Project GENET-FMD (Genetic Investigation of Fibromuscular Dysplasia) | ANR - Agence Nationale de la Recherche ANR funded project | ANR - Agence Nationale de la Recherche

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ANR funded project

JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique (JCJC SVSE 1) 2013
Projet GENET-FMD

Genetic Investigation of Fibromuscular Dysplasia

The GENET-FMD project aims to identify rare and common genetic determinants of fibromuscular dysplasia (FMD), a non-atherosclerotic non-inflammatory rare arterial disease, predominantly described in renal arteries and extra-cranial carotid. FMD is the second common cause for renovascular hypertension and stroke, a leading cause of disability and death in the world.
The aetiology of FMD is totally unknown and treatment by ballon angioplsaty is not totally satisfactory in sever and multi-site stenoses. GENET-FMD is a comprehensive genetic study that aims to be a first important milestone of the deciphering of physiopathology of arterial stenosis in the absence of atherosclerosis, provide insights on artery wall integrity and identify validated genetic biomarkers, that could ultimately classify and predict FMD evolution and complications. GENET-FMD is part of an ongoing translational research program on FMD.
GENET-FMD will be articulated in 2 research axes with 2 aims and includes complementary genetic approaches that cover the whole range of genetic variability in Human, including rare mutations and common variants.
Aim 1: identification of highly penetrant rare mutations involved in FMD aetiology
We will generate and analyze exome sequencing data from 150 unrelated FMD cases. In a pilot study, we have generated the exome sequences of 18 multifocal renal FMD cases and identified a specific enrichment in low frequency (MAF<0.02) coding and predicted to be functional mutations for 20 genes in the 18 FMD patients, compared to controls. The sequencing of 132 remaining FMD cases will be crucial to confirm this finding and also, provide a better analytical situation, considering that FMD is probably polygenic. Wa have already genotyped 300 FMD cases for 260K known rare variants (exome-chip study) as a complement to the sequencing data). We will use a combined strategy of statistical and candidacy arguments to prioritize genes for follow-up. Genes that will be validated by direct sequencing in all FMD cases available locally and in collaboration with clinicians from the US registry for FMD will be confidently declared as causative of FMD.
Aim 2: Identification of genetic susceptibility loci that confer susceptibility risk for FMD
Here we will investigate the role of common genetic variants in FMD aetiology under a polygenic hypothesis, with known environmental factors (female gender, smoking, artery length and lateralisation). We will perform a multi-stage genome-wide association study (GWAS) to assess the impact of frequent (minor allele frequency MAF=0.05) on the risk of FMD using a multi-stage case control design. This will be the most powerful genetic association study ever conducted for FMD and will include a total of ˜1500 cases of FMD ( ˜500 discovery and ˜1000 in the replication, including French and American cases.
Genes mutated or located in the vicinity of confident susceptibility loci for FMD will be validated by preliminary functional studies aiming to provide a putative link with artery, mainly gene expression and protein quantification in artery samples.
We will also assess the modifying role of non-genetic determinants, mainly sex and smoking by conducting stratified and interaction GWAS, the impact of mutated genes and susceptibility loci in circulating biomarker (ex. Metalloproteinases), classification power of histological (intima, media and adventitia FMD) and imaging sub-phenotypes (mulitofocal vs. multifocal). We will test if carotid and renal FMD have a shared genetic architecture (ARCADIA data), and if yes, how FMD genetic biomarkers predict the disease evolution and complications overtime, mainly hypertension and stroke (PROFILE), as a first and promising step in personalized genomic medicine of FMD.

Partners

INSERM UMR970 Institut National de la Recherche Medicale

ANR grant: 299 999 euros
Beginning and duration: novembre 2013 - 48 mois

 

ANR Programme: JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique (JCJC SVSE 1) 2013

Project ID: ANR-13-JSV1-0002

Project coordinator:
Madame Nabila BOUATIA-NAJI (Institut National de la Recherche Medicale)

 

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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.