Génétique de la rigidité artérielle et approches fonctionnelles – GRAF
Genetics of arterial stiffness and functional approaches
Arterial stiffness is a cardiovascular risk factor. Recent genetic studies have revealed specific genes contributing to arterial stiffening. Available data on genome-wide association (GWA) have been initiated on pulse wave velocity but none of the associations attained genome-wide significance.
Identification of new genes contributing to arterial stiffness
The project is focused on 2 complementary tasks: 1) exome sequencing and 2) functional studies of genetic variation derived from the genetic analyses.The post-genomic approach is dedicated to link genetic results to specific biological systems in the vascular cells. Our ultimate goal is to determine whether there is a specific factor contributing to arterial stiffness which over weighs all other known cardiovascular risk factors. The genetic and genomic studies envisaged should lead to the identification of new genes and biological pathways contributing to arterial stiffness. From a medical perspective, this might have 2 types of consequence: 1. to provide new targets that might be further investigated by the drug industries, 2. to provide new diagnostic or prognostic tools based on combinations of genotypes and/or phenotypes.
The genetic study is focused on two tasks: 1/ genome wide association study of arterial stiffness assessed by pulse wave velocity on a first cohort including 1366 patients; 2/ another strategy will be genome-wide scans for the effects of rare variants using exome sequencing on a second cohort including 4600 individuals.
The post-genomic approach is dedicated to link GWA results to specific biological systems in the vascular cells. Three successive steps are scheduled : 1. to study first consequences of SNP on RNA level and protein structure; 2. to examine then intermediate phenotypes in vascular smooth muscle cells and endothelial cells, and 3. mechanical testing in cell preparations, animal models when available or in vitro arterial segments. Genes that will be studied in priority are those for which it is possible to obtain easily a direct measure of arterial stiffness.
The GWA study using the pulse wave velocity as quantitative trait (1366 hypertensive old patients) led to the identification of 6 genes associated with arterial stiffness but none of these assocaitions attained genome-wide significance. Regarding the second genetic analysis, DNA extraction has been performed and exome sequencing is in progress.
We have demonstrated that the expression of the alphavbeta3 gene is increased in response to mechanical forces. The serum response transcription factor (SRF) regulates elasticity of the arterial wall through modulation of vasomotor tone.
The results of the GWA study and the recent developements in the genetic analysis of complex traits lead us to modify our strategy for studying the effects of rare variants using exome sequencing in a large population of 4600 individuals. We will use a particular genotyping chip in which all rare coding variants identified in 3 different populations were included. This methodology will allow us to investigate the association of rare variants with several parameters of arterial elasticity.
1. Mao et al. Cardiovasc Res. 2012. Regulation of alphavbeta3 gene expression by puslatile forces
2. Engelen et al. Eur Heart J. 2012 Nov 27. Reference values for intima media thickness
3. Galmiche et al. Circ Res. 2013 Feb 20. Role of transcription factors in arterial stiffness
Project coordination
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
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Beginning and duration of the scientific project:
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