Research Abstract:
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 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, network x network, 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.
Selected Publications:
Hamvas A, Wegner DJ, Carlson CS, Bergmann KR, Trusgnich MA, Fulton L, Kasai Y, An P, Mardis ER, Wilson RK, Cole FS. Comprehensive genetic variant discovery in the surfactant protein B gene. Pediatr Res 2007 62:170-175. PMID: 17597650.
Garmany TH, Wambach JA, Heins HB, Watkins-Torry JM, Wegner DJ, Bennet K, An P, Land G, Saugstad OD, Henderson H, Nogee LM, Cole FS, Hamvas A. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediatr Res 2008 63:645-649. PMID: 18317237.
McBee AD, Wegner DJ, Carlson CS, Wambach JA, Yang P, Heins HB, Saugstad OD, Trusgnich MA, Watkins-Torry J, Nogee LM, Henderson H, Cole FS, Hamvas A. Recombination as a mechanism for sporadic mutation in the surfactant protein-C gene. Pediatr Pulmon 2008 43:443-450. PMID: 18383112.
Hamvas A, Heins HB, Guttentag SH, Wegner DJ, Trusgnich MA, Bennet KW, Yang P, Carlson CS, An P, Cole FS. Developmental and genetic regulation of surfactant protein-B in vivo. Neonatol 2009 95:117-124. PMID: 18776725.
Druley TE, Vallania FML, Wegner DJ, Varley KE, Knowles OL, Bonds JA, Robison SW, Doniger SW, Hamvas A, Cole FS, Fay JC, Mitra RD. Accurate detection and quantification of rare allelic variants from the pooled genomic DNA of 1,111 individuals. Nat Methods 2009; 6:263-5. Epub 2009 Mar 1. PMID: 19252504.
Last Updated: 08/11/2009 |