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Sponsored by: |
National Heart, Lung, and Blood Institute (NHLBI) |
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Information provided by: | National Heart, Lung, and Blood Institute (NHLBI) |
ClinicalTrials.gov Identifier: | NCT00014859 |
The purpose of this study is to determine the impact of genetic variation in the surfactant protein B gene and other genes in the pulmonary surfactant metabolic pathway on the risk of respiratory distress syndrome (RDS) in infancy.
Condition |
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Lung Diseases Respiratory Distress Syndrome, Newborn |
Study Type: | Observational |
Study Design: | Case Control, Prospective |
Official Title: | Epidemiology of Surfactant Protein-B Deficiency |
DNA and tracheal aspirate samples
Estimated Enrollment: | 1747 |
Study Start Date: | June 2001 |
Estimated Study Completion Date: | June 2012 |
Estimated Primary Completion Date: | June 2012 (Final data collection date for primary outcome measure) |
Groups/Cohorts |
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I
Descriptive cohort of population-based DNA samples from the newborn screening program in Missouri with vital statistics based, linked phenotype data
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II
Case-control cohort of infants with and without neonatal respiratory distress syndrome
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BACKGROUND:
Respiratory distress syndrome (RDS) is the most frequent respiratory cause of death and morbidity in infants less than 1 year of age in the United States. Of approximately 28,000 infant deaths in 2001, 5,421 (19.7%) were diagnosed with respiratory distress as either the primary (1,011 - 3.7%) or secondary (4,410 - 16%) cause of death. Understanding the underlying mechanisms that lead to RDS is crucial for improving outcomes and reducing health care costs associated with RDS. Dr. Cole and his colleagues were the first to identify a gene mutation in the pulmonary surfactant B gene (121ins2) as a cause of RDS. The alteration produces a truncated, unstable transcript but no protein is synthesized. More recently this group used the Missouri linked birth-death database and the New York birth cohort to estimate population-based 121ins2 allele frequency. Approximately 1 per 1-3,000 individuals carry the mutation; the mutant gene appears to be codominant at the molecular level (heterozygotes express subnormal levels of surfactant B), but recessive at the clinical level. No known clinical phenotype exists for heterozygotes. The current study examines the interaction between variation in the surfactant protein B gene and a second critical surfactant gene, surfactant protein C. This study should lead to identification of clinically useful markers of genetic risk and a more rational design of treatment for lethal as well as non-lethal RDS.
DESIGN NARRATIVE:
Surfactant protein B deficiency due to rare, homozygous, loss of function mutations in the surfactant protein B gene (SFTPB) invariably causes lethal, neonatal respiratory distress syndrome. Non lethal genetic variants do not account for all changes in expression of surfactant protein B peptides in symptomatic infants. Disruption of SFTPB expression may also be caused by genetic variants in the surfactant protein C gene (SFTPC). Human and murine studies have demonstrated tight linkage between the biosynthetic itineraries, post-translational processing, and functions in the pulmonary surfactant of surfactant proteins B and C. Misfolded or mistargeted surfactant protein C peptides encoded by dominant negative mutations trigger the unfolded protein response in type 2 pneumocytes by formation of intracellular aggregates and/or retention in the endoplasmic reticulum, disrupt intracellular trafficking of the pulmonary surfactant, and interrupt surfactant protein B secretion. To determine the contribution of genetic variation in SFTPC to risk of surfactant protein B deficiency, we will test the hypothesis that gene - gene interactions between SFTPB and SFTPC increase risk of neonatal respiratory distress. To avoid extrapolation from small patient groups that may exaggerate or underestimate frequency estimates of rare genetic variants due to ethnic stratification, environmental selection, or genotype-phenotype heterogeneity, we have designed descriptive and case-control studies of symptomatic and asymptomatic infants that will provide sufficient statistical power (0.8) to identify combinations of variants and haplotypes in SFTPB and SFTPC associated with neonatal respiratory distress syndrome. Specifically, in the descriptive study, using high throughput automated sequencing of SFTPB and SFTPC and linked vital statistics-based phenotype data, we will determine associations between genotypes or haplotypes and neonatal respiratory distress in an unselected, de-identified, population-based cohort of Missouri infants (N=1,116). In the case-control study (N=480), using automated sequencing of SFTPB and SFTPC and both clinical and biochemical phenotype data, we will determine whether gene-gene interactions reduce or alter surfactant protein B expression. These studies will suggest new strategies for diagnosis and treatment of neonatal respiratory distress syndrome to improve infant outcomes.
Ages Eligible for Study: | up to 1 Year |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
Sampling Method: | Non-Probability Sample |
Cohort I is a population-based cohort from Missouri. Cohort II is a case-control cohort from the Neonatal Intensive Care Unit at St. Louis Children's Hospital and from patients referred from other centers.
Inclusion Criteria:
Exclusion Criteria:
United States, Missouri | |
Washington University School of Medicine | Recruiting |
St. Louis, Missouri, United States, 63110 | |
Contact: F. Sessions Cole, MD 314-454-6148 cole@kids.wustl.edu |
Principal Investigator: | F. Sessions Cole, MD | Washington University, St. Louis |
Responsible Party: | Washington University School of Medicine ( F. Sessions Cole, MD ) |
Study ID Numbers: | 967, R01 HL65174 |
Study First Received: | April 11, 2001 |
Last Updated: | July 28, 2008 |
ClinicalTrials.gov Identifier: | NCT00014859 |
Health Authority: | United States: Federal Government |
Pulmonary surfactant Surfactant protein B Surfactant protein C |
Protein C Respiratory Tract Diseases Lung Diseases Respiration Disorders Respiratory Distress Syndrome, Adult |
Respiratory Distress Syndrome, Newborn Infant, Newborn, Diseases Acute respiratory distress syndrome Infant, Premature, Diseases |
Pathologic Processes Disease Syndrome |