SNPs in Idopathic Pulmonary Artierial Hypertension

特发性肺动脉高压（IPAH）是一种致死性疾病。多因素病因已被证明在疾病的发展。骨形态发生蛋白（BMP）II型受体（BMPR-II）基因（BMPR 2）的突变已被证明是家族性PAH的遗传基础和IPAH的获得性缺陷。由于BMPR 2突变仅涉及不到25%的IPAH人群，因此IPAH的发展可能需要其他基因突变或缺陷。该R21应用被提出来检验以下假设：a）在其他基因中的特定单核苷酸多态性（SNP），例如KCNA 5（K+通道），ANGPT 1（血管生成素-1），TRPC 6（Ca 2+通道），HTR 2B（5-HT受体）和SLC 6A 4（5-HT转运蛋白），存在于有或无BMPR 2突变的IPAH患者中，和B）IPAH患者中肺动脉高压的严重程度与含有IPAH特异性SNP的基因的数量有关。我们提出以下两个具体目标：1）揭示小说 候选基因（BMPR 2、KCNA 5、ANGPT 1、TRPC 6、HTR 2B和SLC 6A 4）中的SNP用于IPAH的发展，并确定这些SNP是否与IPAH相关;以及2）确定BMPR 2中的SNP/突变是否独立地或依赖于其他基因中的SNP而有助于IPAH的发展，并确定这些基因座处的SNP是否相互作用以有助于肺动脉高压的严重程度。我们目前有来自340名IPAH患者的DNA样本和血流动力学数据，这些患者是根据NIH登记处建立的原发性肺动脉高压标准诊断的。此外，我们还有来自70多名血压正常患者和90名血栓栓塞性PAH患者的DNA样本。这项研究将使我们能够在其他与IPAH发生相关的基因中鉴定新的或IPAH特异性的SNPs，并确认多个基因的组合是否会导致IPAH的发生。 突变与IPAH患者肺动脉高压的严重程度相关。

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease. Multifactorial etiology has been demonstrated in the development of the disease. Mutations of the bone morphogenetic protein (BMP) receptor type II (BMPR-II) gene (BMPR2) have been shown to be a genetic basis for familial PAH and an acquired defect for IPAH. Since BMPR2 mutations have only been implicated in less than 25% of the IPAH population, other gene mutations or defects may be required for the development of IPAH. This R21 application is proposed to test the hypothesis that a) specific single nucleotide polymorphysisms (SNPs) in other genes, such as KCNA5 (K+ channel), ANGPT1 (angiopoietin-1), TRPC6 (Ca2+ channel), HTR2B (5-HT receptor) and SLC6A4 (5-HT transporter), are present in IPAH patients with or without BMPR2 mutations, and b) the severity of pulmonary hypertension in IPAH patients is related to the number of genes that contain the IPAH-specific SNPs. We propose the following two specific aims: 1) to reveal novel SNPs in candidate genes (BMPR2, KCNA5, ANGPT1, TRPC6, HTR2B and SLC6A4) for the development of IPAH, and to determine whether these SNPs are associated with IPAH; and 2) to determine whether SNPs/mutations in BMPR2 contribute to the development of IPAH independently or dependency with SNPs in other genes and to determine whether SNPs at these loci interact to contribute to the severity of pulmonary hypertension. We currently have DNA samples and hemodynamic data from 340 IPAH patients, who were diagnosed based on criteria established by the NIH Registry for Primary Pulmonary Hypertension. In addition, we also have DNA samples from more than 70 normotensive patients and 90 patients with thromboembolic PAH. This study will allow us to identify new or IPAH-specific SNPs in other genes that are related to the development of IPAH and confirm whether combination of multiple gene mutations associates with the severity of pulmonary hypertension in IPAH patients.