TY - JOUR
T1 - Identification d'un premier gène de prédisposition à dysplasie fibro-musculaire
AU - Kiando, S.
AU - Tucker, N.
AU - Katz, A.
AU - Tréard, C.
AU - Desca-Mard, V.
AU - Castro-Vega, L.
AU - Barlasina, C.
AU - Cusi, D.
AU - Galan, P.
AU - Empana, J.
AU - Olin, J.
AU - Gornik, H.
AU - Plouin, P.
AU - Kullo, I.
AU - Milan, D.
AU - Ganesh, S.
AU - Boutouyrie, P.
AU - Kovacic, J.
AU - Jeunemaitre, X.
AU - Bouatia-Naji, N.
N1 - Publisher Copyright:
© 2015 Elsevier Masson SAS
PY - 2015/12
Y1 - 2015/12
N2 - Background Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. Methods We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array. Results We followed up 13 loci (p<10−4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, (p = 7.4×10−10, n all cases = 1154, n all controls = 3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (p=0.0009), increased intima media thickness (p=0.001) and wall cross-sectional area (p=0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients (n=20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients (p=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (p=0.003) indicating impaired development of vasculature. Conclusions Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
AB - Background Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. Methods We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array. Results We followed up 13 loci (p<10−4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, (p = 7.4×10−10, n all cases = 1154, n all controls = 3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (p=0.0009), increased intima media thickness (p=0.001) and wall cross-sectional area (p=0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients (n=20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients (p=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (p=0.003) indicating impaired development of vasculature. Conclusions Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
UR - http://www.scopus.com/inward/record.url?scp=84990238084&partnerID=8YFLogxK
U2 - 10.1016/S0003-3928(16)30043-9
DO - 10.1016/S0003-3928(16)30043-9
M3 - Article
AN - SCOPUS:84990238084
SN - 0003-3928
VL - 64
SP - S20
JO - Annales de Cardiologie et d'Angeiologie
JF - Annales de Cardiologie et d'Angeiologie
ER -
