SNPs in Idopathic Pulmonary Artierial Hypertension

特发性肺动脉高压（IPAH）是一种致命性疾病。在该病的发展过程中已证实多因素病因学。骨形态发生蛋白（BMP）受体II型（BMPR-II）基因（BMPR2）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BMPR2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。本R21应用程序旨在验证以下假设：a)其他基因（如KCNA5 （K+通道）、ANGPT1（血管生成素-1）、TRPC6 （Ca2+通道）、HTR2B （5-HT受体）和SLC6A4 （5-HT转运体）在伴有或不伴有BMPR2突变的IPAH患者中存在特异性单核苷酸多态性（snp）； b） IPAH患者肺动脉高压的严重程度与含有IPAH特异性snp的基因数量有关。我们提出以下两个具体目标：1)揭示新颖

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.