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1. Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author

Adrien Georges, Min-Lee Yang, Takiy-Eddine Berrandou, Mark K. Bakker, Ozan Dikilitas, Soto Romuald Kiando, Lijiang Ma, Benjamin A. Satterfield, Sebanti Sengupta, Mengyao Yu, Jean-François Deleuze, Delia Dupré, Kristina L. Hunker, Sergiy Kyryachenko, Lu Liu, Ines Sayoud-Sadeg, Laurence Amar, Chad M. Brummett, Dawn M. Coleman, Valentina d’Escamard, Peter de Leeuw, Natalia Fendrikova-Mahlay, Daniella Kadian-Dodov, Jun Z. Li, Aurélien Lorthioir, Marco Pappaccogli, Aleksander Prejbisz, Witold Smigielski, James C. Stanley, Matthew Zawistowski, Xiang Zhou, Sebastian Zöllner, FEIRI investigators, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, MEGASTROKE, Philippe Amouyel, Marc L. De Buyzere, Stéphanie Debette, Piotr Dobrowolski, Wojciech Drygas, Heather L. Gornik, Jeffrey W. Olin, Jerzy Piwonski, Ernst R. Rietzschel, Ynte M. Ruigrok, Miikka Vikkula, Ewa Warchol Celinska, Andrzej Januszewicz, Iftikhar J. Kullo, Michel Azizi, Xavier Jeunemaitre, Alexandre Persu, Jason C. Kovacic, Santhi K. Ganesh, and Nabila Bouatia-Naji

Subjects
Science
Abstract

Fibromuscular dysplasia is a cardiovascular disease affecting mostly women with a mostly unknown genetic basis. Here the authors have performed a genome-wide association meta-analysis of Fibromuscular dysplasia to identify genetic loci, some of which are shared with common cardiovascular disease and traits.

Published
2021
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2. Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author

Adrien Georges, Min-Lee Yang, Takiy-Eddine Berrandou, Mark K. Bakker, Ozan Dikilitas, Soto Romuald Kiando, Lijiang Ma, Benjamin A. Satterfield, Sebanti Sengupta, Mengyao Yu, Jean-François Deleuze, Delia Dupré, Kristina L. Hunker, Sergiy Kyryachenko, Lu Liu, Ines Sayoud-Sadeg, Laurence Amar, Chad M. Brummett, Dawn M. Coleman, Valentina d’Escamard, Peter de Leeuw, Natalia Fendrikova-Mahlay, Daniella Kadian-Dodov, Jun Z. Li, Aurélien Lorthioir, Marco Pappaccogli, Aleksander Prejbisz, Witold Smigielski, James C. Stanley, Matthew Zawistowski, Xiang Zhou, Sebastian Zöllner, FEIRI investigators, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, MEGASTROKE, Philippe Amouyel, Marc L. De Buyzere, Stéphanie Debette, Piotr Dobrowolski, Wojciech Drygas, Heather L. Gornik, Jeffrey W. Olin, Jerzy Piwonski, Ernst R. Rietzschel, Ynte M. Ruigrok, Miikka Vikkula, Ewa Warchol Celinska, Andrzej Januszewicz, Iftikhar J. Kullo, Michel Azizi, ARCADIA Investigators, Xavier Jeunemaitre, Alexandre Persu, Jason C. Kovacic, Santhi K. Ganesh, and Nabila Bouatia-Naji

Subjects
Science
Published
2022
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3. Investigation of the Matrix Metalloproteinase-2 Gene in Patients with Non-Syndromic Mitral Valve Prolapse

Author

Maëlle Perrocheau, Soto Romuald Kiando, Déwi Vernerey, Christian Dina, Pilar Galan, Albert Hagege, Xavier Jeunemaitre, and Nabila Bouatia-Naji

Subjects
MMP2, mitral valve prolapse, Single Nucelotide Polymorphism, genetic association, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate etiological mechanism is a perturbation of the extracellular matrix (ECM) remodeling of the valve. To test this hypothesis, we assessed the role of genetic variants in the matrix metalloproteinase 2 gene (MMP2) known to regulate the ECM turnover by direct degradation of proteins and for which transgenic mice develop MVP. Direct sequencing of exons of MMP2 in 47 unrelated patients and segregation analyses in families did not reveal any causative mutation. We studied eight common single nucleotide polymorphisms (TagSNPs), which summarize the genetic information at the MMP2 locus. The association study in two case controls sets (NCases = 1073 and NControls = 1635) provided suggestive evidence for the association of rs1556888 located downstream MMP2 with the risk of MVP, especially in patients with the fibroelastic defiency form. Our study does not support the contribution of MMP2 rare variation in the etiology to MVP in humans, though further genetic and molecular investigation is required to confirm our current suggestive association of one common variant.

