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STATE-OF-THE-ART PAPER

Genetics and Genomics of Pulmonary Arterial Hypertension

Rajiv D. Machado, PhD^_*,_*, Oliver Eickelberg, MD, C. Gregory Elliott, MD, Mark W. Geraci, MD, Masayuki Hanaoka, MD, PhD^||, James E. Loyd, MD^¶, John H. Newman, MD^¶, John A. Phillips, III, MD^#, Florent Soubrier, MD, PhD^_**, Richard C. Trembath, BSc^_* and Wendy K. Chung, MD, PhD

^_* Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom
Comprehensive Pneumology Center, Ludwig-Maximilians-Universität, Asklepios Klinik Gauting und Helmholtz Zentrum München, and Institute of Lung Biology and Disease (iLBD), Helmholtz Zentrum München, Munich, Germany
Departments of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, Utah
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado
^|| First Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
^¶ Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
^# Department of Pediatrics and Division of Medical Genetics, Vanderbilt University School of Medicine, Nashville, Tennessee
^_** Faculté de Medicine, Université Paris 6, Hôpital Pitié-Salpêtrière, Paris, France
Departments of Pediatrics and Medicine, Columbia University College of Physicians & Surgeons, New York, New York

Manuscript received February 6, 2009; accepted April 15, 2009.

^_* Reprint requests and correspondence: Dr. Rajiv D. Machado, Department of Medical and Molecular Genetics, King's College London School of Medicine, 9th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, United Kingdom (Email: rajiv.machado{at}genetics.kcl.ac.uk).

Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, 2 other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 (ALK1) and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. We provide a summary of BMPR2 mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.

Key Words: pulmonary hypertension • BMPR2 • genetic • ALK-1 • ENG • incomplete penetrance

Abbreviations and Acronyms   ALK1 = activin-like kinase type 1   BMPR2 = bone morphogenetic protein receptor type 2   ENG = endoglin   GRR = genotypic relative risk   GWA = genome-wide association   HHT = hereditary hemorrhagic telangiectasia   HPAH = heritable pulmonary arterial hypertension   IPAH = idiopathic pulmonary arterial hypertension   PAH = pulmonary arterial hypertension   TGF = transforming growth factor

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