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.
Highlights
Fibromuscular dysplasia (FMD) is a non-atherosclerotic and non-inflammatory vascular disease leading to stenosis, aneurysm, dissection, and/or occlusion of medium-sized arteries, in particular the renal and extracranial cerebrovascular arteries [1,2,3]
Fibromuscular Dysplasia (FMD) is a vascular disease characterized by a succession of occlusions and dilatation of medium-sized arteries (e.g renal, carotid or coronary arteries) with important health consequences, mainly resistant hypertension and stroke
Our genetic study conducted in >1100 patients and >3800 controls demonstrate that a common variant rs9349379 located on chromosome 6 in the phosphatase and actin regulator 1 gene (PHACTR1) increases by ~40% the risk of FMD
Summary
Fibromuscular dysplasia (FMD) is a non-atherosclerotic and non-inflammatory vascular disease leading to stenosis, aneurysm, dissection, and/or occlusion of medium-sized arteries, in particular the renal and extracranial cerebrovascular arteries [1,2,3]. The angiography-based classification of renal FMD distinguishes between patients with multifocal stenoses, including the "string-of-beads” FMD pattern, and unifocal (or focal) FMD with corresponding differences in sex ratio, median age of diagnosis and smoking status [6,7]. We have previously reported familiality of FMD in ~10% of patients [8]. The US FMD registry has described a family history in first or second-degree relatives for FMD (7%) and aneurysm (23%) [3]. The unknown status of most of family members compromised heritability estimates and made the assessment of the genetic mode of inheritance difficult. The complexity of the diagnosis based on computed tomography angiography (CTA) and/or magnetic resonance angiography (MRA) and a general lack of awareness among affected patients and clinicians result in an under-diagnosis bias
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