IRF‐1 SNPs influence the risk for childhood allergic asthma: A critical role for pro‐inflammatory immune regulation |
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| Authors: | Katja Landgraf‐Rauf Andreas Boeck Diana Siemens Elisabeth Klucker Vanessa Vogelsang Susanne Schmidt Sonja Kunze Claudia Weissenbacher Anke Graessel Carsten Schmidt‐Weber Erika von Mutius Michaela Schedel Bianca Schaub |
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| Affiliation: | 1. Department of Pulmonary & Allergy, University Children's Hospital Munich, LMU Munich, Munich, Germany;2. Comprehensive Pneumology Center Munich (CPC‐M), Member of the German Center for Lung Research, Munich, Germany;3. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;4. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;5. Department of Endocrinology, University Children's Hospital Munich, LMU Munich, Munich, Germany;6. ZAUM – Center of Allergy and Environment, Technische Universit?t and Helmholtz Center Munich, Munich, Germany;7. Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA |
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| Abstract: | 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‐γ, 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. |
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| Keywords: | asthma Ca‐signaling childhood IRF‐1 pro‐inflammatory single nucleotide polymorphism |
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