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1. Atteinte pulmonaire du déficit en alpha-1 antitrypsine. Recommandations pratiques pour le diagnostic et la prise en charge

Author

Mornex, J.-F., Balduyck, M., Bouchecareilh, M., Cuvelier, A., Epaud, R., Kerjouan, M., Le Rouzic, O., Pison, C., Plantier, L., Pujazon, M.-C., Reynaud-Gaubert, M., Toutain, A., Trumbic, B., Willemin, M.-C., Zysman, M., Brun, O., Campana, M., Chabot, F., Chamouard, V., Dechomet, M., Fauve, J., Girerd, B., Gnakamene, C., Lefrançois, S., Lombard, J.-N., Maitre, B., Maynié-François, C., Moerman, A., Payancé, A., Reix, P., Revel, D., Revel, M.-P., Schuers, M., Terrioux, P., Theron, D., Willersinn, F., Cottin, V., and Mal, H.

Published
2022
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4. First Genotype-Phenotype Study in TBX4 Syndrome Gain-of-Function Mutations Causative for Lung Disease

Author

Prapa, M., Lago-Docampo, M., Swietlik, E.M., Montani, D., Eyries, M., Humbert, M., Welch, C.C.L., Chung, W., Berger, R.M.F., Bogaard, H.J., Danhaive, O., Escribano-Subías, P., Gall, H., Girerd, B., Hernandez-Gonzalez, I., Holden, S., Hunt, D., Jansen, S.M.A., Kerstjens-Frederikse, W., Kiely, D., Lapunzina, P., McDermott, J., Moledina, S., Pepke-Zaba, J., Polwarth, G.J., Schotte, G., Tenorio-Castaño, J., Thompson, A.A.R., Wharton, J., Wort, S.J., Megy, K., Mapeta, R., Treacy, C.M., Martin, J.M., Li, W., Swift, A.J., Upton, P.D., Morrell, N.W., Gräf, S., Valverde, D., Cardiovascular Centre (CVC), Pulmonary medicine, and ACS - Pulmonary hypertension & thrombosis

Subjects
interstitial lung disease, Pulmonary and Respiratory Medicine, gain-of-function, pulmonary arterial hypertension, TBX4, Critical Care and Intensive Care Medicine, lung developmental disease
Abstract

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis.Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases.Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-functio effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P, 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups.Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

Published
2022
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5. Deciphering a New Phenotype of Pulmonary Arterial Hypertension in Patients Carrying SOX17 Variants

Author

Montani, D., primary, Lechartier, B., additional, Girerd, B., additional, Eyries, M., additional, Ghigna, M.-R., additional, Savale, L., additional, Jais, X., additional, Seferian, A., additional, Jevnikar, M., additional, Boucly, A., additional, Riou, M., additional, Traclet, J., additional, Chaouat, A., additional, Levy, M., additional, Le Pavec, J., additional, Fadel, E., additional, Perros, F., additional, Soubrier, F., additional, Remy-Jardin, M., additional, Sitbon, O., additional, Bonnet, D., additional, and Humbert, M.J.C., additional

Published
2022
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6. French clinical practice guidelines for the diagnosis and management of lung disease with alpha 1-antitrypsin deficiency

Author

Mornex, J.-F., Balduyck, M., Bouchecareilh, M., Cuvelier, A., Epaud, R., Kerjouan, M., Le Rouzic, O., Pison, C., Plantier, L., Pujazon, M.-C., Reynaud-Gaubert, M., Toutain, A., Trumbic, B., Willemin, M.-C., Zysman, M., Brun, O., Campana, M., Chabot, F., Chamouard, V., Dechomet, M., Fauve, J., Girerd, B., Gnakamene, C., Lefrançois, S., Lombard, J.-N., Maitre, B., Maynié-François, C., Moerman, A., Payancé, A., Reix, P., Revel, D., Revel, M.-P., Schuers, M., Terrioux, P., Theron, D., Willersinn, F., Cottin, V., Mal, H., Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Université de Lille, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur le Handicap Ventilatoire et Neurologique (GRHVN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Intercommunal de Créteil (CHIC), Hôpital Pontchaillou, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service de Pneumologie et Immuno-Allergologie [CHU LIlle], Pole Cardio-vasculaire et pulmonaire [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Grenoble Alpes (UGA), Service de pneumologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Nord [CHU - APHM], Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Aix Marseille Université (AMU), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de pneumologie et d'allergologie respiratoire [Perpignan], Centre Hospitalier Régional d'Orléans (CHRO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Référence de l’Hypertension Pulmonaire Sévère [CHU Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Centre Hospitalier Montélimar, CH Montélimar, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Hôpital Jeanne de Flandre [Lille], Centre de référence des Maladies Vasculaires du Foie [Paris] (FILFOIE), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Déficit en alpha 1-antitrypsine, Cirrhose du foie, Emphysème pulmonaire, Bronchopneumopathie chronique obstructive, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract

