CHeartED - Gene- Environment Interactions in Heart Development

From 01-01-2009 to 31-12-2012

Description

Cardiovascular malformation (CVM) is the commonest cause of childhood death in developed countries. In the EU there are 51,000 new cases each year and two million affected individuals. Yet, despite intensive research, the cause of 80% of CVM remains elusive. The mission of CHeartED is to identify genetic and environmental pathways that can be modified with the goal of reducing preventable CVM incidence.

Epidemiological studies have shown that the stress of maternal hypo or hyperglycemia increases the incidence of CVM. We plan a genetic association study in individuals with and without CVM born to diabetic mothers, to test whether genetic variants are associated with CVM. A similar study, without prior risk hypothesis, addresses tetralogy of Fallot, a CVM, which requires surgery in early life. These studies will reveal common genetic variants associated with CVM and thus add to existing knowledge on the aetiology of CVM. Moreover, the identification of genetic factors that differ in the context of maternal diabetes will disclose any associations in genetic pathways influenced by environmental factors. RNA expression studies in the mouse to identify new genes and pathways involved in outflow tract malformations and maternal diabetes associated with CVM, will complement the human studies. Finally, we will develop a 3D atlas of gene expression patterns and cardiac morphology at key developmental stages that will serve as a morphological framework.

Central to our proposal is the development of a bioinformatics tool complemented by an open-access Wiki-based database. The bioinformatics tool will combine the sequence data and expression data generated by the human and mouse studies with morphology and literature to prioritize genes and generate hypotheses. The Wiki, which will contain existing and new genetic and environmental knowledge on heart development, will be an aid for many groups working on cardiovascular development and a novel means of disseminating our findings.

In a major effort to tackle the underlying biological and genetic questions our project has formulated four work themes, bringing together existing and novel knowledge on the environment and its interaction with genetic factors in causing cardiovascular malformation:
The Genetic epidemiology line (1) will focus on genome wide association studies using patient DNA samples referenced and stored at the major European patient CVM databases, readily accessible to the groups in this proposal. The Animal study line (2) will make use of a mouse diabetic pregnancy model and a mouse model of cardiac outflow tract malformations to back up the genetic and bioinformatics studies. The Genetic bioinformatics line (3) will improve existing bioinformatics tools to integrate current and new knowledge and enable better candidate gene identification. The Management and Dissemination line (4) will set up a website for communication within the consortium and will generate an interactive database, containing existing genetic and environmental knowledge on heart development linked to gene expression and genetic association data, allowing dissemination on a pan European scale.

Team

• Yves Moreau, Promoter

Financing

Funding: EU Funding - European Funding

Program/Grant Type: EU Other - Other