title: BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis.
abstract: BACKGROUND
  Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain.
  
  
  METHODS
  We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort.
  
  
  RESULTS
  Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15-1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00-1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality).
  
  
  CONCLUSIONS
  Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations.
  
  
  BACKGROUND
  Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Cardiology, Papworth Hospital, Cambridge, UK.
authors.forename: Jonathan D W
authors.initials: JD
authors.lastname: Evans
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: David
authors.initials: D
authors.lastname: Montani
authors.affiliation: Thrombosis and Vascular Medicine Center, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galiè
authors.affiliation: Department of Paediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Department of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Elliott
authors.affiliation: Division of Pulmonary Medicine, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Asano
authors.affiliation: Centre for Pulmonary Hypertension, Thorax Clinic, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
authors.affiliation: Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Thrombosis and Vascular Medicine Center, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
authors.affiliation: Institute of Cardiology, University of Bologna, Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Manes
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Palazzini
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wheeler
authors.affiliation: Department of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Ikue
authors.initials: I
authors.lastname: Nakayama
authors.affiliation: Division of Cardiology, Department of Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Centre for Pulmonary Hypertension, Thorax Clinic, University Hospital Heidelberg, Heidelberg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Eichstaedt
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Centre for Pulmonary Hypertension, Thorax Clinic, University Hospital Heidelberg, Heidelberg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Department of Pediatric Cardiology, Columbia University Medical Center, New York, NY USA.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rosenzweig
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Laboratoire d'Oncogénétique et Angiogénétique Moléculaire, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gräf
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaptoge
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France; INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. Electronic address: nwm23@cam.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics / Q000401:mortality / Q000601:surgery; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D016040:Lung Transplantation / Q000706:statistics & numerical data*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D055815:Young Adult
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II