Pharmacogenomics in Pulmonary Arterial Hypertension

描述（由申请方提供）：我们的目标是在PAH患者中临床确定西他生坦和波生坦的疗效和毒性与几种关键疾病特异性和治疗特异性基因的几种基因多态性之间是否存在相关性。我们还将使用基线血流动力学或疾病严重程度的临床替代物来表征这些多态性与PAH严重程度之间的关系。假设：多态性通过其对PA重塑、药物反应或代谢的影响，影响特定PAH治疗的疗效和毒性以及PAH的发展/严重程度。该提案将利用大量明确定义的PAH患者人群，这些患者入组了几项大型临床试验，包括Encysive方案FPH 02、02 x、03和06以及来自四家大型PAH中心的前瞻性队列。患者总数约为920例，包括550例PPH患者。这项全球性的努力构成了对这种致命疾病的最大规模的临床研究，因此有很大的潜力通过揭示新的基因-药物相互作用来改变临床实践。我们将通过执行以下目的来测试该假设：目的1：确定PPH中已知疾病特异性多态性（血清素转运蛋白基因和派HindIII）与BMPR 2和SMAD 4中的变体之间的关系，以及西他生坦和波生坦治疗的几个明确定义的临床疗效终点。目标二：确定PAH中ET-1、ETAR、ETBR、NPR-c、前列环素受体和前列环素合酶基因中现有潜在“治疗特异性”多态性与西他生坦和波生坦治疗的几个确定的临床疗效终点之间的关系。 PAH =肺动脉高压 PA =肺动脉 PPH =原发性肺高压

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