Family-Based Association Tests Suggest Linkage Between Surfactant Protein B (SP-B) (and Flanking Region) and Respiratory Distress Syndrome (RDS): SP-B Haplotypes and Alleles From SP-B–Linked Loci Are Risk Factors for RDS

Abstract

Genetic variants of surfactant protein B (SP-B) have been associated with respiratory distress syndrome (RDS) in the prematurely born infant. We wished to determine linkage between RDS and SP-B single nucleotide polymorphisms (SNPs) [Ϫ18 (A/C), 1013 (A/C), 1580 (C/T), and 9306 (A/G)] or SP-B-linked microsatellite [(D2S388, D2S2232, (AAGG)n, and GATA41E01 (or D2S1331)] loci and identify susceptibility or protective alleles and haplotypes. We genotyped 132 families consisting of one or two parents and at least one child affected with RDS and performed biallelic and multiallelic family-based association test (FBAT) analysis, and extended transmission disequilibrium test (ETDT). ETDT analysis identified the microsatellite SP-B-linked loci (except D2S2232) to be linked to RDS. One allele from each of these three marker loci contributes to the risk of RDS. Multiallelic FBAT analysis detected a signal of linkage for the region of the four SNP loci. Three haplotypes within this region contribute to RDS risk. Although no other region showed significant linkage as judged by multiallelic FBAT, biallelic FBAT analysis revealed three potential susceptibility haplotypes formed by two to four loci within the SP-B and SP-B-linked microsatellite region. Each haplotype included GATA41E01, which was identified by ETDT analysis to be linked to RDS. We conclude that SP-B or SP-B-linked loci are linked to RDS and certain alleles or haplotypes are susceptibility or protective factors for the development of RDS in infants born prematurely. Abbreviations: ETDT, extended transmission disequilibrium test; FBAT, family-based association test; PIC, polymorphism information content; RDS, respiratory distress syndrome; SNP, single nucleotide polymorphism; SP-A, surfactant protein A; SP-B, surfactant protein B

Surfactant protein B inhibits secretory phospholipase A2hydrolysis of surfactant phospholipids

“…Therefore, levels of intact SP-B in ALI/ARDS may be even lower than currently assumed and, if damaged, may be more potentially detrimental by increasing susceptibility to hydrolysis. In addition, mutations of SP-B have been demonstrated to be lethal in both knockout mouse models and human newborns (11,12,19,20,28). On the basis of our results, it is interesting to speculate whether these mutations might increase susceptibility of the endogenous surfactant to sPLA 2 -mediated damage and whether this mechanism may be an important contributor to the ensuing progressive respiratory failure and death.…”

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

“…We did not have sufficient power to pursue the contribution of these more rare mutations to the disease-based risk for RDS in our neonatal intensive care unit cohort that was not enriched for lethal RDS. Common variants in SFTPB and SFTPC with minor allele frequencies Ն0.2 have also been associated with the risk for RDS, but the mechanisms by which these variants and combinations thereof impart risk are undetermined (27)(28)(29)(30). To our knowledge, the contribution of common variants in ABCA3 to the risk of RDS has not been evaluated.…”

Comparison of surfactant protein B polymorphisms of healthy term newborns with preterm newborns having respiratory distress syndrome

“…However, significant variations in pulmonary outcomes of similar infants with comparable exposures to oxygen, mechanical ventilation and nutritional deficiencies suggest that genetic factors also contribute to different pulmonary outcomes (28). RDS is considered to be a result of complex interactions between several environmental and genetic factors associated with prematurity, sex, race, and the presence of maternal diseases (5,29). Some genetic variants of surfactant proteins, particularly SP-A and SP-B, were identified as risk factors or protectors in the etiology of RDS (11,14,15,30).…”