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Epidemiology of Surfactant Protein-B Deficiency

Study Purpose

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).

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Yes
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Observational [Patient Registry]
Eligible Ages N/A - 1 Year
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Normal pulmonary function or a diagnosis of RDS.

Exclusion Criteria:

- None

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT00014859
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Washington University School of Medicine
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

F. Sessions Cole, MD
Principal Investigator Affiliation Washington University School of Medicine
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Lung Diseases, Respiratory Distress Syndrome, Newborn, Pulmonary Surfactant, Lung Diseases, Interstitial
Additional Details

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.#46; $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.

Arms & Interventions

Arms

: 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

Interventions

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Washington University School of Medicine, Saint Louis, Missouri

Status

Recruiting

Address

Washington University School of Medicine

Saint Louis, Missouri, 63110

Site Contact

F. Sessions Cole, MD

cole@kids.wustl.edu

314-454-6148