Despite advanced knowledge of the human genome and hundreds of polymorphic candidate genes, a small percentage of the genetic variability of cardiovascular risk factors has been explained and a very small number of SNPs have been proposed for cardiovascular prevention or prediction. Furthermore, given the questionable effectiveness of a large number of strategies for the prevention of cardiovascular pathologies based on the reduction of classic risk factors, there is an urgent need to research and study new risk markers among which genetic factors represent a major target. However, the search for predisposing factors to frequent pathologies of the cardiovascular system requires a global and complex approach including, of course, genotypic analyses but also the measurement of environmental factors and relevant intermediate phenotypes. The classical candidate gene approach, although indispensable, suffers from obvious limitations. In particular, it has been based for the most part on a purely clinical definition of the phenotype (the disease). The clinical homogeneity of a multifactorial pathology has no reason to reflect pathophysiological homogeneity, much less genetic homogeneity. Furthermore, we note that 1) the biological effects of genes and their products and their variations in healthy subjects under physiological conditions are still poorly known; 2) studies focus on a metabolic cycle or on one gene/molecule independently of the others.
This leads us to propose an approach with a complementary and parallel approach to case-control studies that can be described as 'deductive', i.e. going from gene to disease and focusing on metabolic pathways, and therefore on coherent sets of intermediate genes and phenotypes whose variability could influence predisposition to disease. This approach would require two types of studies. Firstly, a study in healthy subjects that would allow, without the influence of pathology and/or treatment, an understanding of the mechanisms regulating the effect of genes, and secondly, case-control studies that would make it possible, following application of the conclusions of the first stage, to propose markers relevant to cardiovascular prevention and prediction.
Thus, the general objective of our Research Program is to advance the knowledge of the mechanisms involved in pathologies of the cardiovascular system through an integrated approach, from genotype to phenotype, including biological phenotype and, of course, environmental factors. We will focus in particular on genes coding for adhesion and inflammation molecules without neglecting metabolic pathways whose importance in atherosclerosis is well established: lipid metabolism, blood pressure regulation, coagulation, homocysteine metabolism and antioxidant systems.