Two Polymorphic Gene Loci Associated with Treprostinil Dose in Pulmonary Arterial Hypertension
| Autor: | V. Thomeas-McEwing, Mark J. Ratain, Eric R. Gamazon, Yusuke Nakamura, Raymond L. Benza, M.A. Psotka, T. Hirota, Mardi Gomberg-Maitland, Michiaki Kubo, P.N. Friedman, Nancy J. Cox, Michael L. Maitland, Anuar Konkashbaev |
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| Rok vydání: | 2019 |
| Předmět: |
Pulmonary and Respiratory Medicine
Transplantation Candidate gene business.industry medicine.medical_treatment Diastole Genome-wide association study Prostacyclin Pharmacology Pathogenesis medicine Surgery Gene polymorphism Cardiology and Cardiovascular Medicine business Cardiac catheterization medicine.drug Treprostinil |
| Zdroj: | The Journal of Heart and Lung Transplantation. 38:S208 |
| ISSN: | 1053-2498 |
| Popis: | Purpose Prostacyclin infusion is an effective therapy for pulmonary arterial hypertension (PAH) but has variable clinical response and dosing requirements. We performed a genome-wide association study (GWAS) to identify biologically-based predictors of prostacyclin response heterogeneity and gene variants associated with PAH pathogenesis . Methods Ninety-eight patients with hemodynamically-defined PAH treated at two academic centers were included. Stably dosed treprostinil therapy was the quantitative phenotype for the GWAS. Candidate genes with the largest effect sizes and strongest statistical associations were further characterized in silico and in vitro to confirm mechanistic hypotheses, and at cardiac catheterization to assess for mechanistically consistent physiological effects. Results Three loci associated with treprostinil dose with P encoded sequence changes with predictable consequences. Production of the prostacyclin-induced pulmonary vasodilator cyclic adenosine monophosphate was reduced in human cell lines by the missense variant rs11078738. The allele of rs10023113 in the promoter of CAMK2D associated with higher treprostinil dose, conferred a reduced affinity for the FOXP1 transcriptional repressor , was associated with increased expression of CAMKIIδ in ventricular tissue, and was associated with elevated right mean atrial and ventricular diastolic pressures in a separate cohort of patients at cardiac catheterization. Conclusion The conduct of effective GWAS is challenging with small numbers of patients. However, by employing the quantitative phenotype of stable treprostinil dose we identified 2 novel loci for treatment response in PAH, gene variants associated with more severe right ventricular dysfunction and higher ultimate dose of treprostinil. Work is ongoing to further characterize these variants. |
| Databáze: | OpenAIRE |
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