BMPR2 revisited: are bigger data better?
Authors: Jeremy A Mazurek, Steven M Kawut
Journal: The Lancet Respiratory Medicine (2016)

Since 2000, mutations in the gene that codes for the bone morphogenetic protein type II receptor (BMPR2) have been recognised as the major genetic cause of heritable pulmonary arterial hypertension (PAH) with a prevalence of about 80% in familial PAH and accounting for a substantial proportion of cases of sporadic PAH.1Deng Z Morse JH Slager SL et al.Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.Am J Hum Genet. 2000; 67: 737-744Summary Full Text Full Text PDF PubMed Scopus (982) Google Scholar, 2Newman JH Wheeler L Lane KB et al.Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred.N Engl J Med. 2001; 345: 319-324Crossref PubMed Scopus (312) Google Scholar, 3Girerd B Montani D Jais X et al.Genetic counselling in a national referral centre for pulmonary hypertension.Eur Respir J. 2016; 47: 541-552Crossref PubMed Scopus (77) Google Scholar In The Lancet Respiratory Medicine, Jonathan Evans and colleagues4Evans JDW Girerd B Montani D et al.BMPR2 mutations and survival in pulmonary arterial hypertension: an individual particpiant data meta-analysis.Lancet Respir Med. 2016; (published online Jan 18.)http://dx.doi.org/10.1016/S2213-2600(15)00544-5Google Scholar report findings from an individual participant data meta-analysis from the BMPR2 Studies Collaboration comprised of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight individual PAH cohorts from six countries. BMPR2 mutations were found in nearly 30% of patients and were associated with younger age at diagnosis, more severe haemodynamic derangement, and lower likelihood of vasoreactivity. In age-adjusted and sex-adjusted models including 1164 patients, a BMPR2 mutation was associated with an increased risk of death or lung transplantation (HR 1·42, 1·15–1·75) which might have been due to worse baseline cardiac function in BMPR2 mutation carriers. This work represents a labour-intensive, multinational effort to harmonise previously collected, patient-level data to more powerfully assess the effect of BMPR2 mutations. Data sharing at the individual patient level fosters collaboration across institutions and geographical regions and can enhance our knowledge beyond the results of any single study or cohort (as in this study).5Insitute of MedicineSharing clinical research data: workshop summary. The National Academies Press, Washington, DC2013Google Scholar Sharing data from both observational studies and clinical trials will be crucial to achieve the full promise of omics technology, comparative effectiveness research, and big data analytics to improve our understanding and treatment of pulmonary vascular disease. However, data sharing is not without barriers, including patient privacy rules (which might differ across countries), intellectual autonomy, and often substantial cost. As opposed to a traditional meta-analysis (which uses aggregate data), an individual participant data meta-analysis analyses individual patient data from many studies. This study methodology affords several advantages, including the use of consistent inclusion criteria across studies, follow-up information potentially beyond that available in the initial studies, accounting for missing data, detailed assessments of statistical assumptions, sensitivity and subgroup analyses, better adjustment for confounders and examination of effect modification, and enhanced statistical power, all of which were leveraged in this study.6Riley RD Lambert PC Abo-Zaid G Meta-analysis of individual participant data: rationale, conduct, and reporting.BMJ. 2010; 340: c221Crossref PubMed Scopus (1031) Google Scholar The authors were able to confirm a significant relation between BMPR2 mutations and worse transplant-free survival, an association that was significantly stronger in younger patients and unrelated to mutation subtype. The authors assessed haemodynamic parameters, including pulmonary vascular resistance, cardiac index, and vasoreactivity, as potentially mediating factors between BMPR2 mutation status and outcome. Lower cardiac index at baseline accounted for most of the increase in risk for mutation carriers for both death or transplantation and all-cause mortality (65% and 79%, respectively). This finding is important as it confirms previous data showing the effect of cardiac index, a somewhat crude metric of right ventricular function, on survival in PAH in general, and in familial PAH specifically.7Humbert M Sitbon O Chaouat A et al.Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era.Circulation. 2010; 122: 156-163Crossref PubMed Scopus (1119) Google Scholar, 8Brittain EL Pugh ME Wheeler LA et al.Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function.Pulm Circ. 2013; 3: 589-598Crossref PubMed Scopus (28) Google Scholar It also implicates mutations in BMPR2 as contributors to right ventricular dysfunction, perhaps via perturbations in right ventricular metabolism and lipotoxicity, as previously described.9Hemnes AR Brittain EL Trammell AW et al.Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension.Am J Respir Crit Care Med. 2014; 189: 325-334Crossref PubMed Scopus (112) Google Scholar Although the study is well executed, some questions remain. First, investigators used a one-stage stratified model for the primary analysis and a two-stage random effects model in a sensitivity analysis. The conclusions were similar, which is reassuring, but the I2Newman JH Wheeler L Lane KB et al.Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred.N Engl J Med. 2001; 345: 319-324Crossref PubMed Scopus (312) Google Scholar estimates from the latter indicate moderate heterogeneity, potentially reflecting differences in study designs or populations. Second, although significant, BMPR2 mutations increased the risk of adverse outcomes by about 30–40% (though more so in younger patients). Thus, for the individual patient, the presence of a mutation might not have sufficient discriminatory power to tailor treatment or predict outcome. Genetic testing is recommended for patients with sporadic, familial, and anorexigen-associated PAH10Galie N Humbert M Vachiery JL et al.2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46: 903-975Crossref PubMed Scopus (2050) Google Scholar but experienced counselling is necessary for the patient and relatives considering the clinical and familial implications (and possible misinterpretations) of the presence of a mutation.3Girerd B Montani D Jais X et al.Genetic counselling in a national referral centre for pulmonary hypertension.Eur Respir J. 2016; 47: 541-552Crossref PubMed Scopus (77) Google Scholar A gene-based precision medicine treatment approach in this population should be studied. The work by Evans and colleagues4Evans JDW Girerd B Montani D et al.BMPR2 mutations and survival in pulmonary arterial hypertension: an individual particpiant data meta-analysis.Lancet Respir Med. 2016; (published online Jan 18.)http://dx.doi.org/10.1016/S2213-2600(15)00544-5Google Scholar revisits the role of BMPR2 mutations in a bigger and better way and shows how collaborative observational patient-oriented studies can enlighten mechanisms of human PAH. Future studies are needed to understand the best approaches to genetic screening and counselling, the role of screening and preventative therapy in mutation carriers without clinical PAH and intensive therapy in mutation carriers with PAH, and haemodynamic response to therapy in mutation carriers compared with non-carriers. Furthermore, the use of common data elements and standardised mapping of variables to an ontology would facilitate the development of a master data structure and common protocol for pulmonary hypertension, facilitating data harmonisation and sharing of future observational studies and clinical trials. Appropriate consent for data sharing with appropriate protections should be obtained as standard, as should subject or global unique identifiers to denote the same patients (or distinguish different ones) in multiple centres or registries. If we “begin with the end in mind”11Covey SR The 7 habits of highly effective people: powerful lessons in personal change. Simon & Schuster, New York1989Google Scholar and plan a priori for data sharing and harmonisation, we can best fulfill our ethical obligations to patients by making the most use of their substantial investments in research. JAM declares no competing interests. SMK reports non-financial support from the American College of Chest Physicians, non-financial support from the American Thoracic Society, personal fees from the European Respiratory Journal, grants from Actelion, United Therapeutics, Gilead, Lung Biotech, and the Pulmonary Hypertension Association to his institution for CME courses, and grants from Actelion, Gilead, GeNO, and Bayer to his institution for research, outside of the submitted work. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysisPatients 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. Full-Text PDF Open Access