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PLoS Genet. 2016 Oct 28;12(10):e1006367. doi: 10.1371/journal.pgen.1006367. eCollection 2016 Oct.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

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INSERM, UMR970 Paris Cardiovascular Research Center (PARCC), Paris F-75015, FRANCE.
Paris-Descartes University, Sorbonne Paris Cité, Paris 75006, FRANCE.
Cardiovascular research Center, Massachusetts General Hospital, Charlestown, MA 02114, USA, Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142.
Department of Internal Medicine and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine, Marie-Josée and Henry R. Kravis Cardiovascular Health Center at Mount Sinai, One Gustave L. Levy Place, Box 1030 New York, NY 10029, New York, NY, USA.
Assistance Publique-Hôpitaux De Paris, Referral Center for Rare Vascular Diseases, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.
Assistance Publique-Hôpitaux De Paris, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA.
Dept. of Health Sciences, Genomic and Bioinformatics Unit, Viale Ortles 22/4, Milano, Chair and Graduate School of Nephrology, University of Milano, Division of Nephrology, San Paolo Hospital, Milano, 20142,ITALY.
Institute of Biomedical Technologies, Italian National Centre of Research, Via F.lli Cervi 93, 20090 Segrate - Milano.
Nutritional Epidemiology Research Group, Sorbonne-Paris-Cité, UMR University of Paris 13/Inserm U-557/INRA U-1125/CNAM, Bobigny, France F-93017, Bobigny, FRANCE.
Assistance Publique-Hôpitaux De Paris, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.
Department of Cardiovascular Medicine, Cleveland Clinic Heart and Vascular Institute, Cleveland, OH 44195, USA.
Assistance Publique-Hôpitaux De Paris, Department of Hypertension, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.
INSERM, Clinical Investigation Center CIC1418, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.
Assistance Publique-Hôpitaux De Paris, Department of Pharmacology, Hôpital Européen Georges Pompidou, Paris, F-75015, FRANCE.


Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

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