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Lancet Respir Med. 2016 Feb;4(2):129-37. doi: 10.1016/S2213-2600(15)00544-5. Epub 2016 Jan 19.

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis.

Author information

1
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Cardiology, Papworth Hospital, Cambridge, UK.
2
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.
3
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.
4
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
5
Department of Paediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
6
Department of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, UT, USA.
7
Division of Pulmonary Medicine, Tokai University School of Medicine, Isehara, Japan.
8
Centre for Pulmonary Hypertension, Thorax Clinic, University Hospital Heidelberg, Heidelberg, Germany.
9
Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
10
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.
11
Institute of Cardiology, University of Bologna, Bologna, Italy.
12
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
13
Division of Cardiology, Department of Medicine, Kyorin University School of Medicine, Tokyo, Japan.
14
Centre for Pulmonary Hypertension, Thorax Clinic, University Hospital Heidelberg, Heidelberg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
15
Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
16
Department of Pediatric Cardiology, Columbia University Medical Center, New York, NY USA.
17
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY USA.
18
Université Pierre et Marie Curie-Paris 6, Laboratoire d'Oncogénétique et Angiogénétique Moléculaire, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
19
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Haematology, University of Cambridge School of Clinical Medicine, Cambridge, UK.
20
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
21
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. Electronic address: nwm23@cam.ac.uk.

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.

FINDINGS:

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).

INTERPRETATION:

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.

FUNDING:

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.

Comment in

PMID:
26795434
PMCID:
PMC4737700
DOI:
10.1016/S2213-2600(15)00544-5
[Indexed for MEDLINE]
Free PMC Article
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