BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis
Year: 2016
Type: review
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.
Source: The Lancet Respiratory Medicine
Authors: Jonathan D W Evans, Barbara Girerd, David Montani, Xiao-Jian Wang, Nazzareno Galiè, Eric D Austin, Greg Elliott, Koichiro Asano, Ekkehard Grünig, Yi Yan, Zhi-Cheng Jing, Alessandra Manes, Massimiliano Palazzini, Lisa A Wheeler, Ikue Nakayama, Toru Satoh, Christina Eichstaedt, Katrin Hinderhofer, Matthias Wolf, Erika B Rosenzweig, Wendy K Chung, Florent Soubrier, Gérald Simonneau, Olivier Sitbon, Stefan Gräf, Stephen Kaptoge, Emanuele Di Angelantonio, Marc Humbert, Nicholas W Morrell
Institutions: University of Cambridge, Royal Papworth Hospital, Université Paris-Sud, Inserm, Université Paris-Saclay, Assistance Publique – Hôpitaux de Paris, Hôpital Marie Lannelongue, Bicêtre Hospital, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Chinese Academy of Medical Sciences & Peking Union Medical College, Fu Wai Hospital, State Key Laboratory of Cardiovascular Disease, University of Bologna, Vanderbilt University, University of Utah, Intermountain Medical Center, Tokai University, Tokai University Hospital, University Hospital Heidelberg, Tongji University, Shanghai Pulmonary Hospital, Kyorin University, Columbia University Irving Medical Center, Pitié-Salpêtrière Hospital, Université Pierre-et-Marie-Curie
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $6,084
Funders: Intermountain Research and Medical Foundation, National Institute for Health and Care Research, British Heart Foundation, Institut National de la Santé et de la Recherche Médicale, Keio University, National Natural Science Foundation of China, Assistance Publique - Hôpitaux de Paris, Natural Science Foundation of Beijing Municipality, Université Pierre et Marie Curie, Università di Bologna, Université Paris-Sud, Assistance publique-Hôpitaux de Paris, National Institutes of Health, Medical Research Council, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Awards: Genetic Aspects of Pulmonary Hypertension, NIHR Senior Investigator Award, Targeting the BMP signalling pathway for the treatment of pulmonary arterial hypertension (renewal), Mechanisms underlying the development of pulmonary arterial hypertension, NIHR Senior Investigator Award, Hormonal, Metabolic and Signaling Interactions in PAH, G3839976931, G4211044638, Variations in estrogen exposures may modify pulmonary arterial hypertension, G4898668424, G6721415678, G753028953, National Cohort Study of Heritable Pulmonary Arterial Hypertension, The Vanderbilt Institute for Clinical and Translational Research (VICTR), RENEWAL: Systematic approaches to the evaluation of emerging coronary risk markers. Large-scale epidemiological analyses of existing data and stored biological samples, G8545996027, G878874547
OpenAlex ID: W2253353716