Katja Landgraf-Rauf1,2, Andreas Boeck1, Diana Siemens1, Elisabeth Klucker1, Vanessa Vogelsang1, Susanne Schmidt1, Sonja Kunze3,4, Claudia Weissenbacher5, Anke Graessel6, Carsten Schmidt-Weber6, Erika von Mutius1,2, Michaela Schedel7, Bianca Schaub1,2. 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 Universität and Helmholtz Center Munich, Munich, Germany. 7. Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
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.
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.
Authors: Britney A Helling; Débora R Sobreira; Grace T Hansen; Noboru J Sakabe; Kaixuan Luo; Christine Billstrand; Bharathi Laxman; Raluca I Nicolae; Dan L Nicolae; Yury A Bochkov; James E Gern; Marcelo A Nobrega; Steven R White; Carole Ober Journal: Commun Biol Date: 2020-11-13
Authors: James F Read; Michael Serralha; Danny Mok; Barbara J Holt; Mark Cruickshank; Yuliya V Karpievitch; David I Broadhurst; Peter D Sly; Deborah H Strickland; Stacey N Reinke; Patrick G Holt; Anthony Bosco Journal: Front Immunol Date: 2022-08-05 Impact factor: 8.786