Abstract 2299: The Endothelin Receptor, Type A, Promoter Region -231 G/A Polymorphism Influences Pulmonary Arterial Hypertension Disease Presentation
Background: Endothelin receptor, type A (ETRA) mediates development of pulmonary arterial hypertension (PAH). The ETRA promoter region -231 G/A polymorphism has been linked to increased pulmonary artery (PA) pressures in PAH, but its role in disease progression is still uncharacterized. This genetic analysis explores the role of the ETRA -231 G/A polymorphism on disease progression and development of PAH symptoms.
Methods: Genotyping of the ETRA -231 G/A polymorphism was performed on 89 PAH patients enrolled in a genetic database. Onset of PAH symptoms, hemodynamic measurements, PAH therapy, and age at death or lung/heart-lung transplant were compared by genotype groups (AA, AG, GG) using Pearsons’ Chi square for non-continuous variables and ANOVA method for continuous variables.
Results: Overall, the percent distribution for the ETRA genotype was AA/AG/GG = 23.6/49.4/27.0. The cohort was 67% female, 93% Caucasion, 35% idiopathic or familial PAH, and 34% PAH associated with connective tissue disease. Use of bosentan (p=0.254) and prostanoid (p=0.441) therapy was similar amongst genotype groups. The most common symptoms were: dyspnea (97%), fatigue (73%), palpitation (50%), dizziness (45%), chest pain (45%), and syncope (14%). The AA genotype was associated with earlier symptom onset by age in years, AA=41±14, AG=48±14, GG=53±14, p=0.008, lower PA saturation, AA=58%, AG=64%, GG=65%, p=0.049, and higher pulmonary vascular resistance indices (mmHg·min·m2/L), AA=25.0±15.5, AG=15.6±7.4, GG=15.0±7.6, p=0.014. Despite differences in phenotype severity, survival was not statistically different amongst genotype groups possibly due to the small number of events (N=25).
Conclusion: The ETRA -231 AA genotype is associated with an earlier onset of PAH symptoms and a more severe PAH phenotype reflected by lower PA saturation and higher pulmonary vascular resistance. Future investigation is necessary to determine if an interaction between endothelin receptor antagonist therapy and the ETRA -231 G/A polymorphism further influences PAH disease progression and outcome.