Published
2015
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4. PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

Author

Soto Romuald Kiando, Nathan R Tucker, Luis-Jaime Castro-Vega, Alexander Katz, Valentina D'Escamard, Cyrielle Tréard, Daniel Fraher, Juliette Albuisson, Daniella Kadian-Dodov, Zi Ye, Erin Austin, Min-Lee Yang, Kristina Hunker, Cristina Barlassina, Daniele Cusi, Pilar Galan, Jean-Philippe Empana, Xavier Jouven, Anne-Paule Gimenez-Roqueplo, Patrick Bruneval, Esther Soo Hyun Kim, Jeffrey W Olin, Heather L Gornik, Michel Azizi, Pierre-François Plouin, Patrick T Ellinor, Iftikhar J Kullo, David J Milan, Santhi K Ganesh, Pierre Boutouyrie, Jason C Kovacic, Xavier Jeunemaitre, and Nabila Bouatia-Naji

Subjects
Genetics, QH426-470
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

Published
2016
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5. Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

Author

Ozan Dikilitas, Marco Pappaccogli, Peter W. de Leeuw, Witold Smigielski, Valentina d'Escamard, Lijiang Ma, Ernst Rietzschel, Kristina L. Hunker, Lu Liu, Michel Azizi, Matthew Zawistowski, Jeffrey W. Olin, Ynte M. Ruigrok, Min-Lee Yang, Stéphanie Debette, Laurence Amar, Xiang Zhou, Sergiy Kyryachenko, Jun Li, Benjamin A. Satterfield, James C. Stanley, Feiri investigators, Miikka Vikkula, Ewa Warchol Celinska, Mengyao Yu, Dawn M. Coleman, Marc De Buyzere, Nabila Bouatia-Naji, Iftikhar J. Kullo, Megastroke, Aleksander Prejbisz, Andrzej Januszewicz, Piotr Dobrowolski, Wojciech Drygas, Takiy-Eddine Berrandou, Jerzy Piwonski, Sebanti Sengupta, Jason C. Kovacic, Mark K Bakker, Santhi K. Ganesh, Xavier Jeunemaitre, Chad M. Brummett, Jean-François Deleuze, Heather L. Gornik, Sebastian Zoellner, Soto Romuald Kiando, Alexandre Persu, Adrien Georges, Aurélien Lorthioir, Natalia Fendrikova-Mahlay, Daniella Kadian-Dodov, and Délia Dupré

Subjects
Pathology, medicine.medical_specialty, Linkage disequilibrium, Vascular smooth muscle, business.industry, Locus (genetics), Fibromuscular dysplasia, Actin cytoskeleton, medicine.disease, Coronary artery disease, Blood pressure, medicine, business, Genetic association
Abstract

Fibromuscular dysplasia (FMD) is an arteriopathy that presents clinically by hypertension and stroke, mostly in early middle-aged women. We report results from the first genome-wide association meta-analysis of FMD including 1962 FMD cases and 7100 controls. We confirmedPHACTR1and identified three new loci (LRP1, ATP2B1, andLIMA1)associated with FMD. Transcriptome-wide association analysis in arteries identified one additional locus (SLC24A3). FMD associated variants were located in arterial-specific enhancers active in vascular smooth muscle cells and fibroblasts. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. Cross-trait linkage disequilibrium analyses identified positive genetic correlations with blood pressure, migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independent from the genetics of blood pressure.

Published
2020

6. The relationship between MTHFR C677T gene polymorphism and essential hypertension in a sample of an Algerian population of Oran city

Author

Soto Romuald Kiando, Xavier Jeunemaitre, Nabila Bouatia-Naji, Cyrielle Treard, and Asma Amrani-Midoun

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Hypertension in Pregnancy, Population, 030204 cardiovascular system & hematology, Essential hypertension, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, Genotype, Humans, Medicine, education, Methylenetetrahydrofolate Reductase (NADPH2), education.field_of_study, Polymorphism, Genetic, biology, business.industry, Middle Aged, medicine.disease, Surgery, 030104 developmental biology, Algeria, Case-Control Studies, Population Surveillance, Methylenetetrahydrofolate reductase, Hypertension, biology.protein, Female, Gene polymorphism, Restriction fragment length polymorphism, Cardiology and Cardiovascular Medicine, business
Abstract

