Pharmacogenomics in Pulmonary Arterial Hypertension

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DESCRIPTION (provided by applicant): Our goal is to determine clinically in PAH patients if associations exist between the efficacy and toxicity of sitaxsentan and bosentan and several gene polymorphisms in several key disease-specific and therapy specific genes. We will also characterize the relationship between these polymorphisms and PAH severity using either baseline hemodynamic or clinical surrogates for disease severity. Hypothesis: Polymorphisms influence the efficacy and toxicity of specific PAH therapy as well as development/severity of PAH via, their effect on PA remodeling, drug response or metabolism. This proposal will make use of a large population of well defined patients with PAH who were enrolled in several large clinical trials including Encysive protocols FPH02, 02x, 03 and 06 and a prospective cohort from four large PAH Centers. The sum total number of patients will be approximately 920, including 550 with PPH. This worldwide effort constitutes the largest clinical study of this deadly disease and in as such has great potential to alter clinical practice by revealing novel gene-drug interactions. We will test this hypothesis by executing the following Aims: Aim 1: Determine in PPH the relationship between known disease-specific polymorphisms (Serotorin transporter gene and PAI Hindlll) and variants in BMPR2 and SMAD4 with several well defined clinical efficacy endpoints of sitaxsentan and bosentan therapy. Aim 2: Determine in PAH the relationship between existing potentially "therapy-specific" polymorphism in the ET-1, ETAR, ETBR, NPR-c, prostacyclin receptor and prostacyclin synthase genes with several defined clinical efficacy endpoints of sitaxsentan and bosentan therapy. PAH = pulmonary arterial hypertension PA = pulmonary artery PPH = primary pulmonary hypertension