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Les déterminants environnementaux et génétiques de phénotypes intermédiaires de l'inflammation dans la cohorte Stanislas

Abstract : Inflammation is a key metabolic pathway of the formation, the progression and the disruption of atherosclerotic plaques. In addition, numerous inflammatory molecules are emerging as potential markers of diagnosis and prognostic of cardiovascular diseases. However, their physiopathologic variations being very important should be better defined in order to refine decision limits ofpathological data. Thus, we investigated in this thesis the variability of intermediate phenotypes of inflammation due to genetic, constitutional and environmental (individual and familial) factors, and their relation with classic risk factors of cardiovascular diseases. These studies were performed on sub-samples of the STANISLAS cohort, a familial cohort of supposed healthy individuals. We defined the constitutional and environmental factors responsible for the interindividual variability of plasma concentration of IL-8 and MCP-1 (2 chemokines) and EGF and VEGF (2 growth factors) in 304 children and 540 adults. In addition, reference values for these 4 molecules were determined. We found that the concentration of hs-CRP is correlated with leucocyte and platelet counts and orosomucoid, haptoglobin, IL-6 and ICAM-1 concentrations and not with IL-8, IL-18, MCP-1, EGF, VEGF, IGF-1, IGFBP-3, TNF-[alpha], TNF-RII and E-, L- and P-selectin concentrations; generating 2 groups that could give complementary information in term of cardiovascular risk. We showed that the evolution of acute phase proteins' concentrations over 5 years is significantly associated with the evolution of BMI ([delta] BMU ou = 1,6 Kg/m2 ) in alll the individual of the family. Genetic studies permit us to show that (i) the polymorphisms LTA 252A>G and TNF-308G>A are associated with the increase of plasma MCP-1 concentration, and that (ii) the number of 84 alleles of the APOE gene is negatively associated with serum hs-CRP concentration. Moreover, we showed that there is a familial resemblance of IL-8, MCP-1, EGF, VEGF and hs-CRP concentrations. Studies of variance components showed that (i) general heritability of IL-8 and EGF are 16% and 26,9%, respectively, and may be wholly explained by the familial environment, that (ii) genetics may explain 60,6% of VEGF concentration variance and the totality ofthe general heritability, and that (iii) general heritabilities of hs-CRP concentration at the 2 points of recruitment are 13% et 11%, respectively, and may be wholly explained by the familial environment. All these results confirm the complexity of the inflammatory process regulation, and could be helpful for the interpretation of biological data of patients and the understanding of the regulation of inflammatory molecules' concentrations in healthy individuals.
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Submitted on : Thursday, March 29, 2018 - 10:48:56 AM
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Hind Khiar-Berrahmoune. Les déterminants environnementaux et génétiques de phénotypes intermédiaires de l'inflammation dans la cohorte Stanislas. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2006. Français. ⟨NNT : 2006NAN10229⟩. ⟨tel-01746977⟩



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