Clinical trial NCT00091546: Genetic and Environmental Characteristics of Primary Pulmonary Hypertension
Official title: Genetic and Environmental Pathogenesis of PPH
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Lung Diseases
Hypertension, Pulmonary
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2004-09-13
Enrollment: 3000
Sex: ALL
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Database and specimen bank developed from 100 families affected by PPH

Brief summary: The goal of this study is to identify the modifying genes and environmental features that regulate the clinical expression of mutations in bone morphogenetic protein receptor 2 (BMPR2); to develop the understanding of how BMPR2 mutations result in disease; and to identify the undiscovered genetic mutations that cause primary pulmonary hypertension (PPH).

Detailed description: BACKGROUND:

PPH is a progressive disease that causes obstruction of the smallest arteries in the lungs, which often leads to heart failure. It threatens the lives of thousands of individuals. PPH affects both genders at any age, although females are affected twice as often as males. In a recent important advance, mutations in BMPR2 were associated with both familial and sporadic PPH. Because only 20% of people with a BMPR2 mutation ever develop PPH, other genes or modifying biologic events must contribute to the clinical development of the disease. PPH was recently renamed Idiopathic Pulmonary Arterial Hypertension or Familial Pulmonary Arterial Hypertension.

DESIGN NARRATIVE:

This study will utilize a database and specimen bank developed from 100 families affected by PPH across the United States. In families with genetic mutations not yet identified, changes in the BMPR2 gene will be studied, including in the promoter and intronic regions, and chance recombination events that could confirm another locus near 2q33 will be examined. New methods will look for modifier genes in large families with known mutations; examine kindreds for mitochondrial DNA haplotypes; and test candidate genes, including NOS-1, NOS-3, and the serotonin transporter. This study will determine the functional mechanisms by which variations found in the BMPR2 alleles alter BMP signal transduction by defining the biochemical effects of the mutant proteins on signaling pathways. In addition, the study will examine the perceived risks and benefits of clinical genetic testing and counseling in individuals from families at high risk for PPH and will determine how this new information might be most helpful to these individuals and their families.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of PPH, or family members of individuals diagnosed with PPH, for inclusion in the database and specimen bank

Primary outcomes:
measure: New development of pulmonary arterial hypertension (penetrance), age of onset, and survival
timeFrame: Measured through genetic analysis
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: James Loyd
role: STUDY_CHAIR
References:
citation: Cogan JD, Vnencak-Jones CL, Phillips JA 3rd, Lane KB, Wheeler LA, Robbins IM, Garrison G, Hedges LK, Loyd JE. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med. 2005 Mar;7(3):169-74. doi: 10.1097/01.gim.0000156525.09595.e9.
citation: Meyrick BO, Friedman DB, Billheimer DD, Cogan JD, Prince MA, Phillips JA 3rd, Loyd JE. Proteomics of transformed lymphocytes from a family with familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008 Jan 1;177(1):99-107. doi: 10.1164/rccm.200703-499OC. Epub 2007 Oct 11.
citation: Phillips JA 3rd, Poling JS, Phillips CA, Stanton KC, Austin ED, Cogan JD, Wheeler L, Yu C, Newman JH, Dietz HC, Loyd JE. Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet Med. 2008 May;10(5):359-65. doi: 10.1097/GIM.0b013e318172dcdf.
citation: Newman JH, Phillips JA 3rd, Loyd JE. Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med. 2008 Feb 19;148(4):278-83. doi: 10.7326/0003-4819-148-4-200802190-00006.
citation: Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, Stanton KC, Wheeler LA, Phillips JA 3rd, Loyd JE, Nichols WC. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006 Sep 1;174(5):590-8. doi: 10.1164/rccm.200602-165OC. Epub 2006 May 25.
citation: Johnson JA, Vnencak-Jones CL, Cogan JD, Loyd JE, West J. Copy-number variation in BMPR2 is not associated with the pathogenesis of pulmonary arterial hypertension. BMC Med Genet. 2009 Jun 16;10:58. doi: 10.1186/1471-2350-10-58.