RGD Reference Report - Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension. - Rat Genome Database

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Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension.

Authors: Stearman, Robert S  Cornelius, Amber R  Lu, Xiao  Conklin, David S  Del Rosario, Mark J  Lowe, Anita M  Elos, Mihret T  Fettig, Lynsey M  Wong, Randall E  Hara, Naoko  Cogan, Joy D  Phillips, John A  Taylor, Matthew R  Graham, Brian B  Tuder, Rubin M  Loyd, James E  Geraci, Mark W 
Citation: Stearman RS, etal., Am J Respir Crit Care Med. 2014 May 1;189(9):1110-20. doi: 10.1164/rccm.201309-1697OC.
RGD ID: 401959406
Pubmed: PMID:24605778   (View Abstract at PubMed)
PMCID: PMC4098107   (View Article at PubMed Central)
DOI: DOI:10.1164/rccm.201309-1697OC   (Journal Full-text)


RATIONALE: 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.
OBJECTIVES: 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.
METHODS: 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.
MEASUREMENTS AND MAIN RESULTS: 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.
CONCLUSIONS: 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanPulmonary Arterial Hypertension susceptibilityIAGP DNA:repeat more ...RGD 
PtgisRatPulmonary Arterial Hypertension susceptibilityISOPTGIS (Homo sapiens)DNA:repeat more ...RGD 
PtgisMousePulmonary Arterial Hypertension susceptibilityISOPTGIS (Homo sapiens)DNA:repeat more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTGISHumanPulmonary arterial hypertension susceptibilityIAGP DNA:repeat more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ptgis  (prostaglandin I2 synthase)

Genes (Mus musculus)
Ptgis  (prostaglandin I2 (prostacyclin) synthase)

Genes (Homo sapiens)
PTGIS  (prostaglandin I2 synthase)


Additional Information