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Considerable progress has been made in the genomics of pulmonary arterial hypertension (PAH) since the 6th World Symposium on Pulmonary Hypertension, with the identification of rare variants in several novel genes, as well as common variants that confer a modest increase in PAH risk. Gene and variant curation by an expert panel now provides a robust framework for knowing which genes to test and how to interpret variants in clinical practice. We recommend that genetic testing be offered to specific subgroups of symptomatic patients with PAH, and to children with certain types of group 3 pulmonary hypertension (PH). Testing of asymptomatic family members and the use of genetics in reproductive decision-making require the involvement of genetics experts. Large cohorts of PAH patients with biospecimens now exist and extension to non-group 1 PH has begun. However, these cohorts are largely of European origin; greater diversity will be essential to characterise the full extent of genomic variation contributing to PH risk and treatment responses. Other types of omics data are also being incorporated. Furthermore, to advance gene- and pathway-specific care and targeted therapies, gene-specific registries will be essential to support patients and their families and to lay the foundation for genetically informed clinical trials. This will require international outreach and collaboration between patients/families, clinicians and researchers. Ultimately, harmonisation of patient-derived biospecimens, clinical and omic information, and analytic approaches will advance the field., Competing Interests: Conflict of interest: E.D. Austin reports grants from NIH (R01FD007627; 1R01HL134802; T32HL160508; R01HL169859; R34HL173389; 5P01HL108800) and the Cardiovascular Medical Research Fund, payment or honoraria for lectures, presentations, manuscript writing or educational events from Acceleron, Inc., participation on a data safety monitoring board or advisory board with NIH, and leadership roles with PHA and TBX4Life. M. Alotaibi reports grants from NIH. M.A. Aldred reports grants from NHLBI and a leadership role with the International Consortium for Genetics Studies in PAH (PAH-ICON). S. Gräf reports a leadership role as Co-Chair of the International Consortium for Genetic Studies in Pulmonary (Arterial) Hypertension (P(A)H-ICON). W.C. Nichols reports grants from NIH/NHLBI. R.C. Trembath reports support for attending meetings from conference organisers. W.K. Chung has no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.

