期刊
PLOS GENETICS
卷 12, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006367
关键词
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资金
- GENET-FMD [ANR-13-JSV1-0002-01]
- ANR GDPM2 [2010-BLANC-1129-02]
- National French clinical grant (PHRC ARCADIA-PROFILE)
- Fondation pour la recherche Medicale (FRM MEDYA)
- Fondation pour la recherche Medicale [Equipe FRM 2015-2018 DEQ20150331716]
- European funding FP7 HYPERGENES [FP7-HEALTH-F4-2007-201550]
- National Institutes of Health [R01-HL127692, T32HL007824, 1RO1HL092577, R01HL128914, K24HL105780]
- Doris Duke Charitable Foundation [2013104]
- American Heart Association [13EIA14220013]
- Fondation Leducq [14CVD01]
- National Institutes of Health, National Center for Research Resources, CTSA, Cleveland, Ohio [1UL1RR024989]
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 (similar to 80%) but its pathophysiology is unclear. We analyzed similar to 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 = 7.4x10(-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 similar to 2,500 healthy volunteers indicate higher intima media thickness (P = 1.97x10(-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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