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Epidemiology of Surfactant Protein-B Deficiency

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ClinicalTrials.gov Identifier: NCT00014859
Recruitment Status : Completed
First Posted : April 12, 2001
Last Update Posted : April 29, 2024
Sponsor:
Information provided by (Responsible Party):
F. Sessions Cole, MD, Washington University School of Medicine

Tracking Information
First Submitted Date April 11, 2001
First Posted Date April 12, 2001
Last Update Posted Date April 29, 2024
Actual Study Start Date June 1, 2001
Actual Primary Completion Date April 26, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 19, 2020)		 Statistical association of rare, functionally disruptive genomic variant with RDS [ Time Frame: 4 weeks ]
Using trio whole exome or whole genome sequencing, next generation sequencing, and in silico prediction of function, discover statistical associations between gene loci with excess, rare, functionally disruptive variants and risk of neonatal respiratory distress syndrome.
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures
 (submitted: July 19, 2020)		 Statistical associations between risk of neonatal respiratory distress syndrome and excess, rare functional variants in gene pathways [ Time Frame: 4 weeks ]
Using trio whole exome or whole genome sequencing, next generation sequencing, in silico prediction of functional variants, and Metacore for pathway construction, identify statistical associations between risk of neonatal respiratory distress syndrome and pathways with excess, rare functional variants
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Epidemiology of Surfactant Protein-B Deficiency
Official Title Epidemiology of Surfactant Protein-B Deficiency
Brief Summary The purpose of this study is to test the hypothesis that excess, rare, functionally disruptive single nucleotide polymorphisms (SNPs) characterize genes (e.g., the surfactant protein-B gene)(SFTPB) and gene networks (e.g., the pulmonary surfactant metabolic network or other gene networks that regulate alveolar type 2 cell function) associated with increased risk of neonatal respiratory distress syndrome (RDS).
Detailed Description

BACKGROUND:

Respiratory distress syndrome is the most frequent respiratory cause of death and morbidity in infants less than 1 year of age in the United States. Of approximately 28,500 infant deaths in 2006, 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. Despite improvement in infant mortality rates over the last 20 years, survivors of respiratory distress syndrome with chronic respiratory disease consume twenty times more annualized dollars than unaffected children and 5.9% of all dollars spent on children from 0-18 years of age. More recent estimates including data from California and New York, the Institute of Medicine, and the 2001 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project suggest that the average cost of hospitalization for each of the 49,900 infants with a diagnosis of respiratory distress syndrome was $56,800 vs. $10,700 for a premature infant without respiratory distress syndrome. The recent increase in late preterm births has contributed to both the frequency of respiratory distress syndrome and its economic impact. These medical costs do not include the economic consequences of infant respiratory morbidity for families, e.g., absence from work, and early intervention costs to optimize outcome. In addition, despite 2-3 fold greater risk of infant mortality for African American infants than European American infants from all other causes, European American infants have greater risk of death from respiratory distress than African American infants, and this increased risk is not attributable to differences in surfactant phospholipid composition, birth weight, gestational age, or confounding socioeconomic factors. Understanding the genetic mechanisms that cause respiratory distress syndrome is critical for improving outcomes of children in the United States, reducing costs of their health care, and reducing racial disparity in infant mortality. Since the original description of deficiency of the pulmonary surfactant in premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most commonly been attributed to developmental immaturity of pulmonary surfactant production. Despite improvement in neonatal survival associated with availability of surfactant replacement therapy for premature infants, gender and race based disparities in disease frequency, morbidity and mortality have persisted, an observation that suggests that genetic factors play an important role in disease pathogenesis. In addition, twin studies indicate high heritability (h2) of neonatal respiratory distress syndrome (0.2 and 0.8). Recent clinical reports of monogenic causes of neonatal respiratory distress syndrome, statistical association of candidate gene variants with increased disease risk, and studies of targeted gene ablation in murine lineages have also strongly suggested that genetic mechanisms contribute to risk of respiratory distress syndrome in newborn infants. When we examined genetic variants in large population-based and case-control cohorts, we found that the population-based frequencies of individual, disruptive mutations in 3 candidate genes (SFTPB, SFTPC, and ABCA3) (<2%) account for <0.1% of the population attributable risk in term or near term infants, and that individual, rare, disruptive mutations are not associated with disease in case-control cohorts. In addition, when we attempted to establish an association between an intermediate biochemical phenotype (surfactant protein-B peptide mobility on western blot) and SFTPB variants (assessed by complete resequencing) in term and near term infants with and without respiratory distress, we failed to identify a SFTPB variant or combination of variants associated with respiratory distress and altered surfactant protein-B structure. Finally, we have recently found that tagSNPs in genes from gene networks expressed in lung but not part of the pulmonary surfactant network (ion channel, lung remodeling, and unfolded protein response genes) confer race-specific risk of neonatal respiratory distress syndrome. These studies suggest that variation in SFTPB, SFTPC, and ABCA3 is under significant purifying selection pressure and that the genetic contribution to neonatal respiratory distress syndrome is based on contributions of rare, independent risk alleles in multiple genes and gene networks.

