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.
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.
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.
Organisations
- University of Cambridge, United Kingdom (Lead Research Organisation)
- Harvard University (Collaboration)
- Queen Mary, University of London, United Kingdom (Collaboration)
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) (Collaboration)
- Novartis (Collaboration)
- Massachusetts General Hospital (Collaboration)
- Merck (Collaboration)
- Brainshake (Collaboration)
- Pfizer, United States (Collaboration)
- University of Leicester, United Kingdom (Collaboration)
Publications

Zwakenberg SR
(2020)
Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study.
in Clinical nutrition (Edinburgh, Scotland)

Zheng JS
(2021)
Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.
in Diabetes care

Zheng JS
(2019)
Association of Plasma Vitamin D Metabolites With Incident Type 2 Diabetes: EPIC-InterAct Case-Cohort Study.
in The Journal of clinical endocrinology and metabolism

Zhao W
(2017)
Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.
in Nature genetics

Zanoni P
(2016)
Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
in Science (New York, N.Y.)

Yao C
(2018)
Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.
in Nature communications

Yang Z
(2016)
Correlation of an epigenetic mitotic clock with cancer risk.
in Genome biology


Woodfield R
(2015)
Accuracy of Patient Self-Report of Stroke: A Systematic Review from the UK Biobank Stroke Outcomes Group.
in PloS one
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 | 09/2015 |
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 | Belgium |
Start | 04/2011 |
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 | Public |
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 |