Background Many studies have investigated the role of 5,10-methylenetetrahydrofolate reductase ( MTHFR ) C677T gene polymorphism in essential hypertension (EH), but with conflicting results. Aim To determine the eventual association between 5,10-methylenetetrahydrofolate reductase ( MTHFR ) C677T gene polymorphism and hypertension in a sample of Algerian population from the Oran city. Methods A case–control study has been performed in 154 subjects including 82 hypertensives defined as subjects with elevated systolic blood pressure SBD≥140mmHg and or sustained diastolic blood pressure DBP≥90mmHg, and 72 normotensive subjects. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to detect the MTHFR C677T variant. Results We observe no significant differences between allelic and genotypic frequencies between cases and controls for C677T polymorphism (OR=1.51, 95% CI=0.89–2.56, P =0.13). Analyses adjusted for age, sex and body mass index improved the association level, though the association was still not significant (30% vs. 22%, OR=1.75, 95% CI=0.95–3.24, P =0.07). Conclusion This work showed that genetic polymorphism related to the MTHFR gene (C677T) is not associated with the risk of hypertension in this sample of Algerian population. Larger case–control samples are required to clearly assess the role of this genetic variant in EH.

Published
2016

7. Genetic association study between T-786C NOS3 polymorphism and essential hypertension in an Algerian population of the Oran city

Author

Soto Romuald Kiando, Cyrielle Treard, Asma Amrani-Midoun, Nabila Bouatia-Naji, and Xavier Jeunemaitre

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Candidate gene, Genotype, Nitric Oxide Synthase Type III, Endocrinology, Diabetes and Metabolism, Population, 030204 cardiovascular system & hematology, Essential hypertension, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Internal Medicine, Medicine, Humans, cardiovascular diseases, education, Genetic association, education.field_of_study, business.industry, Case-control study, General Medicine, Middle Aged, medicine.disease, Prognosis, 030104 developmental biology, Blood pressure, Algeria, Case-Control Studies, Female, Essential Hypertension, business, Body mass index, Biomarkers, Follow-Up Studies
Abstract

Background Essential hypertension is an important risk factor for the development of cardiovascular disease. Important candidate genes such as NOS3 gene have been widely studied and reported to be associated with essential hypertension (HTN) in human populations. Aim We aim in this study to analyze the relationship between NOS3 -786T/C, a common genetic variant and HTN in a sample of the Algerian population of the Oran city. Methods A case-control study has been performed in 154 subjects including 77 hypertensives and 77 normotensives. The recruitment of these subjects was done in local Health Centers of the city of Oran, West Algeria. HTN was defined as elevated systolic blood pressure SBD ≥ 140 mmHg and or sustained diastolic blood pressure DBP≥90 mmHg, measured using an Omron® Automatic BP Monitor - M-3W machine. Consents were obtained from all participants. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to genotype the NOS -786T/C variant. Results The distribution of the allelic frequencies did not differ between cases and controls (OR = 1.48; 95%CI [0.94–2.32], P = 0.09). However, after adjustment with the age, sex, and body mass index, we observed significant association between NOS -786C allele and HTN status (OR = 2.08; 95%CI [1.18–3.66], P = 0.01). Conclusion Our results indicate that the C allele of the NOS3 gene is associated with increased risk of essential hypertension in this sample of the Algerian population of the Oran city. Further validation in larger samples is needed to confirm this finding.

Published
2019

8. Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences

Author

Jean-Philippe Haymann, Delphine Vezzosi, Elisabeth Requeda, Agnès Linglart, Guy Lefort, Jean-Claude Souberbielle, Emmanuelle Dubosclard, Bernadette Lucas-Pouliquen, Jean-Marc Kuhn, Françoise Broux, Pascal Houillier, Lamisse Mansour-Hendili, Michel Polak, Sophie Ouzounian, Stéphanie Baron, Xavier Jeunemaitre, Christophe Simian, Sonia Beltran, Caroline Travers, Gérard Maruani, Xavier Debussche, Caroline Silve, Jean-Philippe Bertocchio, Catherine Cormier, Cyrielle Treard, Odile Camard, Celine Eid, Dominique Robier, Marie-Alice Macher, Sylvie Cloarec, Ivan Tack, Véronique Baudouin, Rosa Vargas-Poussou, and Soto Romuald Kiando

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adaptor Protein Complex sigma Subunits, Genotype, endocrine system diseases, Endocrinology, Diabetes and Metabolism, DNA Mutational Analysis, Clinical Biochemistry, Adaptor Protein Complex 2, Parathyroid hormone, 030209 endocrinology & metabolism, Context (language use), Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Humans, Hyperparathyroidism, Familial hypocalciuric hypercalcemia, Genetic heterogeneity, business.industry, Biochemistry (medical), Middle Aged, Hyperparathyroidism, Primary, medicine.disease, GTP-Binding Protein alpha Subunits, Urinary calcium, Cross-Sectional Studies, Phenotype, 030104 developmental biology, Parathyroid Hormone, Mutation, Calcium ion homeostasis, Hypercalcemia, Calcium, Female, business, Receptors, Calcium-Sensing, Primary hyperparathyroidism
Abstract

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively.This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT.This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults.There were no interventions.Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured.In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped.In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.

Published
2016

9. The MITF, p.E318K variant, as a risk factor for Pheochromocytoma and Paraganglioma

Author

Nelly Burnichon, Laurence Amar, Pilar Galan, Nabila Bouatia-Naji, Christophe Simian, Luis Jaime Castro-Vega, Soto Romuald Kiando, Martin Schlumberger, Amandine Berdelou, Brigitte Bressac-de Paillerets, Judith Favier, Alexandre Buffet, Anne-Paule Gimenez-Roqueplo, Faculté de Médecine, Université de Ngozi, Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Genetique, Hôpital Européen Georges Pompidou, Assistance Publique – Hôpitaux de Paris (AP-HP), Institut Gustave Roussy (IGR), Unité Hypertension Arterielle, Rare Adrenal Cancer Network COMETE, Service Génétique, Union Nationale des Coopératives Agricoles d'Elevage et d'Insémination Animale, Université Paris-Saclay, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Paris Sud (Paris 11), Immunologie intégrative des tumeurs (UMR 1186), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche [ANR-2011-JCJC-00701 MODEOMAPP], European Union Seventh Framework Programme (FP7) [259735], Institut National du Cancer et la Direction de l'Offre de Soins [INCa-DGOS_8663], Université Paris Descartes - Paris 5 ( UPD5 ), UMR 970 Paris - Centre de recherche cardiovasculaire, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou, Assistance Publique – Hôpitaux de Paris ( AP-HP ), Institut Gustave Roussy ( IGR ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Immunologie intégrative des tumeurs ( UMR 1186 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Union nationale des coopératives d’élevage et d’insémination animale (UNCEIA), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Population, Adrenal Gland Neoplasms, Context (language use), Pheochromocytoma, Biochemistry, Cohort Studies, Paraganglioma, 03 medical and health sciences, symbols.namesake, Endocrinology, Germline mutation, Risk Factors, Internal medicine, medicine, Humans, education, Germ-Line Mutation, Aged, Sanger sequencing, education.field_of_study, Microphthalmia-Associated Transcription Factor, integumentary system, [ SDV ] Life Sciences [q-bio], business.industry, Melanoma, Biochemistry (medical), Middle Aged, medicine.disease, Microphthalmia-associated transcription factor, 3. Good health, 030104 developmental biology, symbols, Female, France, business
Abstract

Context: The microphthalmia-associated transcription factor (MITF) regulates the survival, proliferation, and differentiation of neural crest-derived lineages. Recent studies reported an increased risk of melanomain individuals carrying the rare variant MITF, p.E318K (rs149617956). Whether this variant plays a role in other neural crest-derived tumors is unknown. Objective: In the present study, we aimed at determining the prevalence of the MITF, p.E318K variant, in a well-characterized French cohort of pheochromocytomas/paragangliomas (PCC/PGL). Design and Methods: Genomic DNA from 555 unrelated patients with PCC/PGL was genotyped for the p. E318K variant in MITF using Sanger sequencing. Main Outcome Measure: The prevalence of the mutation in the PCC/PGL cohort was compared with a population-based sample of 2348 ethnically matched controls. Results: We identified seven carriers (five patients with sporadic PCCs, two with PGLs). The prevalence of the MITF, p. E318K variant, was higher in the PCC/PGL cohort than in controls, and appears to be a significant risk factor (odds ratio, 3.19; 95% confidence interval, 1.34-7.59; P = .005). Noteworthy, two patients were homozygous for the p.E318K risk allele, a patient with metastatic PCC and an SDHB-mutated patient with PGL. Conclusion: Our results indicate that the germline variant MITF, p.E318K is associated with an increased risk of other neural crest-derived tumors such as PCC/PGL.