International audience; Contexte: Le déficit en alpha 1-antitrypsine (DAAT) est une maladie génétique autosomique récessive associée à l’état homozygote du variant Z du gène SERPINA1. Les manifestations cliniques sont un déficit sévère en alpha 1-antitrypsine, un emphysème pulmonaire et une fibrose hépatique.Méthodes: Des recommandations de prise en charge du DAAT ont été élaborées à l’initiative du centre coordonnateur de référence des maladies pulmonaires rares, sous l’égide de la Société de pneumologie de langue française, par des groupes de coordination, rédaction, et lecture, impliquant des pneumologues de divers modes d’exercice, biologistes, hépatologue, pharmacien hospitalier, conseiller en génétique, radiologues, médecins généralistes, cadre de santé, et associations de patients. La méthode d’élaboration des « Recommandations pour la pratique clinique » de la Haute autorité de santé a été suivie, incluant un vote en ligne selonune échelle Likert.Résultats: Après une analyse bibliographique, 20 recommandations ont été proposées par les groupes de travail, portant sur tous les aspects de la maladie : diagnostic biologique, bilan initial, conseils d’hygiène de vie, information, indications et modalités du traitement substitutif, dépistage.Conclusion: Ces recommandations fondées sur les preuves sont destinées à guider le diagnostic et la prise en charge pratique du DAAT.

Published
2022
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8. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Author

Kariotis, S, Jammeh, E, Swietlik, EM, Pickworth, JA, Rhodes, CJ, Otero, P, Wharton, J, Iremonger, J, Dunning, MJ, Pandya, D, Mascarenhas, TS, Errington, N, Thompson, AAR, Romanoski, CE, Rischard, F, Garcia, JGN, Yuan, JX-J, An, T-HS, Desai, AA, Coghlan, G, Lordan, J, Corris, PA, Howard, LS, Condliffe, R, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, S, Gräf, S, Morrell, NW, Wilkins, MR, Lawrie, A, Wang, D, Bleda, M, Hadinnapola, C, Haimel, M, Auckland, K, Tilly, T, Martin, JM, Yates, K, Treacy, CM, Day, M, Greenhalgh, A, Shipley, D, Peacock, AJ, Irvine, V, Kennedy, F, Moledina, S, MacDonald, L, Tamvaki, E, Barnes, A, Cookson, V, Chentouf, L, Ali, S, Othman, S, Ranganathan, L, Gibbs, JSR, DaCosta, R, Pinguel, J, Dormand, N, Parker, A, Stokes, D, Ghedia, D, Tan, Y, Ngcozana, T, Wanjiku, I, Polwarth, G, Mackenzie Ross, RV, Suntharalingam, J, Grover, M, Kirby, A, Grove, A, White, K, Seatter, A, Creaser-Myers, A, Walker, S, Roney, S, Elliot, CA, Charalampopoulos, A, Sabroe, I, Hameed, A, Armstrong, I, Hamilton, N, Rothman, AMK, Swift, AJ, Wild, JM, Soubrier, F, Eyries, M, Humbert, M, Montani, D, Girerd, B, Scelsi, L, Ghio, S, Gall, H, Ghofrani, A, Bogaard, HJ, Noordegraaf, AV, Houweling, AC, Veld, AHI, and Schotte, G

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.

Published
2021

10. Screening for Pulmonary Arterial Hypertension in Adults Carrying a BMPR2 Mutation

Author

Montani, D., primary, Girerd, B., additional, Jais, X., additional, Laveneziana, P., additional, Lau, E.M.T., additional, Bouchachi, A., additional, Hascoët, S., additional, Günther, S., additional, Godinas, L., additional, Parent, F., additional, Guignabert, C., additional, Beurnier, A., additional, Chemla, D., additional, Hervé, P., additional, Eyries, M., additional, Soubrier, F., additional, Simonneau, G., additional, Sitbon, O., additional, Savale, L., additional, and Humbert, M., additional

Published
2021
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11. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Author

Kariotis, S, Jammeh, E, Swietlik, EM, Pickworth, JA, Rhodes, CJ, Otero, P, Wharton, J, Iremonger, J, Dunning, MJ, Pandya, D, Mascarenhas, TS, Errington, N, Thompson, AAR, Romanoski, CE, Rischard, F, Garcia, JGN, Yuan, JX-J, An, T-HS, Desai, AA, Coghlan, G, Lordan, J, Corris, PA, Howard, LS, Condliffe, R, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, S, Graf, S, Morrell, NW, Wilkins, MR, Lawrie, A, Wang, D, Bleda, M, Hadinnapola, C, Haimel, M, Auckland, K, Tilly, T, Martin, JM, Yates, K, Treacy, CM, Day, M, Greenhalgh, A, Shipley, D, Peacock, AJ, Irvine, V, Kennedy, F, Moledina, S, MacDonald, L, Tamvaki, E, Barnes, A, Cookson, V, Chentouf, L, Ali, S, Othman, S, Ranganathan, L, Gibbs, JSR, DaCosta, R, Pinguel, J, Dormand, N, Parker, A, Stokes, D, Ghedia, D, Tan, Y, Ngcozana, T, Wanjiku, I, Polwarth, G, Mackenzie Ross, RV, Suntharalingam, J, Grover, M, Kirby, A, Grove, A, White, K, Seatter, A, Creaser-Myers, A, Walker, S, Roney, S, Elliot, CA, Charalampopoulos, A, Sabroe, I, Hameed, A, Armstrong, I, Hamilton, N, Rothman, AMK, Swift, AJ, Wild, JM, Soubrier, F, Eyries, M, Humbert, M, Montani, D, Girerd, B, Scelsi, L, Ghio, S, Gall, H, Ghofrani, A, Bogaard, HJ, Noordegraaf, AV, Houweling, AC, Veld, AHI, Schotte, G, Kariotis, Sokratis [0000-0001-9993-6017], Pickworth, Josephine A [0000-0002-7199-364X], Rhodes, Christopher J [0000-0002-4962-3204], Wharton, John [0000-0001-8110-2575], Iremonger, James [0000-0003-3953-8812], Dunning, Mark J [0000-0002-8853-9435], Errington, Niamh [0000-0001-6768-7394], Thompson, AA Roger [0000-0002-0717-4551], Howard, Luke S [0000-0003-2822-210X], Graf, Stefan [0000-0002-1315-8873], Wilkins, Martin R [0000-0003-3926-1171], Lawrie, Allan [0000-0003-4192-9505], Wang, Dennis [0000-0003-0068-1005], Apollo - University of Cambridge Repository, Gräf, Stefan [0000-0002-1315-8873], Pickworth, Josephine A. [0000-0002-7199-364X], Rhodes, Christopher J. [0000-0002-4962-3204], Dunning, Mark J. [0000-0002-8853-9435], Thompson, A. A. Roger [0000-0002-0717-4551], Howard, Luke S. [0000-0003-2822-210X], Wilkins, Martin R. [0000-0003-3926-1171], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, and ACS - Atherosclerosis & ischemic syndromes

