CO-43: Genetic study identifies common variation in phactr1 to associate with fibromuscular dysplasia

S. Kiando, N. Tucker, A. Katz, C. Tréard, V. Desca-Mard, L. Castro-Vega, C. Barlasina, D. Cusi, P. Galan, J. Empana, J. Olin, H. Gornik, P. Plouin, I. Kullo, D. Milan, S. Ganesh, P. Boutouyrie, J. Kovacic, X. Jeunemaitre, N. Bouatia-Naji

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. Methods We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array. Results We followed up 13 loci (p<10−4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, (p = 7.4×10−10, n all cases = 1154, n all controls = 3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (p=0.0009), increased intima media thickness (p=0.001) and wall cross-sectional area (p=0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients (n=20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients (p=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (p=0.003) indicating impaired development of vasculature. Conclusions Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

Original languageEnglish (US)
Pages (from-to)S20
JournalAnnales de Cardiologie et d'Angeiologie
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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