Pharmacogenomics in Pulmonary Arterial Hypertension

描述（由申请人提供）：我们的目标是在临床中确定西塔森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基因多态性之间是否存在关联。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指标来表征这些多态性与PAH严重程度之间的关系。假设：多态性通过对PAH重塑、药物反应或代谢的影响，影响PAH特异性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，这些患者被纳入几个大型临床试验，包括Encysive方案FPH02, 02x， 03和06，以及来自四个大型PAH中心的前瞻性队列。患者总数约为920人，其中包括550名PPH患者。这项全球性的努力构成了对这种致命疾病的最大的临床研究，因此，通过揭示新的基因-药物相互作用，具有改变临床实践的巨大潜力。我们将通过执行以下目标来验证这一假设：目标1：确定PPH中已知的疾病特异性多态性（血清素转运蛋白基因和PAI hindll）与BMPR2和SMAD4变异之间的关系，并确定司他生坦和波生坦治疗的几个明确的临床疗效终点。目的2：确定在PAH中存在的潜在的“治疗特异性”多态性在ET-1、ETAR、ETBR、NPR-c、前列环素受体和前列环素合成酶基因与几个确定的西塔森坦和波生坦治疗的临床疗效终点之间的关系。

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