RGD Reference Report - PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. - Rat Genome Database

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

Authors: Kiando, Soto Romuald  Tucker, Nathan R  Castro-Vega, Luis-Jaime  Katz, Alexander  D'Escamard, Valentina  Tréard, Cyrielle  Fraher, Daniel  Albuisson, Juliette  Kadian-Dodov, Daniella  Ye, Zi  Austin, Erin  Yang, Min-Lee  Hunker, Kristina  Barlassina, Cristina  Cusi, Daniele  Galan, Pilar  Empana, Jean-Philippe  Jouven, Xavier  Gimenez-Roqueplo, Anne-Paule  Bruneval, Patrick  Hyun Kim, Esther Soo  Olin, Jeffrey W  Gornik, Heather L  Azizi, Michel  Plouin, Pierre-François  Ellinor, Patrick T  Kullo, Iftikhar J  Milan, David J  Ganesh, Santhi K  Boutouyrie, Pierre  Kovacic, Jason C  Jeunemaitre, Xavier  Bouatia-Naji, Nabila 
Citation: Kiando SR, etal., PLoS Genet. 2016 Oct 28;12(10):e1006367. doi: 10.1371/journal.pgen.1006367. eCollection 2016 Oct.
RGD ID: 401900294
Pubmed: PMID:27792790   (View Abstract at PubMed)
PMCID: PMC5085032   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1006367   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PHACTR1HumanFibromuscular Dysplasia susceptibilityIAGP DNA:SNPs:intron: (rs1332844 more ...RGD 
Phactr1RatFibromuscular Dysplasia susceptibilityISOPHACTR1 (Homo sapiens)DNA:SNPs:intron: (rs1332844 more ...RGD 
Phactr1MouseFibromuscular Dysplasia susceptibilityISOPHACTR1 (Homo sapiens)DNA:SNPs:intron: (rs1332844 more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PHACTR1HumanArterial fibromuscular dysplasia susceptibilityIAGP DNA:SNPs:intron: (rs1332844 more ...RGD 
PHACTR1HumanIncreased carotid artery intimal medial thickness  IAGP DNA:SNP:intron: (rs9349379)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Phactr1  (phosphatase and actin regulator 1)

Genes (Mus musculus)
Phactr1  (phosphatase and actin regulator 1)

Genes (Homo sapiens)
PHACTR1  (phosphatase and actin regulator 1)


Additional Information