DESIGN NARRATIVE:

Rare mutations in the surfactant protein-B gene (SFTPB) and other genes in the pulmonary surfactant metabolic network cause lethal neonatal respiratory distress syndrome in human newborn infants by disrupting metabolism and function of the pulmonary surfactant. Mutation frequencies (<1-2%) in SFTPB and 2 other candidate genes in the pulmonary surfactant network (SFTPC and ABCA3) do not account for heritability of neonatal respiratory distress syndrome (h2~0.2-0.8) suggested by twin studies. To develop a comprehensive catalogue of genes and gene networks that account for the heritability of this complex disease, we propose to test the hypothesis that excess, rare, functionally disruptive single nucleotide polymorphisms (SNPs) characterize genes and gene networks associated with increased risk of neonatal respiratory distress syndrome. Specifically, using trio whole exome or whole genome sequencing of affected infant (progressive, severe respiratory distress in term or near term infants or children with unexplained interstitial lung disease or other rare lung phenotypes)/parent trios, we will identify de novo or recessively inherited pathogenic variants including single nucleotide variants, small insertions/deletions, and copy number or structural variants (>100 kb). To predict pathogenicity, we will use a suite of computational prediction algorithms (e.g., ANNOVAR, CADD). To confirm variants in genes and gene pathways not previously associated with human infant/child rare respiratory phenotypes, we will use GeneMatcher to identify other affected infants with pathogenic variants at the same gene locus or in the same gene pathway or functional testing of identified variants in a variety of cell-based jor model organism models. Using next-generation sequencing technology and state of the art statistical methods to elucidate the genetic complexity of neonatal respiratory distress syndrome and rare infant lung phenotypes will permit the development of personalized diagnostic tools and preventive therapeutic strategies for high risk infants and young children.
Study Type Observational [Patient Registry]
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration 4 Weeks
Biospecimen Retention:   Samples With DNA
Description:
DNA and tracheal aspirate samples
Sampling Method Non-Probability Sample
Study Population Cohort I is a population-based cohort from Missouri. Cohort II is a cohort of family trios (affected infant/child and parents) which may also include other unaffected or affected siblings from the Neonatal Intensive Care Unit at St. Louis Children's Hospital and from patients referred from other centers.
Condition
  • Lung Diseases
  • Respiratory Distress Syndrome, Newborn
  • Pulmonary Surfactant
  • Lung Diseases, Interstitial
Intervention Not Provided
Study Groups/Cohorts
  • Population-based cohort
    Descriptive cohort of population-based DNA samples from the newborn screening program in Missouri with vital statistics based, linked phenotype data
  • Trio sequencing cohort
    Affected infant/child (term or near term infant with progressive respiratory distress or other rare pulmonary phenotype or older child with interstitial lung disease or other rare pulmonary phenotype) and parents
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: April 26, 2024)		 5176
Original Enrollment Not Provided
Actual Study Completion Date April 26, 2024
Actual Primary Completion Date April 26, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Normal pulmonary function or a diagnosis of RDS

Exclusion Criteria:

  • None
Sex/Gender
Sexes Eligible for Study: All
Ages up to 1 Year   (Child)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT00014859
Other Study ID Numbers 967
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: All new variants will be deposited in public databases immediately after publication.
Current Responsible Party F. Sessions Cole, MD, Washington University School of Medicine
Original Responsible Party Not Provided
Current Study Sponsor Washington University School of Medicine
Original Study Sponsor National Heart, Lung, and Blood Institute (NHLBI)
Collaborators Not Provided
Investigators
Principal Investigator: F. Sessions Cole, MD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date April 2024