies and policy.
 
Description Blood Transplant Research Unit (NIHR - BTRU)
Amount £4,099,619 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2015 
End 09/2020
 
Description EPIC-CVD (Framework Programme 7 - Health)
Amount € 6,000,000 (EUR)
Funding ID 279233 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2012 
End 12/2015
 
Description European Research Council Advanced Investigator Award (EPIC Heart)
Amount € 2,499,154 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 05/2011 
End 04/2016
 
Title EPIC-Heart Assays 
Description Assays have now been completed in all EPIC-Heart participants on the following phenotypes: - 22 clinical chemistry biomarkers - 210,000 genetic variants - a further 450,000 genetic variants - a panel of 37 fatty acids Assays are near completion in these participants for vitamins C and D, a panel of 6 carotenoids and telomere length. These assays are also being extended to stroke cases identified under the FP7 funded project, EPIC-CVD, adding further value to the EPIC-Heart project. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2012 
Provided To Others? Yes  
Impact N/A 
 
Title Methods 
Description To allow the assessment of risk prediction in a multi-centre case-cohort study, novel statistical methods have been developed at the EPIC-Heart Coordinating Centre 
Type Of Material Improvements to research infrastructure 
Year Produced 2011 
Provided To Others? Yes  
Impact A Publication: "Derivation and assessment of risk prediction models using case-cohort data". Sanderson J, Thompson SG, White IR, Aspelund T, Pennells L. BMC Med Res Methodol. 2013 Sep 13;13(1):113 
 
Title EPIC-CVD database 
Description The EPIC-Heart phenotype database is being expanded to stroke outcomes (~9000 incident cases), rather than just coronary disease, adding further value to the initial investment 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact N/A 
 
Title EPIC-Heart Database 
Description Data have been collected and harmonised on 25,000 individuals 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact No impact as yet 
 
Title Exome Chip Consortium 
Description Exome chip consortium 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact N/A 
 
Title Metabochip Consortium 
Description Metabochip Consortium database 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact N/A 
 
Description BRAVE 
Organisation International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Country Bangladesh 
Sector Charity/Non Profit 
PI Contribution Financial contribution to support the BRAVE study, a case-control study of acute vascular events in Bangladesh, including the recruitment of participants to the study, lipid measurements and genetic assays.
Collaborator Contribution icddr,b recruited participants to the BRAVE study, collected biological samples from them and performed lipid assays
Impact N/A
Start Year 2010
 
Description Exome Chip Consortium 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation Massachusetts General Hospital
Country United States 
Sector Hospitals 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation Pfizer Global R & D
Country United States 
Sector Private 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description Exome Chip Consortium 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution coordinating centre
Collaborator Contribution funding, contribution of data and analyses
Impact N/A
Start Year 2012
 
Description NMR Metabolomics 
Organisation Brainshake
Country Finland 
Sector Private 
PI Contribution Provided samples from 50,000 participants in INTERVAL study.
Collaborator Contribution Assays complete for all 50,000 samples, ~240 metabolites measured.
Impact Publication manuscripts in preparation
Start Year 2014
 
Description Alan Turing Institute presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Collaborative workshop MRC Biostatistics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description MRC presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Presentation at BHF Centre of Excellence meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Presentation at BRC Scientific Advisory Board 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Presentation at Wellcome Trust Target Validation Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Presentation at the European Bioinformatics Institute 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Presentation to Takeda 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015
 
Description Talk at AstraZeneca 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation of findings from scientific research
Year(s) Of Engagement Activity 2015