Association of SNP-SNP interactions of surfactant protein genes with severity of respiratory syncytial virus infection in children

The severity of respiratory syncytial virus (RSV) may be linked to host genetic susceptibility. Surfactant protein (SP) genetic variants have been associated with RSV severity, but the impact of single-nucleotide polymorphism (SNP)-SNP interactions remains unexplored. Therefore, we used a novel statistical model to investigate the association of SNP-SNP interactions of <i>SFTP</i> genes with RSV severity in two- and three-interaction models. We analyzed available genotype and clinical data from prospectively enrolled 405 children diagnosed with RSV, categorizing them into moderate or severe RSV groups. Using Wang's statistical model, we studied significant associations of SNP-SNP interactions with RSV severity in a case-control design. We observed, first, association of three interactions with increased risk of severe RSV in a two-SNP model. One intragenic interaction was between SNPs of <i>SFTPA2</i>, and the other two were intergenic, involving SNPs of hydrophilic and hydrophobic SPs alone. We also observed, second, association of 22 interactions with RSV severity in a three-SNP model. Among these, 20 were unique, with 12 and 10 interactions associated with increased or decreased risk of RSV severity, respectively, and included at least one SNP of either <i>SFTPA1</i> or <i>SFTPA2</i>. All interactions were intergenic except one, among SNPs of <i>SFTPA1</i>. The remaining interactions were either among SNPs of hydrophilic SPs alone (<i>n</i> = 8) or among SNPs of both hydrophilic or hydrophobic SPs (<i>n</i> = 11). Our findings indicate that SNPs of all <i>SFTP</i>s may contribute to genetic susceptibility to RSV severity. However, the predominant involvement of <i>SFTPA1</i> and/or <i>SFTPA2</i> SNPs in these interactions underscores their significance in RSV severity.<b>NEW & NOTEWORTHY</b> Although surfactant protein (SP) genetic variants are associated with respiratory syncytial virus (RSV) severity, the impact of single-nucleotide polymorphism (SNP)-SNP interactions of SP genes remained unexplored. Using advanced statistical models, we uncovered 22 SNP-SNP interactions associated with RSV severity, with notable involvement of <i>SFTPA1</i> and <i>SFTPA2</i> SNPs. This highlights the comprehensive role of all SPs in genetic susceptibility to RSV severity, shedding light on potential avenues for targeted interventions.