Ignite Creation Date:
2024-05-05 @ 11:23 AM
Last Modification Date:
2024-10-26 @ 9:06 AM
Study NCT ID:
NCT00014859
Status:
COMPLETED
Last Update Posted:
2024-04-29
First Post:
2001-04-11
Brief Title:
Epidemiology of Surfactant Protein-B Deficiency
Sponsor:
Washington University School of Medicine
Organization:
Washington University School of Medicine
Study Overview
Official Title:
Epidemiology of Surfactant Protein-B Deficiency
Status:
COMPLETED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to test the hypothesis that excess rare functionally disruptive single nucleotide polymorphisms SNPs characterize genes eg the surfactant protein-B geneSFTPB and gene networks eg 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 28500 infant deaths in 2006 5421 197 were diagnosed with respiratory distress as either the primary 1011 - 37 or secondary 4410 - 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 59 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 49900 infants with a diagnosis of respiratory distress syndrome was 56800 vs 10700 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 eg 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 02 and 08 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 01 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 h202-08 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 phenotypesparent trios we will identify de novo or recessively inherited pathogenic variants including single nucleotide variants small insertionsdeletions and copy number or structural variants 100 kb To predict pathogenicity we will use a suite of computational prediction algorithms eg ANNOVAR CADD To confirm variants in genes and gene pathways not previously associated with human infantchild 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
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 28500 infant deaths in 2006 5421 197 were diagnosed with respiratory distress as either the primary 1011 - 37 or secondary 4410 - 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 59 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 49900 infants with a diagnosis of respiratory distress syndrome was 56800 vs 10700 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 eg 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 02 and 08 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 01 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 h202-08 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 phenotypesparent trios we will identify de novo or recessively inherited pathogenic variants including single nucleotide variants small insertionsdeletions and copy number or structural variants 100 kb To predict pathogenicity we will use a suite of computational prediction algorithms eg ANNOVAR CADD To confirm variants in genes and gene pathways not previously associated with human infantchild 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None