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Genetic basis of pulmonary arterial hypertension

Current understanding and future directions

John H. Newman, MD^*,*, Richard C. Trembath, MD, Jane A. Morse, MD, Ekkehard Grunig, MD, James E. Loyd, MD^*, Serge Adnot, MD^||, Fabio Coccolo, MD^¶, Carlo Ventura, MD, PhD^¶, John A. Phillips, III, MD^*, James A. Knowles, PhD, Bart Janssen, PhD, Oliver Eickelberg, MD^**, Saadia Eddahibi, PhD^||, Phillipe Herve, PhD, William C. Nichols, PhD and Gregory Elliott, MD

^* Vanderbilt University School of Medicine, Nashville, Tennessee, United Kingdom
Department of Medicine and Genetics, University of Leicester, Leicester, United Kingdom
Columbia University College of Physicians and Surgeons, New York, New York, USA
Heidelberg University, Heidelberg, Germany
^|| Hopital Henri Mondor, Creteil, France
^¶ University of Bologna, Bologna, Italy
^** Giessen University School of Medicine, Giessen, Germany
University Paris Sud, Paris, France
University of Cincinatti Medical School, Cincinatti, Ohio, USA
University of Utah School of Medicine, Salt Lake City, Utah, USA

Manuscript received December 16, 2003; accepted February 3, 2004.

^* Reprint requests and correspondence: Dr. John H. Newman, Division of Pulmonary and Critical Care Medicine, T 1219 Vanderbilt University Medical Center North, Nashville, Tennessee, United Kingdom 37220-2650.
John.Newman{at}med.va.gov

Mutations in two receptors of the transforming growth factor-beta family have recently been shown to be present in the majority of cases of inherited (familial) pulmonary arterial hypertension (PAH). Study of the biology of these receptors, bone morphogenetic protein receptor type-2 (BMPR2), and activin-like kinase type-1 (ALK-1) will certainly reveal pathogenic mechanisms of disease. Exonic mutations in BMPR2 are found in about 50% of patients with familial PAH, and ALK1 mutations are found in a minority of patients with hereditary hemorrhagic telangiectasia and co-existent PAH. Because familial PAH is highly linked to chromosome 2q33, it is likely that the remaining 50% of family cases without exonic mutations have either intronic BMPR2 abnormalities or alterations in the promoter or regulatory genes. Also, only about 10% of patients with "sporadic" idiopathic PAH have identifiable BMPR2 mutations. Mutations in BMPR2 confer a 15% to 20% chance of developing PAH in a carrier's lifetime. Thus, there must be gene-gene or gene-environment interactions that either enhance or prevent the development of the vascular disease in persons carrying a mutation, and there must be other patterns of susceptibility based on genetic makeup. To elucidate the genetic basis of PAH further, investigations are needed, including genome scanning for major and minor genes, analysis of genetic profiles of patients for candidate genes likely to modify risk for disease (e.g., serotonin transporter alleles, nitric oxide-synthases), proteomics, transgenic mice, and altered signal transduction. Advances in genetic testing, presymptomatic screening, and biomarkers should permit early detection of disease in those at risk of PAH and allow trials of preventive therapy in carriers.

Abbreviations and Acronyms   ALK1 = activin-like kinase type-1   BMPR2 = bone morphogenetic protein receptor type-2   HHT = hereditary hemorrhagic telangiectasia   PAH = pulmonary arterial hypertension   PASP = pulmonary artery systolic pressure   PPH = primary pulmonary hypertension (now termed idiopathic PAH)   TGF = transforming growth factor

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