Published
2016

10. PHACTR1 Is a genetic susceptibility locus for fibromuscular dysplasia supporting its complex genetic pattern of inheritance

Author

Nabila Bouatia-Naji, Cyrielle Treard, David J. Milan, Esther Soo Hyun Kim, Patrick T. Ellinor, Iftikhar J. Kullo, Xavier Jeunemaitre, Min-Lee Yang, Daniel Fraher, Nathan R. Tucker, Pilar Galan, Pierre-François Plouin, Jason C. Kovacic, Heather L. Gornik, Erin Austin, Patrick Bruneval, Jeffrey W. Olin, Santhi K. Ganesh, Daniella Kadian-Dodov, Daniele Cusi, Alexander Katz, Xavier Jouven, Michel Azizi, Kristina L. Hunker, Valentina d'Escamard, Pierre Boutouyrie, Zi Ye, Juliette Albuisson, Jean Philippe Empana, Luis Jaime Castro-Vega, Cristina Barlassina, Soto Romuald Kiando, Anne Paule Gimenez-Roqueplo, Bouatia-Naji, Nabila, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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], 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], European Project: 201550,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HYPERGENES(2008), and European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model - HYPERGENES - - EC:FP7:HEALTH2008-01-01 - 2011-12-31 - 201550 - VALID

Subjects
Male, 0301 basic medicine, Cancer Research, Pathology, Fibromuscular dysplasia, 030204 cardiovascular system & hematology, Vascular Medicine, Carotid Intima-Media Thickness, Muscle hypertrophy, Coronary artery disease, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Fibromuscular Dysplasia, Exome, Zebrafish, Genetics (clinical), Connective Tissue Cells, Microfilament Proteins, Arteries, 3. Good health, Stroke, Carotid Arteries, medicine.anatomical_structure, facteur de risque, maladie vasculaire, Connective Tissue, Hypertension, cardiovascular system, Female, Anatomy, Cellular Types, Research Article, medicine.medical_specialty, Genotype, lcsh:QH426-470, Endothelium, Myocytes, Smooth Muscle, Single-nucleotide polymorphism, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Genetic Predisposition, 03 medical and health sciences, Renal Arteries, Genetics, medicine, Genetic predisposition, méta analyse, Animals, Humans, Genetic Predisposition to Disease, Vascular Diseases, cardiovascular diseases, Molecular Biology, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, locus, prévalence, Vascular disease, Biology and Life Sciences, Human Genetics, Cell Biology, Fibroblasts, medicine.disease, Disease Models, Animal, lcsh:Genetics, Biological Tissue, 030104 developmental biology, Gene Expression Regulation, Intima-media thickness, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Genetics of Disease, Immunology, Cardiovascular Anatomy, Blood Vessels, cellule endotheliale
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, Author Summary 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. FMD is an atypical vascular disease because it is not associated with overweight or dyslipidemia and 80% of patients are early middle aged women. 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. This is the first time a genetic risk factor is reported for FMD because it has been longtime considered rare and potentially under a Mendelian mode of inheritance. We also show that rs9349379 correlates with the expression of PHACTR1 in fibroblasts from FMD patients and controls. Interestingly, the same allele that increases the risk of FMD is at risk for cervical artery dissection and migraine, often reported in FMD patients but protective from myocardial infarction and coronary disease, where atherosclerosis is more common. The clear role of PHACTR1 in maintaining vascular well integrity is not fully elucidated. Using a specific antibody we detected PHACTR1 both on endothelial and smooth muscle cells of human FMD and control carotids, which suggests that PHACTR1 may have multiple functions depending on the cell type and the degree of atherosclerosis of the arteries.

