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Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

Nature Genetics volume 45, pages 518–521 (2013)Cite this article

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Abstract

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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Figure 1: CBLN2 mRNA levels are higher in lungs from individuals with PAH.
Figure 2: Immunostaining of pulmonary arteries with an antibody to CBLN2.
Figure 3: CBLN2 mRNA levels in pulmonary vascular cells from individuals with PAH.
Figure 4: Cell proliferation in PA-SMCs treated with CBLN2.

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Acknowledgements

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.

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Authors and Affiliations

  1. Unité Mixte de Recherche en Santé (UMRS) 937, Université Pierre & Marie Curie (UPMC) Université Paris 6 and Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    Marine Germain & David A Trégouët

  2. Institut Hospitalo-Universitaire (IHU) Cardiométabolisme et Nutrition (ICAN), Paris, France

    Marine Germain, Mélanie Eyries, Odette Poirier, Sophie Nadaud, Svetlana Maugenre, David A Trégouët & Florent Soubrier

  3. UMRS 956, UPMC Université Paris 6 and INSERM, Paris, France

    Mélanie Eyries, Odette Poirier, Sophie Nadaud, Svetlana Maugenre & Florent Soubrier

  4. Department of Genetics, Hôpital Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France

    Mélanie Eyries, Florence Coulet & Florent Soubrier

  5. Université Paris–Sud, Faculté de Médecine, Le Kremlin Bicêtre, France

    David Montani, Barbara Girerd, Peter Dorfmüller, Christophe Guignabert, Gerald Simonneau & Marc Humbert

  6. Département Hospitalo-Universitaire (DHU) Thorax Innovation, Centre National de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie, Hôpital de Bicêtre, AP-HP, Le Kremlin Bicêtre, France

    David Montani, Barbara Girerd, Peter Dorfmüller, Christophe Guignabert, Gerald Simonneau & Marc Humbert

  7. UMRS 999, INSERM and Université Paris–Sud, Laboratoire d'Excellence (LabEx) en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

    David Montani, Barbara Girerd, Peter Dorfmüller, Christophe Guignabert, Gerald Simonneau & Marc Humbert

  8. Department of Pathology, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France

    Peter Dorfmüller

  9. Post-Genomic Platform (P3S), UPMC Université Paris 6, Paris, France

    Wassila Carpentier

  10. Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands

    Anton Vonk-Noordegraaf

  11. Cardiac Surgery Department, Hôpital Necker–Enfants Malades, AP-HP, Paris, France

    Marilyne Lévy

  12. UMRS 765, INSERM and Université Paris Descartes, Paris, France

    Marilyne Lévy

  13. Respiratory Disease Department, Centre Hospitalier Universitaire (CHU) Brabois, Vandoeuvre-lès-Nancy, France

    Ari Chaouat

  14. UMRS 744, Université de Lille Nord de France and INSERM, Institut Pasteur, Lille, France

    Jean-Charles Lambert & Philippe Amouyel

  15. UMRS 708, UPMC Université Paris 6 and INSERM, Paris, France

    Marion Bertrand

  16. UMRS 888, Université Montpellier and INSERM, Montpellier, France

    Anne-Marie Dupuy

  17. U897, Université Bordeaux and INSERM, Institut de Santé Publique d'Epidémiologie et de Développement, Bordeaux, France

    Luc Letenneur

  18. Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France

    Mark Lathrop

  19. Centre Hospitalier Régional Universitaire de Lille, Lille, France

    Philippe Amouyel

  20. Centre for Human Genetics, University Hospitals of Leuven, Leuven, Belgium

    Thomy J L de Ravel

  21. Department of Pneumology, Catholic University of Leuven (KU Leuven), Leuven, Belgium

    Marion Delcroix

  22. Department of Pneumology, Gasthuisberg University Hospital, Leuven, Belgium

    Marion Delcroix

  23. Department of Pediatrics, Division of Pulmonary, Allergy, and Immunology Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Eric D Austin

  24. Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Ivan M Robbins, Anna R Hemnes & James E Loyd

  25. Department of Pediatrics, Columbia University, New York, New York, USA

    Erika Berman-Rosenzweig, Robyn J Barst & Wendy K Chung

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  1. Marine Germain
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Contributions

F.S. initiated and supervised the study. F.S., D.A.T., G.S. and M.H. conceived and designed the experiments. D.M., B.G., G.S., M.H., A.V.-N., M.Lévy, A.C., T.J.L.d.R. and M.D. analyzed clinical data of collected individuals with PAH for the discovery cohort. J.-C.L., M.B., A.-M.D., L.L., M.Lathrop and P.A. provided genotyped data for control subjects. E.D.A., I.M.R., A.R.H., J.E.L., E.B.-R., R.J.B. and W.K.C. analyzed the clinical data of the collected individuals with PAH for the replication cohort. M.E. and F.C. managed DNA samples. W.C. performed genotyping. M.G. and D.A.T. performed statistical analysis. M.E., O.P., S.N. and S.M. performed functional analyses. C.G. isolated vascular cells. P.D. performed tissue imaging. D.A.T., M.G., M.E., O.P., S.N. and F.S. analyzed data. F.S., M.G., M.E. and D.A.T. wrote the manuscript. O.P., S.N., M.H., D.M., E.D.A., J.E.L. and W.K.C. reviewed the manuscript.

Corresponding author

Correspondence to Florent Soubrier.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1, 3, 5 and 6 (PDF 494 kb)

Supplementary Table 2

Association in the replication cohort of the 319 most significant SNPs with i/fPAH detected in the discovery GWAS (XLS 123 kb)

Supplementary Table 4

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. (XLS 113 kb)

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Germain, M., Eyries, M., Montani, D. et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 45, 518–521 (2013). https://doi.org/10.1038/ng.2581

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