Projects
Scope of my research
My group aims to decipher the genetic causes of diseases and traits related to cardiovascular disease. I have investigated in the past the genetic basis of several obesity and type 2 diabetes related traits, especially fasting glucose an insulin. My recent focus is on the genetic study of Fibromuscular Dysplasia (FMD) and Mitral Valve Prolapse (MVP).
My aim is to understand the aetiology of these diseases to improve their diagnosis and provide biological leads toward more precise treatments.
We apply complementary scientific strategies combining Genetic Epidemiology, Molecular Genetics, Cellular Biology:
1) The investigation of the genetic basis of FMD and MVP using GWAS, exome and targeted sequencing in case control cohorts and families.
2) The study of the functional significance of the genetic susceptibility variants at confirmed loci and the regulation of their targeted genes.
3)The exploration of the mechanistic link between susceptibility genes and the physiopathology of FMD and MVP (e.g engineered cell lines, and total expression in human arteries, valves).
Fibromuscular dysplasia (FMD), a clinical and genetic challenge
FMD is a common cause of secondary hypertension that highly predisposes to stroke and is associated with coronary dissection in patients with atypical clinical presentation. Patients carry a succession of stenoses and aneurysms at their medium-sized arteries, mostly renal and carotid arteries presenting the typical “string-of-beads” aspect in angiography examination.
- The complexity of the diagnosis based on angiography
- The absence of classic risk factors, especially dyslipidaemia and obesity
- The early onset (median age of diagnosis < 50 years)
- The high prevalence in women (80% of patients)
All intriguing and challenging features for the diagnosis and the investigation of this peculiar vascular disease.
Read more: Fibromuscular dysplasia (FMD), a clinical and genetic challenge
Mitral valve prolapse (MVP), common cause of valve repair and cardiac death)
Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 persons in the general population. MVP result in regurgitation with fatigueis a frequent cause of valve repair or replacement and most importantly heart failure and sudden cardiac death.
By the investigation of the genetics in families and large cohorts of patients we have identified novel genetic predisposing factors. Recent collaborative studies involving an International Transatlantic Leducq Network allowed us to support the role of DCHS1 involved in cell polarity in MVP. On the other hand, our first GWAS of MVP identified six risk loci and provide functional evidence from mouse and zebrafish models, for strong candidate genes. We highlight LMCD1 encoding a transcription factor, for which morpholino knockdown in zebrafish results in atrioventricular (AV) valve defect with regurgitation. A similar zebrafish phenotype was obtained for tensin1 (TNS1), a focal adhesion protein involved in cytoskeleton organization. We also show the expression of tensin1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1-/- mice (Dina, Bouatia-Naji et al., Nat Genet 2015).
Read more: Mitral valve prolapse (MVP), common cause of valve repair and cardiac death)
