BACKGROUND: Allergic and non-allergic childhood asthma has been characterized by distinct immune mechanisms. While interferon regulating factor 1 (IRF-1) polymorphisms (SNPs) influence atopy risk, the effect of SNPs on asthma phenotype-specific immune mechanisms is unclear. We assessed whether IRF-1 SNPs modify distinct immune-regulatory pathways in allergic and non-allergic childhood asthma (AA/NA). METHODS: In the CLARA study, asthma was characterized by doctor's diagnosis and AA vs NA by positive or negative specific IgE. Children were genotyped for four tagging SNPs within IRF-1 (n = 172). mRNA expression was measured with qRT-PCR. Gene expression was analyzed depending on genetic variants within IRF-1 and phenotype including haplotype estimation and an allelic risk score. RESULTS: Carrying the risk alleles of IRF-1 in rs10035166, rs2706384, or rs2070721 was associated with increased risk for AA. Carrying the non-risk allele in rs17622656 was associated with lower risk for AA but not NA. In AA carrying the risk alleles, an increased pro-inflammatory expression of ICAM3, IRF-8, XBP-1, IFN-gamma, RGS13, RORC, and TSC2 was observed. NOD2 expression was decreased in AA with risk alleles in rs2706384 and rs10035166 and with risk haplotype. Further, AA with risk haplotype showed increased IL-13 secretion. NA with risk allele in rs2070721 compared to non-risk allele in rs17622656 showed significantly upregulated calcium, innate, mTOR, neutrophil, and inflammatory-associated genes. CONCLUSION: IRF-1 polymorphisms influence the risk for childhood allergic asthma being associated with increased pro-inflammatory gene regulation. Thus, it is critical to implement IRF-1 genetics in immune assessment for childhood asthma phenotypes.
- Landgraf-Rauf, K.
- Boeck, A.
- Siemens, D.
- Klucker, E.
- Vogelsang, V.
- Schmidt, S.
- Kunze, S.
- Weissenbacher, C.
- Graessel, A.
- Schmidt-Weber, C.
- von Mutius, E.
- Schedel, M.
- Schaub, B.
Keywords
- Adolescent
- Asthma/*genetics
- Child
- Child, Preschool
- Cytokines/metabolism
- Genetic Predisposition to Disease
- Genotype
- Humans
- Immunoglobulin E/blood
- Interferon Regulatory Factor-1/*genetics
- Polymorphism, Single Nucleotide
- Real-Time Polymerase Chain Reaction
- Respiratory Function Tests/methods
- Risk
- *Ca-signaling
- *irf-1
- *asthma
- *childhood
- *pro-inflammatory
- *single nucleotide polymorphism