1. To determine the factors affecting interindividual variation in apo E plasma concentration, in particular the role of apo E genetic polyrnorphism
2. To establish apo E genotype related reference ranges for plasma apo E concentration
3. To study the distribution of apo E genotype / apo E plasma concentration across different European populations
4. To study, in case-control studies, the role of apo E plasma concentration together with apo E genotype as risk factors for: (i) CAD, (ii) AD
There is now much evidence implicating apolipoprotein E (apo E) in the pathogenesis of CAD and AD. The apo E gene is polymorphic with 3 common alleles (2, (3 and (4. The (4 allele appears to be associated with higher plasma cholesterol and is also associated with an increased risk of AD. The role of plasma apo E concentration as a risk factor in these conditions is unclear investigated and is the focus of this project. A prerequisite to the study of apo E as a risk factor is an understanding of the factors controlling apo E concentration in health. The first working hypothesis of this project is that apo E plasma concentration is determined by an interaction of environmental (e.g. obesity, diet) and genetic factors (in particular apo E genotype). The second working hypothesis is that apo E concentration together with apo E genotype serves as a risk marker for AD and CAD. Thus, the project will determine the factors affecting interindividual variation in apo E plasma concentration, in particular the role of apo E genetic polymorphism and to establish apo E genotype related reference ranges for plasma apo E concentration in healthy subjects. The distribution of apo E genotype / apo E plasma concentration across different European populations will be investigated. The role of apo E plasma concentration together with apo E genotype as risk factors for the development of CAD and AD will be investigated in case-control studies.
The first series of objectives will be attained by studying 9.000 healthy subjects recruited in 9 European centers. The CAD study will use data and samples from both a previous case-control study: European Atherosclerosis Research Study (EARS) and the Monitoring Trends and Determinants in Cardiovascular disease (MONICA) Project. The AD case-control study will require the recruitment of patients with Alzheimer's disease fulfilling recognised and uniform diagnostic criteria. Standardised data collection, laboratory methods (including calibration material) will be used.
The use of multicentre recruitment will allow the study of allele prevalence and gene-envirornment interactions throughout Europe, from North to South. The results obtained may have implications for screening, prevention and early intervention, and follow up in CAD and AD. Furthermore, the demonstration of a clinical role for apo E plasma concentration would undoubtedly stimulate the European Pharmaceutical industry to produce and market diagnostic kits.
The project is proposed as a reinforced concerted action since it draw together many of the major European teams working on apo E to perform collaborative research at European Union level. It provides a network resource through the provision of a central laboratory for biological analyses and will allow targetted training for young researchers.