Genetics and Genomics of Pulmonary Arterial Hypertension

Rajiv D. Machado, Oliver Eickelberg, C. Gregory Elliott, Mark W. Geraci, Masayuki Hanaoka, James E. Loyd, John H. Newman, John A. Phillips, Florent Soubrier, Richard C. Trembath, Wendy K. Chung

Research output: Contribution to journalArticle

244 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalJournal of the American College of Cardiology
Volume54
Issue number1 SUPPL. 1
DOIs
StatePublished - Jun 30 2009
Externally publishedYes

Fingerprint

Type II Bone Morphogenetic Protein Receptors
Genomics
Pulmonary Hypertension
Mutation
Genes
Penetrance
Biomarkers
Hereditary Hemorrhagic Telangiectasia
Fenfluramine
Activins
Genome-Wide Association Study
Genetic Counseling
Transforming Growth Factors
Genetic Predisposition to Disease
Pharmaceutical Preparations
Disease Progression
Heart Diseases
Phosphotransferases
hydralazine 4-anisaldehyde hydrazone
Technology

Keywords

  • ALK-1
  • BMPR2
  • ENG
  • genetic
  • incomplete penetrance
  • pulmonary hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Machado, R. D., Eickelberg, O., Elliott, C. G., Geraci, M. W., Hanaoka, M., Loyd, J. E., ... Chung, W. K. (2009). Genetics and Genomics of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology, 54(1 SUPPL. 1). https://doi.org/10.1016/j.jacc.2009.04.015

Genetics and Genomics of Pulmonary Arterial Hypertension. / Machado, Rajiv D.; Eickelberg, Oliver; Elliott, C. Gregory; Geraci, Mark W.; Hanaoka, Masayuki; Loyd, James E.; Newman, John H.; Phillips, John A.; Soubrier, Florent; Trembath, Richard C.; Chung, Wendy K.

In: Journal of the American College of Cardiology, Vol. 54, No. 1 SUPPL. 1, 30.06.2009.

Research output: Contribution to journalArticle

Machado, RD, Eickelberg, O, Elliott, CG, Geraci, MW, Hanaoka, M, Loyd, JE, Newman, JH, Phillips, JA, Soubrier, F, Trembath, RC & Chung, WK 2009, 'Genetics and Genomics of Pulmonary Arterial Hypertension', Journal of the American College of Cardiology, vol. 54, no. 1 SUPPL. 1. https://doi.org/10.1016/j.jacc.2009.04.015
Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE et al. Genetics and Genomics of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. 2009 Jun 30;54(1 SUPPL. 1). https://doi.org/10.1016/j.jacc.2009.04.015
Machado, Rajiv D. ; Eickelberg, Oliver ; Elliott, C. Gregory ; Geraci, Mark W. ; Hanaoka, Masayuki ; Loyd, James E. ; Newman, John H. ; Phillips, John A. ; Soubrier, Florent ; Trembath, Richard C. ; Chung, Wendy K. / Genetics and Genomics of Pulmonary Arterial Hypertension. In: Journal of the American College of Cardiology. 2009 ; Vol. 54, No. 1 SUPPL. 1.
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