Functional Prostacyclin Synthase Promoter Polymorphisms: Impact in Pulmonary Arterial Hypertension

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 recept...

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Published in:	American journal of respiratory and critical care medicine Vol. 189; no. 9; pp. 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:	Journal Article
Language:	English
Published:	New York, NY American Thoracic Society 01-05-2014
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 Lung disease lung diseases Intensive care Intramolecular oxidoreductases Enzyme Respiratory disease Cardiovascular disease Prostaglandin-I synthase Genetic determinism Artery Pulmonary hypertension Genetic disease Promoter Isomerases Predisposition Genetics genetic predisposition to disease genetic polymorphism Resuscitation Polymorphism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current affiliations: A.R.C., Division Infectious Disease and Immunology, Department of Medicine, School of Medicine, New York University, New York, New York; X.L., Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania; D.S.C., Wake Forest University School of Medicine, Winston-Salem, North Carolina; M.J.D.R., Department of Internal Medicine, Banner Good Samaritan Medical Center, Phoenix, Arizona; A.M.L., Stanford University School of Medicine, Stanford, California.
ISSN:	1073-449X 1535-4970
DOI:	10.1164/rccm.201309-1697oc