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PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance
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 pathophysiolog...
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| Published in: | PLoS genetics 2016-10, Vol.12 (10), p.e1006367-e1006367 |
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| creator | 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 |
| description | 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 |
| doi_str_mv | 10.1371/journal.pgen.1006367 |
| format | article |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1006367</identifier><identifier>PMID: 27792790</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Arteries - metabolism ; Arteries - pathology ; Biology and Life Sciences ; Carotid Arteries - metabolism ; Carotid Arteries - pathology ; Carotid Intima-Media Thickness ; Colleges & universities ; Danio rerio ; Disease Models, Animal ; Disease susceptibility ; Dysplasia ; Epigenetic inheritance ; Exome - genetics ; Experiments ; Female ; Fibromuscular Dysplasia - genetics ; Fibromuscular Dysplasia - pathology ; Gene Expression Regulation ; Genetic aspects ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetics ; Genotype ; Health aspects ; Hospitals ; Human genetics ; Humans ; Hypertension ; Hypertension - genetics ; Hypertension - pathology ; Internal medicine ; Life Sciences ; Male ; Medicine ; Medicine and Health Sciences ; Microfilament Proteins - biosynthesis ; Microfilament Proteins - genetics ; Myocytes, Smooth Muscle ; Nephrology ; Population genetics ; Stroke - genetics ; Stroke - pathology ; Zebrafish - genetics</subject><ispartof>PLoS genetics, 2016-10, Vol.12 (10), p.e1006367-e1006367</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genet 12(10): e1006367. doi:10.1371/journal.pgen.1006367</rights><rights>Attribution</rights><rights>2016 Kiando et al 2016 Kiando et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genet 12(10): e1006367. doi:10.1371/journal.pgen.1006367</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c859t-7188803b9a60dc2838e70b5e1593d82ea499344494000ae94ee40f4d3aa6aa9f3</citedby><cites>FETCH-LOGICAL-c859t-7188803b9a60dc2838e70b5e1593d82ea499344494000ae94ee40f4d3aa6aa9f3</cites><orcidid>0000-0003-4555-769X ; 0000-0001-7407-2697 ; 0000-0001-9492-5730 ; 0000-0001-5925-381X ; 0000-0002-5849-4010 ; 0000-0002-8947-6499 ; 0000-0002-4816-670X ; 0000-0002-6748-7728 ; 0000-0002-0815-0586 ; 0000-0002-2350-2914 ; 0000-0003-1706-3107 ; 0000-0002-1469-7772</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1840944066/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1840944066?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27792790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02379438$$DView record in HAL$$Hfree_for_read</backlink></links><search><contributor>McPherson, Ruth</contributor><creatorcontrib>Kiando, Soto Romuald</creatorcontrib><creatorcontrib>Tucker, Nathan R</creatorcontrib><creatorcontrib>Castro-Vega, Luis-Jaime</creatorcontrib><creatorcontrib>Katz, Alexander</creatorcontrib><creatorcontrib>D'Escamard, Valentina</creatorcontrib><creatorcontrib>Tréard, Cyrielle</creatorcontrib><creatorcontrib>Fraher, Daniel</creatorcontrib><creatorcontrib>Albuisson, Juliette</creatorcontrib><creatorcontrib>Kadian-Dodov, Daniella</creatorcontrib><creatorcontrib>Ye, Zi</creatorcontrib><creatorcontrib>Austin, Erin</creatorcontrib><creatorcontrib>Yang, Min-Lee</creatorcontrib><creatorcontrib>Hunker, Kristina</creatorcontrib><creatorcontrib>Barlassina, Cristina</creatorcontrib><creatorcontrib>Cusi, Daniele</creatorcontrib><creatorcontrib>Galan, Pilar</creatorcontrib><creatorcontrib>Empana, Jean-Philippe</creatorcontrib><creatorcontrib>Jouven, Xavier</creatorcontrib><creatorcontrib>Gimenez-Roqueplo, Anne-Paule</creatorcontrib><creatorcontrib>Bruneval, Patrick</creatorcontrib><creatorcontrib>Hyun Kim, Esther Soo</creatorcontrib><creatorcontrib>Olin, Jeffrey W</creatorcontrib><creatorcontrib>Gornik, Heather L</creatorcontrib><creatorcontrib>Azizi, Michel</creatorcontrib><creatorcontrib>Plouin, Pierre-François</creatorcontrib><creatorcontrib>Ellinor, Patrick T</creatorcontrib><creatorcontrib>Kullo, Iftikhar J</creatorcontrib><creatorcontrib>Milan, David J</creatorcontrib><creatorcontrib>Ganesh, Santhi K</creatorcontrib><creatorcontrib>Boutouyrie, Pierre</creatorcontrib><creatorcontrib>Kovacic, Jason C</creatorcontrib><creatorcontrib>Jeunemaitre, Xavier</creatorcontrib><creatorcontrib>Bouatia-Naji, Nabila</creatorcontrib><title>PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>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.</description><subject>Animals</subject><subject>Arteries - metabolism</subject><subject>Arteries - pathology</subject><subject>Biology and Life Sciences</subject><subject>Carotid Arteries - metabolism</subject><subject>Carotid Arteries - pathology</subject><subject>Carotid Intima-Media Thickness</subject><subject>Colleges & universities</subject><subject>Danio rerio</subject><subject>Disease Models, Animal</subject><subject>Disease susceptibility</subject><subject>Dysplasia</subject><subject>Epigenetic inheritance</subject><subject>Exome - genetics</subject><subject>Experiments</subject><subject>Female</subject><subject>Fibromuscular Dysplasia - genetics</subject><subject>Fibromuscular Dysplasia - pathology</subject><subject>Gene Expression Regulation</subject><subject>Genetic aspects</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Health aspects</subject><subject>Hospitals</subject><subject>Human genetics</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension - genetics</subject><subject>Hypertension - pathology</subject><subject>Internal medicine</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Microfilament Proteins - biosynthesis</subject><subject>Microfilament Proteins - genetics</subject><subject>Myocytes, Smooth Muscle</subject><subject>Nephrology</subject><subject>Population genetics</subject><subject>Stroke - genetics</subject><subject>Stroke - pathology</subject><subject>Zebrafish - 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W</creatorcontrib><creatorcontrib>Gornik, Heather L</creatorcontrib><creatorcontrib>Azizi, Michel</creatorcontrib><creatorcontrib>Plouin, Pierre-François</creatorcontrib><creatorcontrib>Ellinor, Patrick T</creatorcontrib><creatorcontrib>Kullo, Iftikhar J</creatorcontrib><creatorcontrib>Milan, David J</creatorcontrib><creatorcontrib>Ganesh, Santhi K</creatorcontrib><creatorcontrib>Boutouyrie, Pierre</creatorcontrib><creatorcontrib>Kovacic, Jason C</creatorcontrib><creatorcontrib>Jeunemaitre, Xavier</creatorcontrib><creatorcontrib>Bouatia-Naji, Nabila</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale in Context : Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale in Context: Science</collection><collection>ProQuest Central 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UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Biological Science Journals</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kiando, Soto Romuald</au><au>Tucker, Nathan R</au><au>Castro-Vega, Luis-Jaime</au><au>Katz, Alexander</au><au>D'Escamard, Valentina</au><au>Tréard, Cyrielle</au><au>Fraher, Daniel</au><au>Albuisson, Juliette</au><au>Kadian-Dodov, Daniella</au><au>Ye, Zi</au><au>Austin, Erin</au><au>Yang, Min-Lee</au><au>Hunker, Kristina</au><au>Barlassina, Cristina</au><au>Cusi, Daniele</au><au>Galan, Pilar</au><au>Empana, Jean-Philippe</au><au>Jouven, Xavier</au><au>Gimenez-Roqueplo, Anne-Paule</au><au>Bruneval, Patrick</au><au>Hyun Kim, Esther Soo</au><au>Olin, Jeffrey W</au><au>Gornik, Heather L</au><au>Azizi, Michel</au><au>Plouin, Pierre-François</au><au>Ellinor, Patrick T</au><au>Kullo, Iftikhar J</au><au>Milan, David J</au><au>Ganesh, Santhi K</au><au>Boutouyrie, Pierre</au><au>Kovacic, Jason C</au><au>Jeunemaitre, Xavier</au><au>Bouatia-Naji, Nabila</au><au>McPherson, Ruth</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2016-10-28</date><risdate>2016</risdate><volume>12</volume><issue>10</issue><spage>e1006367</spage><epage>e1006367</epage><pages>e1006367-e1006367</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27792790</pmid><doi>10.1371/journal.pgen.1006367</doi><orcidid>https://orcid.org/0000-0003-4555-769X</orcidid><orcidid>https://orcid.org/0000-0001-7407-2697</orcidid><orcidid>https://orcid.org/0000-0001-9492-5730</orcidid><orcidid>https://orcid.org/0000-0001-5925-381X</orcidid><orcidid>https://orcid.org/0000-0002-5849-4010</orcidid><orcidid>https://orcid.org/0000-0002-8947-6499</orcidid><orcidid>https://orcid.org/0000-0002-4816-670X</orcidid><orcidid>https://orcid.org/0000-0002-6748-7728</orcidid><orcidid>https://orcid.org/0000-0002-0815-0586</orcidid><orcidid>https://orcid.org/0000-0002-2350-2914</orcidid><orcidid>https://orcid.org/0000-0003-1706-3107</orcidid><orcidid>https://orcid.org/0000-0002-1469-7772</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2016-10, Vol.12 (10), p.e1006367-e1006367 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_1840944066 |
| source | PubMed (Medline); Publicly Available Content Database |
| subjects | Animals Arteries - metabolism Arteries - pathology Biology and Life Sciences Carotid Arteries - metabolism Carotid Arteries - pathology Carotid Intima-Media Thickness Colleges & universities Danio rerio Disease Models, Animal Disease susceptibility Dysplasia Epigenetic inheritance Exome - genetics Experiments Female Fibromuscular Dysplasia - genetics Fibromuscular Dysplasia - pathology Gene Expression Regulation Genetic aspects Genetic Association Studies Genetic Predisposition to Disease Genetics Genotype Health aspects Hospitals Human genetics Humans Hypertension Hypertension - genetics Hypertension - pathology Internal medicine Life Sciences Male Medicine Medicine and Health Sciences Microfilament Proteins - biosynthesis Microfilament Proteins - genetics Myocytes, Smooth Muscle Nephrology Population genetics Stroke - genetics Stroke - pathology Zebrafish - genetics |
| title | PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance |
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