Subjects
HYPOXIA-INDUCED PROLIFERATION, OPERATED CALCIUM-ENTRY, Classification and taxonomy, Science, PROGNOSTIC IMPACT, General Physics and Astronomy, Down-Regulation, 631/114/2404, General Biochemistry, Genetics and Molecular Biology, 38/91, Functional clustering, Genomic analysis, 631/114/1386, 631/1647/2217, Humans, Familial Primary Pulmonary Hypertension, HLA-DP beta-Chains, RISK SCORE CALCULATOR, OUTCOMES, Pulmonary Arterial Hypertension, Science & Technology, Multidisciplinary, Gene Expression Profiling, 692/4019/592/75, article, 49/39, General Chemistry, Multidisciplinary Sciences, IRON-DEFICIENCY, Cardiovascular diseases, UK National PAH Cohort Study Consortium, REGISTRY, ASSESSMENTS, SURVIVAL, Science & Technology - Other Topics, Transcriptome, 5-Aminolevulinate Synthetase
Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH., Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Published
2020
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13. Pulmonary hypertension in orphan lung diseases

Author

Montani, D., primary, Bertoletti, L., additional, Jais, X., additional, Dorfmuller, P., additional, Price, L., additional, Girerd, B., additional, Sitbon, O., additional, Humbert, M., additional, and Simonneau, G., additional

Published
2011
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15. Hypertension pulmonaire associée à la neurofibromatose de type 1 : données du registre français de l’hypertension pulmonaire

Author

Jutant, E.M., primary, Jais, X., additional, Girerd, B., additional, Mignard, X., additional, Ghigna, M.R., additional, Bourlier, D., additional, Tromeur, C., additional, Bergot, E., additional, Prévot, G., additional, Dauphin, C., additional, Favrolt, N., additional, Traclet, J., additional, Moceri, P., additional, Soumagne, T., additional, Bauer, F., additional, Degroote, P., additional, Chabanne, C., additional, Magro, P., additional, Bertoletti, L., additional, Savale, L., additional, Soubrier, F., additional, Simonneau, G., additional, Sitbon, O., additional, Wolkenstein, P., additional, Brillet, P.Y., additional, Humbert, M., additional, and Montani, D., additional

Published
2020
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16. Phénotype clinique et évolution des patients atteints d’HTAP héritable présentant une mutation du gène TBX4

Author

Thoré, P., primary, Girerd, B., additional, Jaïs, X., additional, Laurent, S., additional, Eyries, M., additional, Levy, M., additional, Ovaert, C., additional, Servettaz, A., additional, Guillaumot, A., additional, Dauphin, C., additional, Chabanne, C., additional, Boiffard, E., additional, Cottin, V., additional, Sitbon, O., additional, Chaouat, A., additional, Humbert, M., additional, and Montani, D., additional

Published
2020
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17. Association of a KCNA5 gene polymorphism with systemic sclerosis–associated pulmonary arterial hypertension in the European Caucasian population

Author

Wipff, J., Dieudé, P., Guedj, M., Ruiz, B., Riemekasten, G., Cracowski, J. L., Matucci-Cerinic, M., Melchers, I., Humbert, M., Hachulla, E., Airo, P., Diot, E., Hunzelmann, N., Caramaschi, P., Sibilia, J., Valentini, G., Tiev, K., Girerd, B., Mouthon, L., Riccieri, V., Carpentier, P. H., Distler, J., Amoura, Z., Tarner, I., Degano, B., Avouac, J., Meyer, O., Kahan, A., Boileau, C., and Allanore, Y.

Published
2010
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18. Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study

Author

Rhodes, C.J., Wharton, J., Ghataorhe, P., Watson, G., Girerd, B., Howard, L.S., Gibbs, J.S.R., Condliffe, R., Elliot, C.A., Kiely, D.G., Simonneau, G., Montani, D., Sitbon, O., Gall, H., Schermuly, R.T., Ghofrani, H.A., Lawrie, A., Humbert, M., Wilkins, M.R., Imperial College Healthcare NHS Trust, National Institute for Health Research, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)

Subjects
EXPRESSION, Adult, Male, Proteomics, Proteome, Hypertension, Pulmonary, Respiratory System, BIOMARKERS, DIAGNOSIS, Risk Assessment, 1117 Public Health and Health Services, Cohort Studies, PREDICTING SURVIVAL, Critical Care Medicine, Risk Factors, General & Internal Medicine, Humans, Arterial Pressure, Familial Primary Pulmonary Hypertension, Aged, Science & Technology, IDENTIFICATION, RECEPTOR, Gene Expression Profiling, 1103 Clinical Sciences, Blood Proteins, Articles, Middle Aged, ST2, Hypertension, Female, Life Sciences & Biomedicine, 1199 Other Medical and Health Sciences
Abstract

