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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL080033-01
Application #
6897388
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Denholm, Elizabeth M
Project Start
2005-05-10
Project End
2007-04-30
Budget Start
2005-05-10
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$153,917
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Platoshyn, Oleksandr; Brevnova, Elena E; Burg, Elyssa D et al. (2006) Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 290:C907-16
Fantozzi, Ivana; Huang, Wei; Zhang, Jifeng et al. (2005) Divergent effects of BMP-2 on gene expression in pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic pulmonary arterial hypertension. Exp Lung Res 31:783-806