Neonatal respiratory distress syndrome due to pulmonary surfactant deficiency is the most frequent respiratory cause of morbidity and mortality among infants <1 year of age in the United States. Although disease pathogenesis has been attributed to developmental delay in pulmonary surfactant production, studies of gender, race, and twins demonstrate significant disease heritability (h2~0.2-0.8). Low frequencies of functional variants, allelic heterogeneity, low linkage disequilibrium in pulmonary surfactant metabolic network genes (SFTPB, SFTPC, and ABCA3), and natural selection against variants that disrupt neonatal lung function suggest that rare, high penetrance alleles of independent origin in multiple candidate genes and gene pathways account for missing disease heritability. Using race-specific, discovery and replication case-control cohorts, next generation sequencing platforms, and Combined Multivariate and Collapsing (CMC) statistical methods, 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. First, to select a comprehensive, hierarchical list of candidate genes (~1,300) and their cognate gene networks expressed in human lung, we will use a candidate gene identification algorithm and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. Secondly, to rank gene loci by race-specific disease risk, we will use exonic sequencing, in silico evaluation of exonic SNP function, CMC statistical methods, and separate European American and African American case- control cohorts sized to provide adequate statistical power (>0.8). Thirdly, to validate the ranking of gene loci by race-specific disease risk and to search for epistatic and gene x environment interactions that confer disease risk, we will use exonic sequencing and CMC, Bayesian, and logic tree statistical methods in replication and merged case-control cohorts. The overall impact on child health of unraveling the genetic basis of neonatal respiratory distress syndrome includes reduction in neonatal morbidity and mortality through development of clinically useful diagnostic tools and identification of novel therapeutic targets to prevent genetic disruption of pulmonary surfactant metabolism.

Public Health Relevance

Using state of the art, inexpensive, rapid methods for evaluating genetic code in multiple genes and gene networks and state of the art statistical methods, we will develop preventive and personalized diagnostic and therapeutic strategies to reduce genetic risk of neonatal respiratory distress syndrome, the most common cause of respiratory morbidity and mortality in infants <1 year of age in the United States.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065174-13
Application #
8502296
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Blaisdell, Carol J
Project Start
2000-04-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$693,110
Indirect Cost
$237,116
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wambach, Jennifer A; Casey, Alicia M; Fishman, Martha P et al. (2014) Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 189:1538-43
Szafranski, Przemyslaw; Dharmadhikari, Avinash V; Wambach, Jennifer A et al. (2014) Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A 164A:2013-9
Wambach, Jennifer A; Wegner, Daniel J; Heins, Hillary B et al. (2014) Synonymous ABCA3 variants do not increase risk for neonatal respiratory distress syndrome. J Pediatr 164:1316-21.e3
van Meel, Eline; Wegner, Daniel J; Cliften, Paul et al. (2013) Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med Genet 14:106
Hamvas, Aaron; Deterding, Robin R; Wert, Susan E et al. (2013) Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144:794-804
Willander, Hanna; Askarieh, Glareh; Landreh, Michael et al. (2012) High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C. Proc Natl Acad Sci U S A 109:2325-9
Anadkat, J S; Kuzniewicz, M W; Chaudhari, B P et al. (2012) Increased risk for respiratory distress among white, male, late preterm and term infants. J Perinatol 32:780-5
Tomazela, Daniela M; Patterson, Bruce W; Hanson, Elizabeth et al. (2010) Measurement of human surfactant protein-B turnover in vivo from tracheal aspirates using targeted proteomics. Anal Chem 82:2561-7
Wambach, Jennifer A; Yang, Ping; Wegner, Daniel J et al. (2010) Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription. Pediatr Res 68:216-20
Hamvas, Aaron; Nogee, Lawrence M; Wegner, Daniel J et al. (2009) Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes. J Pediatr 155:854-859.e1

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