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

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.

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.