A major new frontier in biomedicine is to identify interactions of specific components of nature and nurture in determining risk of complex diseases. Coronary heart disease (CHD) - the single leading cause of death in Europe - is jointly determined by genetic and lifestyle factors. It is unknown, however, how diet, nutrients, and lifestyle factors modulate genetic susceptibility. For scientific and public health reasons, there is a strategic need to study such interactions reliably. There is a unique opportunity for a cost-effective and powerful study because we have:-conducted detailed assessment of diet and other lifestyle factors in 520K participants in a pan-European prospective study-identified >12K incident CHD cases accrued during >5M person-years at risk-identified a random sub-cohort of >15K participants without CHD to serve as referents-commenced assay of lipid and other markers in 12K cases and 15K referents-prepared DNA for genetic assay.In 12K CHD cases and 15K referents, we will assay: >217K genetic variants contained in the state-of-the-art metabochip; 37 fatty acids; and vitamin D metabolites. Analyses will focus on: discovery of interactions; causal evaluation of biomarkers; CHD risk scores.The findings should open new horizons and contribute towards: 1) explaining missing heritability 2) shaping nutritional guidelines 3) personalising preventive medicine 4) defining approaches to modify genetic susceptibility by avoiding deleterious lifestyles 5) identifying biomarkers that are priority therapeutic targets and 6) innovative prognostic tools.Gene-lifestyle interplay is a major future growth area. This world-leading study will enhance Europes strengths in public health, nutrition and genetic epidemiology, and create a valuable future resource.