Intérêt de la génomique du VEGF en endocrinologie clinique

Abstract : The vascular endothelial growth factor (VEGF-A) plays a key role in a large variety of physiological and pathological processes, including cardiovascular and inflammatory diseases and cancer. Consequently, during this thesis, we have developed a functional genomics and integrative approach of the VEGF-A roles in order to better describe the diversity of the processes in which it is implicated by adding in the investigation panel phenotypes the thyroid hormones, which are essential in the human physiopathology. The final objective of this work was to identify the VEGF-A plasma variability linked polymorphisms and the VEGF-A expression products useful for personalized medicine. Therefore, studies on common among diseases intermediate phenotypes such as adhesion, and inflammation molecules, metabolic syndrome and lipids have been conducted on the STANISLAS cohort (healthy volunteers), as well as on other replication-directed populations of the team. Studies in a pathological population aiming to investigate links with thyroid hormones and thyroiditis have been conduced in a Tunisian “case-control” population with cases treated for thyroiditis during 6 months. Here are our main results: 1.Association between VEGF-A145 and ICAM-1, L-selectin and TNF-[alpha] mRNA levels. 2.Association between plasma levels of VEGF-A and ICAM-1 and E-selectin. 3.Epistasis interactions between VEGF-A variants for E-selectin, TNF-[alpha], ICAM-1 and IL-6 plasma levels. 4.Association between rs4416670 and L-selectin mRNA levels. 5.Association between the rs10738760 and the risk for metabolic syndrome. 6.Association between rs6921438 and HDL and LDL plasma levels. 7.Interaction between rs4416670 and hypertension for plasma variation of apolipoprotein E. 8.Positive correlation between plasma levels of VEGF-A and FT4 in Tunisian controls. 9.Negative association between plasma FT4 levels and VEGF-A145 levels in the entire Tunisian population (patients and controls). 10.Increase of VEGF-A165 levels in Grave’s patients in comparison with controls. 11.Increase of VEGF-A165b levels in Hashimoto patients in comparison with Graves patients. 12.Increase of VEGF-A165b levels in hypothyroid patients in comparison with hyperthyroid patients after 6 months of treatment. 13.Decrease of VEGF-A189 levels in all after 6 months of treatment thyroiditis patients in comparison with controls. 14.Association between VEGF-A145 and thyroid status, only in Hashimoto patients. 15.Association between anti-TPO antibodies positivity and VEGF-A165 in the entire Tunisian population (patients and controls). 16.Association between the A allele of rs10738760 and an increased risk of Graves’ disease. 17.Association of the A allele of rs692148 with an increased risk for Grave’s disease. 18.Association of the T allele of rs4416770 with a higher risk of hyperthyroidism regardless of the initial diagnosis and treatment of patients. 19.Association of A allele of rs10738760 with higher FT3 plasma levels in the entire Tunisian population (patients and controls). This thesis shows, through an important number of results of stratified medicine, the central implication of VEGF-A genomics in the regulation of physiological and pathological processes. The identification of its role in the regulation of thyroid hormones could highlight the role of VEGF-A as a new common denominator of cardiovascular, inflammatory and oncological diseases that has to be clinically validated
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Marc Robert Rancier. Intérêt de la génomique du VEGF en endocrinologie clinique. Médecine humaine et pathologie. Université de Lorraine, 2015. Français. ⟨NNT : 2015LORR0054⟩. ⟨tel-01751643⟩



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