Functional Prostacyclin Synthase Promoter Polymorphisms: Impact in Pulmonary Arterial Hypertension

• Published in: American journal of respiratory and critical care medicine 2014-05, Vol.189 (9), p.1110-1120
• Main Authors: STEARMAN, Robert S, CORNELIUS, Amber R, COGAN, Joy D, PHILLIPS, John A, TAYLOR, Matthew R, GRAHAM, Brian B, TUDER, Rubin M, LOYD, James E, GERACI, Mark W, XIAO LU, CONKLIN, David S, DEL ROSARIO, Mark J, LOWE, Anita M, ELOS, Mihret T, FETTIG, Lynsey M, WONG, Randall E, HARA, Naoko
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone Morphogenetic Protein Receptors, Type II - genetics; Case-Control Studies; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - physiology; Disease; Disease Progression; Familial Primary Pulmonary Hypertension; Female; Genetic testing; Haplotypes; Heterozygote; Humans; Hypertension, Pulmonary - genetics; Intensive care medicine; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - physiology; Kinases; Male; Medical sciences; Mutation; Original; Pneumology; Polymerase Chain Reaction; Polymorphism; Polymorphism, Genetic; Proteins; Pulmonary arteries; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Reporters; Veins & arteries
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201309-1697oc

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers. To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations. Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes' transcriptional activities were determined with luciferase reporter assays. We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype. Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH.