SNP–SNP Interactions of Surfactant Protein Genes in Persistent Respiratory Morbidity Susceptibility in Previously Healthy Children

Abstract

We studied associations of persistent respiratory morbidity (PRM) at 6 and 12 months after acute respiratory failure (ARF) in previously healthy children with single-nucleotide polymorphisms (SNPs) of surfactant protein (SP) genes. Of the 250 enrolled subjects, 155 and 127 were followed at 6 and 12 months after an ARF episode, respectively. Logistic regression analysis and SNP–SNP interaction models were used. We found that 1) in the multivariate analysis, an increased risk at 6 and 12 months was associated with rs1124_A and rs4715_A of SFTPC, respectively; 2) in a single SNP model, increased and decreased risks of PRM at both timepoints were associated with rs1124 of SFTPC and rs721917 of SFTPD, respectively; an increased risk at 6 months was associated with rs1130866 of SFTPB and rs4715 of SFTPC, and increased and decreased risks at 12 months were associated with rs17886395 of SFTPA2 and rs2243639 of SFTPD, respectively; 3) in a two-SNP model, PRM susceptibility at both timepoints was associated with a number of intergenic interactions between SNPs of the studied SP genes. An increased risk at 12 months was associated with one intragenic (rs1965708 and rs113645 of SFTPA2) interaction; 4) in a three-SNP model, decreased and increased risks at 6 and 12 months, respectively, were associated with an interaction among rs1130866 of SFTPB, rs721917 of SFTPD, and rs1059046 of SFTPA2. A decreased risk at 6 months was associated with an interaction among the same SNPs of SFTPB and SFTPD and the rs1136450 of SFTPA1. The findings revealed that SNPs of all SFTPs appear to play a role in long-term outcomes of ARF survivors and may serve as markers for disease susceptibility.

Single Nucleotide Polymorphisms (SNP) and SNP-SNP Interactions of the Surfactant Protein Genes Are Associated With Idiopathic Pulmonary Fibrosis in a Mexican Study Group; Comparison With Hypersensitivity Pneumonitis

“…One of its SNPs, rs1136450, was the most frequently observed SFTPA1 SNP in the 3-SNP interactions. This SNP was found to be significant either by itself, as part of significant haplotypes, or part of significant 3-SNP interactions and has been found previously to associate with susceptibility with other pulmonary diseases including community acquired pneumonia ( 61 ), cystic fibrosis ( 47 ), acute respiratory distress of the newborn ( 59 ) and pediatric acute and chronic respiratory failure ( 58 , 62 ). The rs1136450 SNP encodes (leu/val) amino acid 50 (AA50), and it is located within the collagen-like region of SP-A1.…”

Hydrophilic But Not Hydrophobic Surfactant Protein Genetic Variants Are Associated With Severe Acute Respiratory Syncytial Virus Infection in Children

“…A total of 16 target SNPs of SP genes, SFTPA1 , SFTPA2 , SFTPB , SFTPC , and SFTPD were selected that included, 5 SNPs from SFTPA1 , rs1059047, rs1136450, rs1136451, rs1059057, and rs4253527; 4 SNPs from SFTPA2 , rs1059046, rs17886395, rs1965707, and 1965708; 3 SNPs from SFTPB , rs2077079, rs3024798, and rs1130866; 2 SNPs from SFTPC , rs4715 and rs1124; and 2 SNPs from SFTPD , rs721917 and rs2243639. Several acute and chronic pulmonary diseases of all age groups, such as, neonatal RDS ( 31 – 35 ), CF ( 36 ), COPD ( 37 , 38 ), ARDS ( 23 ), hypersensitivity pneumonitis ( 39 , 40 ), pediatric ARF ( 41 ), and persistent respiratory morbidity in pediatric ARF survivors ( 42 ) have been shown to be associated with the studied SNPs. The SP-A1 (6A, 6A m , m=0-13) and SP-A2 (1A, 1A n , n=0-15) genotypes were assigned as described ( 19 ).…”

“…Several acute and chronic pulmonary diseases of all age groups, such as, neonatal RDS (31)(32)(33)(34)(35), CF (36), COPD (37,38), ARDS (23), hypersensitivity pneumonitis (39,40), pediatric ARF (41), and persistent respiratory morbidity in pediatric ARF survivors (42) have been shown to be associated with the studied SNPs. The SP-A1 (6A, 6A m , m=0-13) and SP-A2 (1A, 1A n , n=0-15) genotypes were assigned as described (19).…”

“…SP-B, SP-C, and SP-D are each encoded by a single gene, SFTPB, SFTPC, and SFTPD, respectively (22), and several polymorphisms have been described for each (23)(24)(25)(26). Moreover, SP genetic polymorphisms have been shown to associate with RSV (27)(28)(29)(30), as well as other pulmonary diseases, such as neonatal respiratory distress syndrome (RDS) (31)(32)(33)(34)(35), cystic fibrosis (CF) (36), chronic obstructive pulmonary disease (COPD) (37,38), acute respiratory distress syndrome (ARDS) (23), hypersensitivity pneumonitis (39,40), pediatric acute respiratory failure (ARF) (41), and persistent respiratory morbidity in pediatric ARF survivors (42). However, the majority of previous RSV association studies with SP genetic variants were case-control in design, comparing RSVinfected children with healthy children without RSV infection (27,28,30,43).…”

Association of surfactant protein A2 with acute respiratory failure in children

“…These SNPs have been shown to associate with various acute and chronic pulmonary diseases, such as cystic fibrosis, 7 acute respiratory distress syndrome, 8 neonatal respiratory distress syndrome (RDS), 9 hypersensitivity pneumonitis, 10 interstitial pulmonary fibrosis, 11 the severity of respiratory syncytial virus (RSV) 12 and tuberculosis (TB) 13 . We showed that SNP‐SNP interactions among SP genes are associated with pediatric ARF and its short‐ 14 and long‐term outcomes 15 . However, these interactions do not provide any information about the contribution of individual SNPs in the given interaction.…”