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

Abstract

Surfactant proteins (SPs) are important for normal lung function and innate immunity of the lungs and their genes have been identified with significant genetic variability. Changes in quantity or quality of SPs due to genetic mutations or natural genetic variability may alter their functions and contribute to the host susceptibility for particular diseases. Alternatively, SP single nucleotide polymorphisms (SNPs) can serve as markers to identify disease risk or response to therapies, as shown for other genes in a number of other studies. In the current study, we evaluated associations of SFTP SNPs with idiopathic pulmonary fibrosis (IPF) by studying novel computational models where the epistatic effects (dominant, additive, recessive) of SNP-SNP interactions could be evaluated, and then compared the results with a previously published hypersensitivity pneumonitis (HP) study where the same novel models were used. Mexican Hispanic patients (IPF=84 & HP=75) and 194 healthy control individuals were evaluated. The goal was to identify SP SNPs and SNP-SNP interactions that associate with IPF as well as SNPs and interactions that may be unique to each of these interstitial diseases or common between them. We observed: 1) in terms of IPF, i) three single SFTPA1 SNPs to associate with decreased IPF risk, ii) three SFTPA1 haplotypes to associate with increased IPF risk, and iii) a number of three-SNP interactions to associate with IPF susceptibility. 2) Comparison of IPF and HP, i) three SFTPA1 and one SFTPB SNP associated with decreased risk in IPF but increased risk in HP, and one SFTPA1 SNP associated with decreased risk in both IPF and HP, ii) a number of three-SNP interactions with the same or different effect pattern associated with IPF and/or HP susceptibility, iii) one of the three-SNP interactions that involved SNPs of SFTPA1, SFTPA2, and SFTPD, with the same effect pattern, was associated with a disease-specific outcome, a decreased and increased risk in HP and IPF, respectively. This is the first study that compares the SP gene variants in these two phenotypically similar diseases. Our findings indicate that SNPs of all SFTPs may play an important role in the genetic susceptibility to IPF and HP. Importantly, IPF and HP share some SP genetic variants, suggesting common pathophysiological mechanisms and pathways regarding surfactant biogenesis, but also some differences, highlighting the diverse underlying pathogenic mechanisms between an inflammatory-driven fibrosis (HP) and an epithelial-driven fibrosis (IPF). Alternatively, the significant SNPs identified here, along with SNPs of other genes, could serve as markers to distinguish these two devastating diseases.

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 were selected because of their associations with several acute and chronic pulmonary diseases. 7,[9][10][11]14,15 The SP-A1 (6A, 6A m , m = 0-13) and SP-A2 (1A, 1A n , n = 0-15) genotypes were assigned as described. 6…”

“…3 Multiple single-nucleotide polymorphisms (SNPs) have been identified for each of these genes. [4][5][6] 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.…”