Surfactant protein (SP) B associations and interactions with SP‐A in white and black subjects with respiratory distress syndrome

It has been well established that deficiency of pulmonary surfactant (a lipoprotein complex) leads to respiratory distress syndrome (RDS) in a prematurely born infant. It has also been well documented that although surfactant replacement therapy has reduced the number of deaths from RDS and/or has ameliorated the severity of symptoms, it has not eliminated the incidence of RDS. Thus, in spite of pulmonary surfactant replacement therapy and/or other therapies (i.e. maternal steroid treatment), RDS remains a cause for concern. This observation supports the notion that the etiology of RDS is multifactorial and/or multigenic and that genetics may play a role in its pathogenesis.1–3 Both lipid and protein components of surfactant have been studied extensively with regards to their role in the pathogenesis of RDS and have been used as markers for predicting the risk for RDS. In the last several years, the surfactant protein genes have been used as candidate genes in the study of the genetics of RDS. A number of case–control association studies of unrelated individuals or family-based association studies have identified surfactant protein A (SP-A) and SP-B genetic variants as risk or protective factors for RDS, and have linked the SP-A and SP-B loci to RDS.4–8 Surfactant protein B has been shown to be essential for normal lung function by both animal studies and human studies.9 A number of variants and mutations have been identified for SP-B.10 The SP-B genetic variants may compromise levels and/or functional capabilities of SP-B, as suggested by animal studies of heterozygous (+/−) SP-B knockout mice.11 The levels of SP-B were lower than those in the wild type and small, but significant physiological abnormalities (i.e. decreased compliance and increased air-trapping in the distal airspaces) were observed under normal conditions. Surfactant protein B is encoded by a single gene and in humans the SP-B gene has been localized on the short arm of chromosome 2.12 An SP-B intron 4 genetic size variant has been identified in a case–control study of mixed racial composition as a risk factor for RDS.4 This size variant characterized by insertion or deletion of certain motifs, appeared to have race-related characteristics. Although the insertion (ins) variant was more frequently found in black subjects and the deletion (del) variant was more frequently found in white subjects, no specific association between the ins variant and RDS in black subjects or between the del variant and RDS in white subjects could be made in the previous study. Furthermore, no association of the SP-B intron 4 variant and RDS could be made in a study group of Finnish subjects. Whether an inadequate sample size in the former and a low frequency of intron 4 variant in the Finnish population contributed to lack of association, is unknown.4,13 The SP-A plays a role in aspects of surfactant physiology and structure,14 as well as in innate host defense and regulation of inflammatory processes in the lung.15 The human SP-A locus includes two linked functional genes, SP-A1 and SP-A2, in opposite transcriptional orientation.16 Several genetic variants (alleles) have been characterized for each SP-A gene with 10 of these found frequently in the general population.17 Certain SP-A variants have been identified as risk or protective factors for RDS in several studies of homogeneous or mixed ethnic origin. The SP-A2, 1A0 allele, and the SP-A1, 6A2 allele, as well as the corresponding haplotype 1A0/6A2 have been identified as risk factors in association studies of unrelated individuals and in family-based association using transmission disequilibrium test (TDT) analysis.5–7 Moreover, the SP-A1 and SP-A2 loci have been linked to RDS by TDT and extended TDT analyses.7 Protective SP-A alleles have also been identified by either association studies of unrelated individuals5–7 or by family-based associations. These include alleles 6A3, 6A4, and 1A5. Surfactant protein-A and SP-B may interact functionally, as assessed by in vitro studies, and may work synergistically to reduce surface tension.18 Both SP-A and SP-B are necessary for the tubular myelin (TM) formation, a structural form of surfactant.19,20 The levels of SP-A and SP-B, as well as those of TM, are significantly reduced or absent in babies with RDS.21–23 In one study, the combined frequency of certain SP-A and SP-B alleles was found to be significantly higher in babies with RDS than the frequency of either allele alone, suggesting a synergistic effect of the two marker loci.5 In a recent study, an SP-B variant, the frequency of which did not differ significantly between RDS and control, appeared to be a determinant for RDS with certain SP-A alleles in RDS.13 In the present study, we wished to investigate (a) associations between SP-B polymorphisms and RDS in white and black subjects and (b) interactions between SPA and SP-B genetic variants with regards to their potential to modulate risk or protection from RDS in white and black subjects.