The long-term goal of this training program is to develop scientific expertise in and new understanding of the pathophysiology of pulmonary vascular diseases such as Hepatopulmonary syndrome (HPS). The specific goal is to examine a mechanistic hypothesis for the etiology of HPS using state-of-the-art genetic/genomic approaches. HPS, the triad of liver disease, intrapulmonary vascular dilatations and increased alveolar- arterial oxygen gradient, affects 25% of patients with advanced liver disease. There are no medical therapies for HPS;presence of HPS portends a worse survival for patients with advanced liver disease, with or without liver transplantation. Recent evidence from animal and human HPS implicates abnormal heme oxygenase and carbon monoxide signaling in the disease process. We hypothesize that genetic variation in heme oxygenase determines individual pulmonary vascular response to cirrhosis. SA1: To determine whether common genetic variation in HO1 and HO2 is associated with HPS. SA2: To define rare (1-10%) genetic variation in conserved segments of the H01 promoter using denaturing high pressure liquid chromatography, and then examine the association of this variation with HPS. SA3: To identify novel genetic loci associated with HPS using a genome-wide analysis of copy number polymorphisms. SA4: To assess the association between HO genotype and outcome in advanced liver disease. Using a case-control design, and 364 patients with advanced liver disease prospectively recruited to partipate in the Pulmonary Complications of Liver Disease study, we will perform a genetic association study looking at the outcomes of case status (primary) and measures of CO production and oxygenation (secondary) as a function of genotype. Chronic liver disease is the 12th leading cause of death in the United States. The vast majority of patient deaths are due to the complications of portal hypertension including HPS. Identification of genetic determinants of HPS will provide novel therapeutic targets, and improved diagnostic and prognostic assessment for patients. The results of this investigation will also provide insight to the genetic epidemiology of known and cryptic polymorphisms in heme oxygenase, an enzyme implicated in the the pathogenesis of numerous disorders including pulmonary hypertension, asthma and ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL089812-05
Application #
8269996
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$128,790
Indirect Cost
$9,540
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Sadoughi, Ali; Roberts, Kari E; Preston, Ioana R et al. (2013) Use of selective serotonin reuptake inhibitors and outcomes in pulmonary arterial hypertension. Chest 144:531-41
Roberts, Kari E; Kawut, Steven M; Krowka, Michael J et al. (2010) Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease. Gastroenterology 139:130-9.e24
Roberts, Kari E; Fallon, Michael B; Krowka, Michael J et al. (2009) Serotonin transporter polymorphisms in patients with portopulmonary hypertension. Chest 135:1470-5