Department of Pulmonary & Allergy, University Children's Hospital Munich, LMU Munich, Munich, Germany.
Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany.
Pediatr Allergy Immunol. 2018 Feb;29(1):34-41. doi: 10.1111/pai.12821. Epub 2017 Nov 27.
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).
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.
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.
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.
过敏性和非过敏性儿童哮喘的特点是不同的免疫机制。虽然干扰素调节因子 1（IRF-1）多态性（SNP）影响特应性风险，但 SNP 对哮喘表型特异性免疫机制的影响尚不清楚。我们评估了 IRF-1 SNP 是否会改变过敏性和非过敏性儿童哮喘（AA/NA）中不同的免疫调节途径。
在 CLARA 研究中，哮喘通过医生诊断确定，AA 与 NA 通过特异性 IgE 阳性或阴性确定。对 172 名儿童的 IRF-1 内的四个标记 SNP 进行基因分型。采用 qRT-PCR 测量 mRNA 表达。根据 IRF-1 内的遗传变异和表型（包括单倍型估计和等位风险评分）分析基因表达。
在 rs10035166、rs2706384 或 rs2070721 中携带 IRF-1 的风险等位基因与 AA 风险增加相关。在 rs17622656 中携带非风险等位基因与 AA 风险降低相关，但与 NA 无关。在携带风险等位基因的 AA 中，观察到 ICAM3、IRF-8、XBP-1、IFN-γ、RGS13、RORC 和 TSC2 的促炎表达增加。在 rs2706384 和 rs10035166 中携带风险等位基因以及携带风险单倍型的 AA 中，NOD2 表达降低。此外，携带风险单倍型的 AA 显示出增加的 IL-13 分泌。与 rs17622656 中的非风险等位基因相比，rs2070721 中的风险等位基因在 NA 中显示出钙、先天、mTOR、中性粒细胞和炎症相关基因的显著上调。
IRF-1 多态性影响儿童过敏性哮喘的风险，与促炎基因调控增加相关。因此，在儿童哮喘表型的免疫评估中实施 IRF-1 遗传学至关重要。