Summary Background Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. Methods In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. Findings 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77–0·89; p

Published
2017

19. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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20. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Knight, J, Hanscombe, KB, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RV, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, A, Waisfisz, Q, Walsworth, AK, Walter, RE, Wharton, J, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, Consortium, UK NIHR Bioresource Rare Diseases, Consortium, UK PAH Cohort Study, Consortium, US PAH Biobank, McCarthy, M, Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, APH - Quality of Care, and ACS - Microcirculation

Subjects
Male, Pulmonary Arterial Hypertension, Genotyping Techniques, [SDV]Life Sciences [q-bio], Genetic Variation, HLA-DP alpha-Chains, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Survival Analysis, Article, SOXF Transcription Factors, Humans, Female, Genetic Predisposition to Disease, HLA-DP beta-Chains, Genome-Wide Association Study, Signal Transduction
Abstract

Background Raregenetic variantscause pulmonary arterial hypertension, but the contribution of commongenetic variationto disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS usedgenotypesfrom 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals.Cross-validationof loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration ofsurvival.All-cause mortalitywas the primary endpoint in survival analyses. Findings A locus nearSOX17(rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus inHLA-DPA1andHLA-DPB1(collectively referred to asHLA-DPA1/DPB1here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. TheSOX17locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional andepigenomicdata indicate that the risk variants nearSOX17altergene regulationvia anenhanceractive inendothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reducedSOX17expression. TheHLA-DPA1/DPB1rs2856830 genotype was strongly associated with survival. Median survival fromdiagnosisin patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baselinedisease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer nearSOX17and inHLA-DPA1/DPB1is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by raremutationsinSOX17. Further studies are needed to confirm the association betweenHLA typingor rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improvesrisk stratificationin clinical practice or trials.

Published
2019
Full Text
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21. Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis

Author

Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Walter, RE, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Walsworth, AK, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Knight, J, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, Hanscombe, KB, US PAH Biobank Consortium, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RVM, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)

Subjects
ALPHA, Science & Technology, US PAH Biobank Consortium, Critical Care Medicine, ENDODERM FORMATION, General & Internal Medicine, UK NIHR BioResource Rare Diseases Consortium, Respiratory System, UK PAH Cohort Study Consortium, SUSCEPTIBILITY, SOX17, Life Sciences & Biomedicine, DISEASE
Abstract

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.

Published
2018

22. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

23. 5022Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease

Author

Girerd, B., primary, Montani, D., additional, Jais, X., additional, Levy, M., additional, Savale, L., additional, Dorfmuller, P., additional, Lau, E., additional, Le Pavec, J., additional, Parent, F., additional, Bonnet, D., additional, Soubrier, F., additional, Fadel, E., additional, Sitbon, O., additional, Simonneau, G., additional, and Humbert, M., additional

Published
2017
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28. Association of KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population

Author

Wipff, J, Dieudé, P, Guedj, M, Ruiz, B, Riemekasten, G, Cracowski, J, Matucci Cerinic, M, Melchers, I, Humbert, M, Hachulla, E, Airo, P, Diot, E, Hunzelmann, N, Caramaschi, Paola, Sibilia, J, Valentini, G, Tiev, K, Girerd, B, Mouthon, L, Riccieri, V, Carpentier, P, Distler, J, Amoura, Z, Tarner, I, Degano, B, Avouac, J, Meyer, O, Kahan, A, Boileau, C, and Allanore, Y.

