Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases1,2,3. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59–2.45; P = 7.47 × 10−10). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.
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We thank E. Fadel and O. Mercier from the Centre Médico-Chirurgical Marie-Lannelongue for their help in lung sample collection. The Pulmonary Hypertension Allele-Associated Risk (PHAAR) project was financially supported by the Agence Nationale pour la Recherche (Project ANR-07-MRAR-021) and by PHRC AOM07-041, INSERM and UPMC. The 3C Study is conducted under a partnership agreement between INSERM, the Victor Segalen–Bordeaux II University and Sanofi-Synthelabo. The Fondation pour la Recherche Médicale funded the preparation and first phase of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, the Direction Générale de la Santé, the Mutuelle Générale de l'Education Nationale, the Institut de la Longévité, the Agence Française de Sécurité Sanitaire des Produits de Santé, the regional governments of Aquitaine, Bourgogne and Languedoc-Roussillon and the Fondation de France, and the Ministry of Research–INSERM Programme Cohorts and Collection of Biological Material. The Lille Genopole received an unconditional grant from Eisai. The financial supporters had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. M.G. was funded by a grant from the Agence Nationale pour la Recherche (Project PHAAR, ANR-07-MRAR-021) and the Program Hospitalier de Recherche Clinique (PHRC2009 RENOVA-TV). Statistical analyses used the C2BIG computing centre funded by the Fondation pour la Recherche Médicale and Région Ile de France. Collection and management of samples from Vanderbilt University were supported by US NIH grants P01 HL072058 and K23 HL0987431 and Vanderbilt General Clinical Research Center (GCRC) RR000095. Collection of the samples from Columbia University was supported by US NIH grant R01 HL060056.
Association in the replication cohort of the 319 most significant SNPs with i/fPAH detected in the discovery GWAS
Association analysis of all SNPs located within a 100kb upstream or downstream distance from the CBLN2 gene with ("conditional") and without adjusting for the rs2217560 effect in the discovery GWAS sample.
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Nature Reviews Cardiology (2019)