Pharmacogenomics in Pulmonary Arterial Hypertension

描述(由申请人提供)：我们的目标是在临床上确定西塔森坦和波生坦的疗效和毒性与几个关键的疾病特异性和治疗特异性基因中的几个基因多态之间是否存在关联。我们还将使用基线血流动力学或临床替代物来表征这些基因多态与PAH严重程度之间的关系。假设：基因多态性影响特定PAH治疗的疗效和毒性，以及PAH VIA的发展/严重程度，以及它们对PA重塑、药物反应或代谢的影响。这项建议将利用大量定义明确的PAH患者，他们参加了几项大型临床试验，包括Encysive方案FPH02、02x、03和06，以及来自四个大型PAH中心的预期队列。患者总数将约为920人，其中包括550名PPH患者。这一全球范围内的努力构成了这种致命疾病最大的临床研究，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检验这一假设：目标1：确定PPH中已知的疾病特异性基因(Serotorin Transporter基因和PAI Hind11)和BMPR2和Smad4变异与西塔森坦和波生坦治疗几个明确的临床疗效终点之间的关系。目的：确定帕金森病患者ET-1、ETAR、ETBR、NPR-c、前列环素受体和前列环素合成酶基因潜在的“治疗特异性”多态与西塔森坦和波生坦治疗的临床疗效终点之间的关系。 PAH=肺动脉高压 PA=肺动脉 PPH=原发性肺动脉高压

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