Genetic and Environmental Characteristics of Primary Pulmonary Hypertension

NCT ID: NCT00091546

Last Updated: 2016-02-02

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 3000 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2003-08-31
• Study Completion Date: 2009-07-31

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.

Conditions

Lung Diseases; Hypertension, Pulmonary

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Eligibility Criteria

Inclusion Criteria

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

• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Jim Loyd

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

James Loyd

Role: STUDY_CHAIR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 15775752 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17932379 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18496036 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18283205 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16728714 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 19531247 (View on PubMed)

Other Identifiers

P01HL072058

Identifier Type: NIH

Identifier Source: secondary_id

View Link

166

Identifier Type: -

Identifier Source: org_study_id