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

Soto Romuald Kiando, Nathan R. Tucker, Luis Jaime Castro-Vega, Alexander Katz, Valentina D’Escamard, Cyrielle Tréard, Daniel Fraher, Juliette Albuisson, Daniella Kadian-Dodov, Zi Ye, Erin Austin, Min Lee Yang, Kristina Hunker, Cristina Barlassina, Daniele Cusi, Pilar Galan, Jean Philippe Empana, Xavier Jouven, Anne Paule Gimenez-Roqueplo, Patrick BrunevalEsther Soo Hyun Kim, Jeffrey W. Olin, Heather L. Gornik, Michel Azizi, Pierre François Plouin, Patrick T. Ellinor, Iftikhar J. Kullo, David J. Milan, Santhi K. Ganesh, Pierre Boutouyrie, Jason C. Kovacic, Xavier Jeunemaitre, Nabila Bouatia-Naji

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere1006367
JournalPLoS genetics
Volume12
Issue number10
DOIs
StatePublished - Oct 2016

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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