Published
2016

11. Abstract 15370: Genetic Study Identifies Common Variation in PHACTR1 to Associate With Fibromuscular Dysplasia (Best of Basic Science Abstract)

Author

Soto Romuald Kiando, Nathan Tucker, Alexander Katz, Cyrielle Tréard, Valentina D’Escamard, Luis J Castro-Vega, Zi Ye, Carin Y Smith, Erin Austin, Cristina Barlasina, Daniele Cusi, Pilar Galan, Jean-Philippe Empana, Xavier Jouven, Patrick Brunval, Jeffrey W Olin, Heather Gornik, Pierre-François Plouin, Iftikhar J Kullo, David J Milan, Santhi K Ganesh, Pierre Boutouyrie, Jason Kovacic, Xavier Jeunemaitre, and Nabila Bouatia-Naji

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid arteries. 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. We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed ∼26K common variants (MAF>0.05) using an exome-chip array. We followed up 13 loci (P 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. The correlation of genotypes with the expression of PHACTR1 in primary cultured human fibroblasts showed higher expression in FMD risk allele carriers, compared to non carriers (N=57, P=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (P=0.003) indicating impaired vascular development. In conclusion, 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.

Published
2015

12. Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

Author

Pilar Galan, Pierre-François Plouin, Xavier Jeunemaitre, Soto Romuald Kiando, Nabila Bouatia-Naji, Daniele Cusi, Mark Lathrop, Cristina Barlassina, Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité, Università degli Studi di Milano [Milano] (UNIMI), Consiglio Nazionale delle Ricerche (CNR), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Département Hypertension, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Univ Paris 05, PRES Sorbonne Paris Cite, Paris, France, Partenaires INRAE, INSERM, Paris Cardiovasc Res Ctr PARCC UMR970, F-75015 Paris, France, Italian joint agency grant (INTEROMICS PB05-MIUR-CNR Italian Flagship Project), French National research agency [ANR GDPM2, ANR-13-ISV1-0006-0], National French clinical grant (PHRC ARCADIA-PROFILE), Fondation pour la recherche Medicale support (FRM MEDYA), European Project: 201550,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HYPERGENES(2008), Università degli Studi di Milano = University of Milan (UNIMI), and National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR)

Subjects
Cytoplasmic Dyneins, Pathology, medicine.medical_specialty, Genotype, Physiology, [SDV]Life Sciences [q-bio], Ubiquitin-Protein Ligases, Fibromuscular dysplasia, Protein Serine-Threonine Kinases, whole exome sequencing, Genetic Heterogeneity, Internal Medicine, Medicine, Fibromuscular Dysplasia, Humans, Exome, cardiovascular diseases, Stroke, Myosin-Light-Chain Kinase, Exome sequencing, Genetic Association Studies, Genetic association, Aged, Adenosine Triphosphatases, Renal ischemia, business.industry, Genetic heterogeneity, Vascular disease, Calcium-Binding Proteins, Sequence Analysis, DNA, Middle Aged, medicine.disease, 3. Good health, Stenosis, Case-Control Studies, cardiovascular system, Female, gene-based association test, Cardiology and Cardiovascular Medicine, business, Rho Guanine Nucleotide Exchange Factors
Abstract

International audience; Background: Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in women with nearly four out of 1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. Method: We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3971 genes were prioritized on frequency (minor allele frequency

Published
2015

13. Investigation of the Matrix Metalloproteinase-2 Gene in Patients with Non-Syndromic Mitral Valve Prolapse

Author

Albert Hagège, Soto Romuald Kiando, Christian Dina, Xavier Jeunemaitre, Dewi Vernerey, Maelle Perrocheau, Nabila Bouatia-Naji, Pilar Galan, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Marfan syndrome, Pathology, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, genetic association, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Locus (genetics), 030204 cardiovascular system & hematology, Biology, Sudden death, Single Nucelotide Polymorphism, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Mitral valve prolapse, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, Gene, 030304 developmental biology, Genetic association, 0303 health sciences, medicine.disease, MMP2, 3. Good health, lcsh:RC666-701, Etiology, mitral valve prolapse
Abstract

International audience; Non-syndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy, predisposing to arrhythmia and sudden death. The etiology of MVP is suspected to be under genetic control, as supported by familial cases and its manifestation in genetic syndrome (e.g., Marfan syndrome). One candidate etiological mechanism is a perturbation of the extracellular matrix (ECM) remodeling of the valve. To test this hypothesis, we assessed the role of genetic variants in the matrix metalloproteinase 2 gene (MMP2) known to regulate the ECM turnover by direct degradation of proteins and for which transgenic mice develop MVP. Direct sequencing of exons of MMP2 in 47 unrelated patients and segregation analyses in families did not reveal any causative mutation. We studied eight common single nucleotide polymorphisms (TagSNPs), which summarize the genetic information at the MMP2 locus. The association study in two case controls sets (NCases = 1073 and NControls = 1635) provided suggestive evidence for the association of rs1556888 located downstream MMP2 with the risk of MVP, especially in patients with the fibroelastic defiency form. Our study does not support the contribution of MMP2 rare variation in the etiology to MVP in humans, though further genetic and molecular investigation is required to confirm our current suggestive association of one common variant.