Subjects
pulmonary arterial hypertension, Systemic sclerosis, KCNA5 gene polymorphism
Published
2010

32. Conseil génétique dans l’hypertension artérielle pulmonaire

Author

Girerd, B., primary, Montani, D., additional, Yaici, A., additional, Eyries, M., additional, Savale, L., additional, Sztrymf, B., additional, Jais, X., additional, Coulet, F., additional, Soubrier, F., additional, Sitbon, O., additional, Simonneau, G., additional, and Humbert, M., additional

Published
2012
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35. La scintigraphie pulmonaire dans la maladie veno-occlusive

Author

Seferian, A., primary, Helal, B., additional, Jais, X., additional, Girerd, B., additional, Gunther, S., additional, Savale, L., additional, Dorfmuller, P., additional, Parent, F., additional, Sitbon, O., additional, Humbert, M., additional, Simonneau, G., additional, and Montani, D., additional

Published
2012
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44. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

Author

Tu L, De Man FS, Girerd B, Huertas A, Chaumais MC, Lecerf F, François C, Perros F, Dorfmüller P, Fadel E, Montani D, Eddahibi S, Humbert M, Guignabert C, Tu, Ly, De Man, Frances S, Girerd, Barbara, Huertas, Alice, Chaumais, Marie-Camille, and Lecerf, Florence

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.Objectives: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).Measurements and Main Results: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.Conclusions: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals. [ABSTRACT FROM AUTHOR]

Published
2012
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46. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension.

Author

Perros F, Dorfmüller P, Montani D, Hammad H, Waelput W, Girerd B, Raymond N, Mercier O, Mussot S, Cohen-Kaminsky S, Humbert M, and Lambrecht BN

Abstract

Rationale: Patients with idiopathic pulmonary arterial hypertension (IPAH) present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs). Objectives: To assess the frequency of tLTs in IPAH lungs, as compared with control subjects and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation, and function. Methods: tLT composition and structure were studied by multiple immunostainings. Cytokine/chemokine and growth factor expression was quantified by real-time polymerase chain reaction and localized by immunofluorescence. The systemic mark of pulmonary lymphoid neogenesis was investigated by flow cytometry analyses of circulating lymphocytes. Measurements and Main Results: As opposed to lungs from control subjects and patients with Eisenmenger syndrome, IPAH lungs contained perivascular tLTs, comprising B- and T-cell areas with high endothelial venules and dendritic cells. Lymphocyte survival factors, such as IL-7 and platelet-derived growth factor-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-[alpha]/-[beta], CCL19, CCL20, CCL21, and CXCL13, which might explain the depletion of circulating CCR6(+) and CXCR5(+) lymphocytes. tLTs were connected with remodeled vessels via an ER-TR7(+) stromal network and supplied by lymphatic channels. The presence of germinal center centroblasts, follicular dendritic cells, activation-induced cytidine deaminase, and IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell accumulation around remodeled vessels in areas of immunoglobulin deposition argued for local immunoglobulin class switching and ongoing production. Conclusions: We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH, providing new evidence of immunological mechanisms in this severe condition. [ABSTRACT FROM AUTHOR]

Published
2012
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48. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation.

Author

Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jaïs X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, Sitbon O, O'Callaghan DS, Simonneau G, Soubrier F, and Humbert M

Abstract

RATIONALE: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). OBJECTIVES: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. METHODS: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. MEASUREMENTS AND MAIN RESULTS: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 +/- 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 +/- 14.9 and 47.6 +/- 16.3 yr, respectively; P < 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P < 0.0001). CONCLUSIONS: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression. [ABSTRACT FROM AUTHOR]

Published
2010
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49. Pulmonary arterial hypertension in a patient with Cowden syndrome and anorexigen exposure.

Author

Natali D, Girerd B, Montani D, Soubrier F, Simonneau G, Humbert M, Sitbon O, Natali, Delphine, Girerd, Barbara, Montani, David, Soubrier, Florent, Simonneau, Gérald, Humbert, Marc, and Sitbon, Olivier

Abstract

We report a case of pulmonary arterial hypertension (PAH) occurring in a patient with Cowden syndrome with a mutation in the phosphatase and tensin (PTEN) tumor suppressor gene, in the context of exposure to the appetite suppressant dexfenfluramine. Anorexigen exposure is known to be a risk factor for PAH. However, the role of PTEN in cell function and the development of pulmonary vascular remodeling and histopathologic signs of PAH in mice with a Pten depletion in smooth muscle cells suggest that the association of PAH and Cowden syndrome may be relevant. In this case report, we hypothesize that PTEN mutations may be a predisposing factor for the development of PAH, with anorexigen exposure as a potential trigger. [ABSTRACT FROM AUTHOR]

Published
2011
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