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Epidemiology of Surfactant Protein-B Deficiency

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by F. Sessions Cole, MD, Washington University School of Medicine
Information provided by (Responsible Party):
F. Sessions Cole, MD, Washington University School of Medicine Identifier:
First received: April 11, 2001
Last updated: June 1, 2015
Last verified: June 2015
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) associated with increased risk of neonatal respiratory distress syndrome (RDS).

Lung Diseases
Respiratory Distress Syndrome, Newborn
Pulmonary Surfactants

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Target Follow-Up Duration: 4 Weeks
Official Title: Epidemiology of Surfactant Protein-B Deficiency

Resource links provided by NLM:

Further study details as provided by F. Sessions Cole, MD, Washington University School of Medicine:

Primary Outcome Measures:
  • Statistical association of rare, functionally disruptive genomic variant with RDS [ Time Frame: 4 weeks ]
    Using custom exon capture, 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.

Secondary Outcome Measures:
  • Statistical associations between risk of neonatal respiratory distress syndrome and excess, rare functional variants in gene pathways [ Time Frame: 4 weeks ]
    Using custom exon capture, 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

Biospecimen Retention:   Samples With DNA
DNA and tracheal aspirate samples

Estimated Enrollment: 5000
Study Start Date: June 2001
Estimated Study Completion Date: June 2019
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Descriptive cohort of population-based DNA samples from the newborn screening program in Missouri with vital statistics based, linked phenotype data
Case-control cohort of infants with and without neonatal respiratory distress syndrome

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Detailed Description:


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.


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 an agnostic candidate gene identification algorithm and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, we will select a comprehensive list of genes (~2,000) and their cognate gene networks expressed in human lung. Next, to identify a subgroup of genes (N=250) and gene networks with excess, rare, disruptive exonic SNPs associated with neonatal respiratory distress syndrome, we will use hybridization selection/exon capture, next-generation sequencing technology, and new statistical strategies (e.g., Combined Multivariate and Collapsing (CMC) method) in a case-control cohort (N=250 cases, 250 controls) sized to provide adequate statistical power (>0.8). Finally, to validate the highest risk genes and to optimize statistical power to search for epistatic and network x network interactions that confer disease risk, we will use CMC, Bayesian, and logic tree methods to analyze exonic SNPs in a second case-control cohort (N=100 cases, 100 controls) also sized to provide adequate statistical power (>0.8). Using next-generation sequencing technology and state of the art statistical methods to elucidate the genetic complexity of neonatal respiratory distress syndrome will permit the development of personalized diagnostic tools and preventive therapeutic strategies that target whole gene networks rather than individual genes.


Ages Eligible for Study:   up to 1 Year   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
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:

  • Normal pulmonary function or a diagnosis of RDS

Exclusion Criteria:

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00014859

United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: F. Sessions Cole, MD    314-454-6148   
Sponsors and Collaborators
Washington University School of Medicine
Principal Investigator: F. Sessions Cole, MD Washington University School of Medicine
  More Information

Sen P, Yang Y, Navarro C, Silva I, Szafranski P, Kolodziejska KE, Dharmadhikari AV, Mostafa H, Kozakewich H, Kearney D, Cahill JB, Whitt M, Bilic M, Margraf L, Charles A, Goldblatt J, Gibson K, Lantz PE, Garvin AJ, Petty J, Kiblawi Z, Zuppan C, McConkie-Rosell A, McDonald MT, Peterson-Carmichael SL, Gaede JT, Shivanna B, Schady D, Friedlich PS, Hays SR, Palafoll IV, Siebers-Renelt U, Bohring A, Finn LS, Siebert JR, Galambos C, Nguyen L, Riley M, Chassaing N, Vigouroux A, Rocha G, Fernandes S, Brumbaugh J, Roberts K, Ho-Ming L, Lo IF, Lam S, Gerychova R, Jezova M, Valaskova I, Fellmann F, Afshar K, Giannoni E, Muhlethaler V, Liang J, Beckmann JS, Lioy J, Deshmukh H, Srinivasan L, Swarr DT, Sloman M, Shaw-Smith C, van Loon RL, Hagman C, Sznajer Y, Barrea C, Galant C, Detaille T, Wambach JA, Cole FS, Hamvas A, Prince LS, Diderich KE, Brooks AS, Verdijk RM, Ravindranathan H, Sugo E, Mowat D, Baker ML, Langston C, Welty S, Stankiewicz P. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum Mutat. 2013 Jun;34(6):801-11. doi: 10.1002/humu.22313. Epub 2013 Apr 12.

Responsible Party: F. Sessions Cole, MD, Professor of Pediatrics, Washington University School of Medicine Identifier: NCT00014859     History of Changes
Obsolete Identifiers: NCT00200915
Other Study ID Numbers: 967
Study First Received: April 11, 2001
Last Updated: June 1, 2015

Keywords provided by F. Sessions Cole, MD, Washington University School of Medicine:
Pulmonary surfactant
Surfactant protein B
Surfactant protein C

Additional relevant MeSH terms:
Lung Diseases
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Pulmonary Alveolar Proteinosis
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Pulmonary Surfactants
Respiratory System Agents processed this record on May 25, 2017