Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Cardiology, Papworth Hospital, Cambridge, UK.
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.
Lancet Respir Med. 2016 Feb;4(2):129-37. doi: 10.1016/S2213-2600(15)00544-5. Epub 2016 Jan 19.
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.
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.
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).
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.
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.
骨形成蛋白受体 2 型（BMPR2）基因突变是肺动脉高压（PAH）最常见的遗传原因。然而，BMPR2 突变对临床表型和结局的影响仍不确定。
我们分析了来自 8 个队列的 1550 名特发性、遗传性和食欲抑制剂相关性 PAH 患者的个体参与者数据，这些患者已接受系统性 BMPR2 突变检测。主要结局是死亡或肺移植的复合结局。全因死亡率是次要结局。使用 Cox 比例风险模型，按队列分层计算存在 BMPR2 突变与死亡或移植和全因死亡率相关的风险比（HR）。
总体而言，1550 名患者中有 448 名（29%）存在 BMPR2 突变。突变携带者的诊断年龄更小（平均年龄 35.4[14.8]岁 vs 42.0[17.8]岁），平均肺动脉压更高（60.5[13.8]mmHg vs 56.4[15.3]mmHg）和肺血管阻力更高（16.6[8.3]Wood 单位 vs 12.9[8.3]Wood 单位），而心指数更低（2.11[0.69]L/min/m2 vs 2.51[0.92]L/min/m2；均<0.0001）。BMPR2 突变患者对急性血管扩张剂试验的反应性更低（3%[380 名患者中的 10 名] vs 16%[907 名患者中的 147 名]；<0.0001）。在 1164 名具有可用生存数据的个体中，年龄调整和性别调整的 BMPR2 突变携带者与非携带者的复合死亡或肺移植的 HR 为 1.42（95%CI 1.15-1.75；p=0.0011），全因死亡率的 HR 为 1.27（1.00-1.60；p=0.046）。在调整潜在介质（包括肺血管阻力、心指数和血管反应性）后，这些 HR 减弱。BMPR2 突变与死亡或移植和全因死亡率相关的 HR 在男性和女性中相似，但在诊断年龄较小的患者中更高（死亡或移植的 p=0.0030，全因死亡率的 p=0.011）。
与没有 BMPR2 突变的患者相比，患有 PAH 和 BMPR2 突变的患者发病年龄更小，疾病更严重，死亡风险以及死亡或移植的风险增加。
剑桥大学国家卫生研究院生物医学研究中心、医学研究委员会、英国心脏基金会、巴黎公立医院、法国国家健康与医学研究院、巴黎南大学、爱默生间研究和医疗基金会、范德比尔特大学、国家转化医学科学中心、美国国立卫生研究院、中国国家自然科学基金会和北京市自然科学基金。
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