Published
2015

14. [OP.7C.04] GENETIC ASSOCIATION STUDY IDENTIFIES COMMON VARIATION IN PHACTR1 TO ASSOCIATE WITH FIBROMUSCULAR DYSPLASIA

Author

Jeffrey W. Olin, Pierre Boutouyrie, Luis Jaime Castro-Vega, Heather L. Gornik, Pilar Galan, P.-F. Plouin, Empana J.-P., David J. Milan, Soto Romuald Kiando, Iftikhar J. Kullo, Nabila Bouatia-Naji, Jason C. Kovacic, Santhi K. Ganesh, Nathan R. Tucker, Daniele Cusi, and Xavier Jeunemaitre

Subjects
Pathology, medicine.medical_specialty, Endothelium, Physiology, business.industry, Vascular disease, Fibromuscular dysplasia, medicine.disease, Pathophysiology, Coronary artery disease, medicine.anatomical_structure, Intima-media thickness, cardiovascular system, Internal Medicine, Medicine, cardiovascular diseases, Cardiology and Cardiovascular Medicine, business, Allele frequency, Genetic association
Abstract

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD has higher prevalence in females (80-90%) and predisposes to hypertension and stroke but its pathophysiology is unclear. We performed a multistage genetic association study (1,154 patients and 3,895 controls) from five case-control cohorts. We investigated the association between rs9349379 in the phosphatase and actin regulator 1 gene (PHACTR1) and carotid traits by echo-tracking in healthy volunteers, the expression of PHACTR1 by genotypes in human fibroblasts, protein staining pattern in human carotids, and vasculature development after Phactr1 knockdown in zebrafish. We show significant and replicated association of rs9349379, a common variant (effect allele frequency 0.60) in PHACTR1 with FMD (OR = 1.39, P = 7.4 × 10-10). rs9349379 associates with greater intima media thickness (P = 3.9 × 10-5) and wall to lumen ratio (P = 0.001), previously reported to be increased in FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal carotid arteries. We also found higher expression of PHACTR1 in FMD risk allele carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating impaired vascular development. We report the first susceptibility locus for FMD in the largest genetic association study conducted so far. Our data reveal a common genetic variant in PHACTR1, previously reported to associate with coronary artery disease, migraine, and cervical artery dissection supporting a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neuromuscular diseases.

Published
2016

15. CO-43: Genetic study identifies common variation in phactr1 to associate with fibromuscular dysplasia

Author

Jeffrey W. Olin, Luis Jaime Castro-Vega, Jean Philippe Empana, Pierre Boutouyrie, David J. Milan, Nabila Bouatia-Naji, Iftikhar J. Kullo, Cyrielle Treard, Pilar Galan, Pierre-François Plouin, Heather L. Gornik, C. Barlasina, Xavier Jeunemaitre, Daniele Cusi, Alexander Katz, V. Desca-Mard, Jason C. Kovacic, Santhi K. Ganesh, Nathan R. Tucker, and Soto Romuald Kiando

Subjects
education.field_of_study, medicine.medical_specialty, Pathology, business.industry, Vascular disease, Population, Locus (genetics), Fibromuscular dysplasia, medicine.disease, Gastroenterology, Pathophysiology, Coronary artery disease, Intima-media thickness, Internal medicine, cardiovascular system, medicine, Cardiology and Cardiovascular Medicine, education, business, Genetic association
Abstract

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 −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.

Published
2015

16. 0382 : Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

Author

Pierre-François Plouin, Soto Romuald Kiando, Nabila Bouatia-Naji, and Xavier Jenuemaitre

Subjects
Pathology, medicine.medical_specialty, business.industry, Vascular disease, Genetic heterogeneity, Family aggregation, Fibromuscular dysplasia, medicine.disease, Minor allele frequency, cardiovascular system, Medicine, cardiovascular diseases, Cardiology and Cardiovascular Medicine, business, Stroke, Exome sequencing, Genetic association
Abstract

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in females with ~4/1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3,971 genes were prioritized on frequency (minor allele frequency

Published
2015

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