title: Genetic basis of pulmonary arterial hypertension: current understanding and future directions.
abstract: 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.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee, United Kingdom. John.Newman@med.va.gov
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Jane A
authors.initials: JA
authors.lastname: Morse
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grunig
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
authors.forename: Fabio
authors.initials: F
authors.lastname: Coccolo
authors.forename: Carlo
authors.initials: C
authors.lastname: Ventura
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.forename: Bart
authors.initials: B
authors.lastname: Janssen
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.forename: Phillipe
authors.initials: P
authors.lastname: Herve
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Gregory
authors.initials: G
authors.lastname: Elliott
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II; D005544:Forecasting; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000639:trends; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011651:Pulmonary Artery / Q000473:pathology*; D012307:Risk Factors
chemical_list: D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II