Purpose: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing., Methods: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence., Results: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time., Conclusion: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered., Competing Interests: Conflict of interest: C.A. Eichstaedt reports lecture fees from MSD, outside the submitted work; and has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued. C. Belge reports consulting fees, participation on advisory boards and lecture honoraria from Janssen and MSD/Bayer; travel support from MSD/Bayer, outside the submitted work. W.K. Chung reports scientific advisory board participation with Regeneron Genetics Center, outside the submitted work. E. Grünig reports grants from Actelion, Bayer, GSK, United Therapeutics, Novartis, Bellerophon, OMT, Pfizer and REATA; lecture fees and consultancy fees from Actelion, Bayer/MSD and GSK; travel support from Janssen; advisory board participation with MSD and Ferrer, outside the submitted work; has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued; and has also served in leadership roles for ADue and pH e.V., outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. R.C. Trembath reports lecture fees from Clinical Cases, outside the submitted work. N.W. Morrell reports employment and stock/stock options from Centessa Pharmaceuticals. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis -pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80-2.01) in a multicentre case-control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (OR causal 1.07, 95% CI 0.92-1.24) or the secondary (OR causal 1.09, 95% CI 0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH., Competing Interests: Conflict of interest: A. Ulrich has nothing to disclose. Conflict of interest: J. Wharton has nothing to disclose. Conflict of interest: T.E. Thayer has nothing to disclose. Conflict of interest: E.M. Swietlik has nothing to disclose. Conflict of interest: T.R. Assad has nothing to disclose. Conflict of interest: A.A. Desai has nothing to disclose. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: L. Harbaum has nothing to disclose. Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, personal fees from Actelion, Merck and from United Therapeutics, outside the submitted work. Conflict of interest: N.W. Morrell reports personal fees from Actelion and Morphogen-IX, outside the submitted work. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: L. Southgate has nothing to disclose. Conflict of interest: D-A. Trégouët has nothing to disclose. Conflict of interest: R.C. Trembath reports personal fees for advisory board work from Ipsen Pharmaceuticals, personal fees for non-executive board membership from King's College Hospital NHS Foundation Trust, outside the submitted work. Conflict of interest: E.L. Brittain reports personal fees for advisory board work from Bayer, outside the submitted work. Conflict of interest: M.R. Wilkins reports grants from Vifor Pharma, outside the submitted work. Conflict of interest: I. Prokopenko has nothing to disclose. Conflict of interest: C.J. Rhodes reports personal fees from Actelion, outside the submitted work., (Copyright ©ERS 2020.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted β -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (β +75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology., Competing Interests: Conflict of interest: M. Newnham reports education support (travel, registration and accommodation) to attend conferences from MSD and GSK, outside the submitted work. Conflict of interest: K. South has nothing to disclose. Conflict of interest: M. Bleda has nothing to disclose. Conflict of interest: W.R. Auger reports grants and non-financial support for advisory board work (travel support only) from Bayer, outside the submitted work. Conflict of interest: J.A. Barberà has nothing to disclose. Conflict of interest: H. Bogaard has nothing to disclose. Conflict of interest: K. Bunclark has nothing to disclose. Conflict of interest: J.E. Cannon reports grants for educational meetings from Actelion, GSK and MSD, outside the submitted work. Conflict of interest: M. Delcroix has nothing to disclose. Conflict of interest: C. Hadinnapola has nothing to disclose. Conflict of interest: L.S. Howard reports grants from Bayer PLC, during the conduct of the study. Conflict of interest: D. Jenkins reports grants and personal fees from Bayer, and personal fees from Actelion, outside the submitted work. Conflict of interest: E. Mayer reports speaker and consultancy fees from Actelion, Bayer and MSD, and speaker fees from Pfizer, outside the submitted work. Conflict of interest: C. Ng has nothing to disclose. Conflict of interest: C.J. Rhodes has nothing to disclose. Conflict of interest: N. Screaton has nothing to disclose. Conflict of interest: K. Sheares reports educational support (travel, registration and accommodation) to attend conferences from Actelion, Bayer, MSD and GSK, and has been on an advisory board for Actelion, outside the submitted work. Conflict of interest: M.A. Simpson has a contract of service with Genomics PLC, outside the submitted work. Conflict of interest: M. Southwood has nothing to disclose. Conflict of interest: L. Su has nothing to disclose. Conflict of interest: D. Taboada reports speaker honoraria and education/travel grants from Actelion, Bayer, GlaxoSmithKline, Lilly, MDS and Pfizer, outside the submitted work. Conflict of interest: M. Traylor has nothing to disclose. Conflict of interest: R.C. Trembath has nothing to disclose. Conflict of interest: S.S. Villar has nothing to disclose. Conflict of interest: M.R. Wilkins has nothing to disclose. Conflict of interest: J. Wharton reports personal fees for advisory board work from Actelion Pharmaceuticals Ltd, outside the submitted work. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: J. Pepke-Zaba (or her institution) has received research/educational grants and has been serving on advisory boards for Actelion, Bayer, Merck and GSK. Conflict of interest: M. Laffan reports grants from British Heart Foundation during the conduct of the study; and support to attend conferences from Shire, outside the submitted work. Conflict of interest: D.A. Lane has nothing to disclose. Conflict of interest: N.W. Morrell has nothing to disclose. Conflict of interest: M. Toshner reports grants and personal fees from Bayer, Merck and Actelion, personal fees from GSK, and grants from Roche, during the conduct of the study., (Copyright ©ERS 2019.)

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH., Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured., Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival., Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation., (© 2017 The Authors.)

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality., Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis., Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects., Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients., (© 2016 The Authors.)

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., (Copyright © 2016 Evans et al. Open Access article distributed under the terms of CC-BY. Published by Elsevier Ltd.. All rights reserved.)

Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools., (© 2015 WILEY PERIODICALS, INC.)

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.