TLR Signaling Pathway Gene Polymorphisms, Gene–Gene and Gene–Environment Interactions in Allergic Rhinitis

Abstract

Background Allergic rhinitis (AR) is a nasal inflammatory disease resulting from a complex interplay between genetic and environmental factors. The association between Toll-like receptor (TLR) signaling pathway and environmental factors in AR pathogenesis remains to be explored. This study aims to assess the genetic association of AR with single nucleotide polymorphisms (SNPs) in TLR signaling pathway, and investigate the roles of gene–gene and gene–environment interactions in AR. Methods A total of 452 AR patients and 495 healthy controls from eastern China were enrolled in this hospital-based case–control study. We evaluated putatively functional genetic polymorphisms in TLR2, TLR4 and CD14 genes for their association with susceptibility to AR and related clinical phenotypes. Interactions between environmental factors (such as traffic pollution, residence, pet keeping) and polymorphisms with AR were examined using logistic regression. Models were stratified by genotype and interaction terms, and tested for the significance of gene–gene and gene–environment interactions. Results In the single-locus analysis, two SNPs in CD14 , rs2563298 (A/C) and rs2569191 (C/T) were associated with a significantly decreased risk of AR. Compared with the GG genotype, the GT and GT/TT genotypes of TLR2 rs7656411 (G/T) were associated with a significantly increased risk of AR. Gene–gene interactions (eg, TLR2 rs7656411, TLR4 rs1927914, and CD14 rs2563298) was associated with AR. Gene–environment interactions (eg, TLR4 or CD14 polymorphisms and certain environmental exposures) were found in AR cases, but they were not significant after Bonferroni correction. Conclusion The genetic polymorphisms of TLR2 and CD14 and gene–gene interactions in TLR signaling pathway were associated with susceptibility to AR in this Han Chinese population. However, the present results were limited to support the association between gene–environment interactions and AR.

GARP Polymorphisms Associated with Susceptibility to House Dust Mite-Sensitized Persistent Allergic Rhinitis in a Chinese Population

“…The controls were recruited from the hospital seeking health care or routine health examinations and were frequency-matched with the cases in age (±5 years) and sex. The selection criteria for controls: 12 , 13 , 21 (1) no symptoms and medical history of AR and nasal diseases; (2) no symptoms and medical history of other allergic diseases, such as asthma, eczema and urticaria; (3) negative blood test for serum allergen-specific IgE in the phadiatop assay (Phadia, Uppsala, Sweden); (4) no history of AR or other allergic diseases in the immediate family. The exclusion criteria for all subjects: (1) complicated with acute upper respiratory tract infection, severe deviation of nasal septum, rhinosinusitis with or without nasal polyps, neoplasms in paranasal sinuses and nasal cavity; (2) combined with other immune diseases and systemic diseases; (3) use of corticosteroids during previous 4 weeks and antihistamines/antileukotrienes during previous 2 weeks.…”

When the allergy alarm bells toll: The role of Toll-like receptors in allergic diseases and treatment

“…This study is the first to report the association between TLR2 rs7656411 and AR, although this SNP has been previously associated with asthma in the Chinese population. Notably, the results of studies on TLR2 SNPs and the risk of asthma in different populations are contradictory, and meta-analyses suggest that other SNPs, such as rs4696480 and rs3804099, are associated with asthma ( Chen et al, 2022 ).…”

Tolerogenic dendritic cells and TLR4/IRAK4/NF-κB signaling pathway in allergic rhinitis

“…In the presence of LPS-binding protein (LBP) and CD14, TLR4 binds to LPS with the help of co-receptor myeloid differentiation protein 2 (MD-2) ( 53 , 59 ). The surroundings have an effect on the bond between them ( 60 ). Stimulated activation of TLR4 consists of two major intracellular signaling pathways: the myeloid differentiation primary response 88 (MyD88)-dependent pathway and the toll-interleukin-1 receptor (TIR) structural domain-containing adapter-induced IFN-β (TRIF) pathway ( 54 ).…”

“…With abundant leucine repeats, TLRs regulate Th1/Th2 immune balance through DCs, mast cells and Tregs ( 52 , 60 ). The adaptive immune response can be skewed toward Th1 by TLRs, which can cause DCs maturation and T cell activation ( 60 ). A variety of inflammatory cytokines and chemokines are released when TLRs activate DCs ( 95 ).…”