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ANR funded project

Innovation biomédicale (DS0404) 2014
Projet BIOCADRE

Mechanistic and biological determinants of chronic vasculopathy in sickle cell disease

Background: Sickle cell disease (SCD) is the most frequent monogenic disease in the world, due to a unique mutation on the ß-globin gene. Most affected individuals live in sub-Saharan Africa, yet, the natural history of the disease in Africa remains largely unknown. SCD usually presents in childhood and is characterized by the association of a chronic hemolytic anemia with episodes of acute vaso-occlusive events and progressive vascular organ damage. SCD is now widely recognized as a vascular disease with marked endothelial dysfunction. Hemolysis probably plays a key role by reducing NO bioavailability, but other involved mechanisms are not fully understood.

Objectives: The project aims at better understanding SCD chronic vascular complications and in particular to explore extensively the different mechanisms associated with hemolysis. This will be addressed through both an epidemiological approach and a hypotheses-driven pathophysiological approach. On the one hand, a descriptive and analytic epidemiological study will isolate clusters of clinical, functional and usual biological phenotypes in SCD patients and look for new mechanistic and biological markers predictive of chronic vascular complications in SCD with SS and SC hemoglobin phenotype. We will specifically investigate i) microcirculation functions using peripheral arterial tonometry, ii) blood and plasma viscosities, iii) level of plasma blood cell derived microparticles, free hemoglobin, and the free heme content of erythrocytes-derived microparticles and expression of Duffy erythrocyte antigen, the unique erythroid receptor for chemokines. One the other hand, we will test novel markers and modifiers of hemolysis and heme metabolism and assess their relationship with inflammation and vascular phenotypes. In particular we will characterize the phenotype of blood leukocytes using flow cytometry analysis (FACS) and RNA sequencing, measure the level of inflammatory cytokines. These different biomarkers will be compared between the selected subgroups of patients with extreme vascular phenotype.

Methods: The project involves a transversal case control study, nested in the CADRE cohort, recently built up by Partner 1 and African collaborators. CADRE is the largest ongoing epidemiological cohort, including 4,300 SCD patients and 1,000 controls in five west and central African countries, in which various chronic complications of SCD have already been registered. The present second phase study will be conducted in the centres of Dakar and Bamako. Patients’ selection will be performed in the existing database to obtain 6 subgroups of 40 SS and 20 SC patients with one of the main vascular chronic complications or none of them, for a total of 360 patients. Selected patients will be recalled during one year in parallel in the 2 recruiting centres. Clinical phenotyping, usual biology, functional microvascular functions (peripheral arterial tonometry), FACS on blood and blood/plasma viscosities analyses will be performed in the African recruiting centres after training of technicians, PhD and MD students by the French partners. Plasma samples, microparticles and extracellular DNA, will be prepared and frozen for further analyses in the partner’s laboratories. DNA will be collected for each subject. A principal component analysis will isolate clusters of clinical complications, functional and biological markers and a multivariate logistic regression will quantify the effect of these markers on the risk of vasculopathy, with adjustment on all known SCD modifying factors.

Expected results: 1) The identification of high risk SCD patients for chronic vascular complications using new biomarkers, 2) A better understanding of chronic vascular disease process at the mechanistic and biological (viscosity, hemolysis, erythrocyte derived microparticles, inflammatory cytokines and receptors) levels, 3) The identification of endophenotypes and constitution of DNA bank for further genetic studies.

Partners

PARCC Renal and Cardiovascular Development and Pathophysiology UMR_S970

UMR_S1134 Integrated Biology of the Red Cell UMR_S1134

UMR_S970 Cardiovascular epidemiology UMR_S970

ANR grant: 468 304 euros
Beginning and duration: mars 2015 - 36 mois

 

ANR Programme: Innovation biomédicale (DS0404) 2014

Project ID: ANR-14-CE15-0018

Project coordinator:
Monsieur Xavier Jouven (Cardiovascular epidemiology UMR_S970)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.