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J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D13-21. doi: 10.1016/j.jacc.2013.10.035.

Genetics and genomics of pulmonary arterial hypertension.

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Genetics Department, Hospital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris (APHP), Unité Mixte de Recherche en Sante (UMRS) 956 Institut National de la Sante et de la Recherche Medicale INSERM, Université Pierre et Marie Curie Paris 06 (UPMC), and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France. Electronic address:
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.
University of Lincoln, School of Life Sciences, Lincoln, United Kingdom.
Centre for Pulmonary Hypertension at University Hospital Heidelberg, Heidelberg, Germany.
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado.
Pulmonary Hypertension Center, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center North, Nashville, Tennessee.
Departments of Medicine at Intermountain Medical Center and the University of Utah, Salt Lake City, Utah.
Division of Genetics and Molecular Medicine, Kings College, London, United Kingdom.
Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie, Hôpital de Bicêtre, APHP, Le Kremlin Bicêtre, Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre; Département Hospitalo-Universitaire (DHU) thorax Innovation, AP-HP, Le Kremlin Bicêtre; UMR_S 999, INSERM and Université Paris-Sud, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.


Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.


BMP; BMPR2; CHD; GINA; GSD; Genetic Information Non-Discrimination Act; HDAC; HHT; HPAH; IL; IPAH; PAEC; PAH; PASMC; SNP; TGF; bone morphogenetic protein; congenital heart disease; genetics; genomic; glycogen storage disease; hereditary hemorrhagic telangiectasia; heritable pulmonary arterial hypertension; histone deacetylase; idiopathic pulmonary arterial hypertension; interleukin; mRNA; messenger ribonucleic acid; miRNA; micro ribonucleic acid; pulmonary arterial hypertension; pulmonary artery endothelial cell; pulmonary artery smooth muscle cell; pulmonary hypertension; single nucleotide polymorphism; transforming growth factor

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