Investigating fibROmuscular dysplasia and spontaneous coronary Artery dissection using genetic and functionaL genomics to decipher the origIN of two female specific cardiovascular Diseases

Informations projet

ROSALIND

N° de convention de subvention: 716628

DOI

10.3030/716628

Projet clôturé

Date de signature de la CE 22 Février 2017

Date de début 1 Mars 2017

Date de fin 28 Février 2023

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 500 000,00

Contribution de l’UE

€ 1 500 000,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - ROSALIND (Investigating fibROmuscular dysplasia and spontaneous coronary Artery dissection using genetic and functionaL genomics to decipher the origIN of two female specific cardiovascular Diseases)

Période du rapport: 2021-09-01 au 2023-02-28

Résumé du contexte et des objectifs généraux du projet

Cardiovascular disease (CVD) is under-diagnosed and under-investigated specifically in women. Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are two devastating arterial diseases due to non-atherosclerotic-related stenosis of medium-size arteries at renal and cerebrovascular arteries in FMD, and dissection of the coronary artery causing an ischemic myocardial infarction due to hematoma formation in SCAD. Both diseases share numerous clinical features, including the age of onset under 50 years, a high proportion of women among patients (80-90%), and the absence of cardiovascular risk factors in most cases. Asymptomatic FMD is reported in extra-coronary arteries of 50% of SCAD patients, and both diseases include migraine and
ROSALIND project provided major advances in the genetic risk factors and biological mechanisms underlying FMD and SCAD pathogenesis. We generated large-scale genomic and genetic data for the first time for these neglected and understudied forms of cardiovascular disease. We identified globally 20 novel genes involved in the polygenic risk that we found to be high in both diseases. Through several studies combining genetic, transcriptomic, and epigenomic data, we pointed at several biological mechanisms at play in FMD and SCAD pathogenesis, mainly related to calcium exchange in link with smooth muscle cells contraction function, extracellular composition and maintenance, and tissue-mediated blood coagulation. We provided a novel cellular model of smooth muscle cells derived from induced pluripotent stem cells that we have validated through the study of one of the genes identified.
Overall, ROSALIND provided many novel leads into FMD and SCAD pathogenesis and disease prevention. We found several biological mechanisms that are now the focus of future investigation aiming at the conception of innovative treatments for FMD and SCAD.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The ROSALIND project provided major advances in deciphering the genetic basis of FMD and SCAD using genomic analyses, mainly genome-wide association (GWAS) methodology. We showed that both diseases present high polygenic heritability, are genetically close to hypertension, migraine, cervical artery dissection, and intracranial aneurysm, supporting shared genetic risk factors. We also provided support for an opposite direction of genetic link between SCAD and atherosclerotic form of coronary artery disease at a number of risk loci and at the genomic level (Adlam et la., Nature genetics 2023). We examined the functional properties using genomic annotations in silico and in vitro and provided evidence for genetic variants at play in FMD and SCAD risk are mostly relevant to the regulation of genes related to smooth muscle cells and fibroblasts biology (Georges et al., Nat Com 2021, and Adlam et al., Nat Genetics 2023). Most genes prioritized were mainly in link with calcium exchange involved in cell contraction, extracellular matrix secretion and organization and prostacyclin signaling through the study of rare variations. Interestingly, we identified a novel biological mechanism in SCAD related to tissue factor coagulation through the identification of a genetic risk locus specific to the risk of SCAD.
ROSALIND has allowed the generation of an unprecedented wealth of genetic and genomic data related to FMD and SCAD and beyond, as we found novel biological mechanisms also related to a large spectrum of arterial diseases. Our findings set the stage for an ambitious follow-up with aim to translate those genetic and genomic findings into specific preventive and therapeutic strategies to cardiovascular diseases predominantly affecting women.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

In this project, we performed an extensive genetic investigation not only for FMD but also for SCAD through a full GWAS and functional exploration at SCAD loci. The initial plan was to validate FMD genes in SCAD, and we did this through 2 studies: PHACTR1 (Adlam JACC 2019) and PTGIR (Georges et al Cardiovascular Res 2020). We have now generated a full GWAS in the French cohort, in addition to the coordination of a meta-analysis including 7 additional GWAS for SCAD (Adlam Nat Genet 2023). This is partially due to an increase in awareness about the disease that our work is fueling every time we publish a new genetic study. There is now a clear interest from the cardiology community to understand the genetics and physiopathology of SCAD, and my group, thanks to ERC funding, has become a significant contributor to this field.
In the functional and cellular part, we have decided to create SMC models from iPSCs, a new technical strategy I have adopted to go beyond the limitations of primary cell lines planned initially. We succeeded to generated valid models using iPSC-derived SMCs to comprehensively study gene regulation and function at FMD and SCAD loci. We provided a validation of this new cellular tool to study the LRP1 locus that is under consideration for publication.

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