Association between the Interaction of Key Genes Involved in Effector T-Cell Pathways and Susceptibility to Develop allergic Rhinitis: A Population-Based Case-Control Association Study.

Yuan Zhang,Chengshuo Wang,Luo Zhang,Jingyun Li

doi:10.1371/journal.pone.0131248

Abstract

BackgroundEvidence suggests that interaction between key genes mediating signaling and transcriptional networks involving effector T-cell responses may influence an individual’s susceptibility to develop allergic rhinitis(AR).ObjectiveThe aim of this study was todetermine whether specific interactions between key genes involved in effector T-cell pathways are associated with an individual’s susceptibility to develop AR in Han Chinese subjects.MethodA cohort of 489 patients with AR and 421 healthy controls was enrolled from the Han Chinese population in Beijing, China. AR was established by questionnaire and clinical examination, and peripheral blood was drawn from all subjects for DNA extraction. A total of 96 single nucleotide polymorphisms (SNPs) in 26 reprehensive candidate genes involved in T helper 1 (Th1), Th2, Th17, Th9 and T regulatory cell pathways were selected from the International Haplotype Mappingdatabase for Han Chinese in Beijing (CHB) population, and IlluminaGoldenGate assay was conducted for SNP genotyping. The PLINK software package was used to perform statistical analyses.ResultsSimple SNP-phenotype association analysis using logistic regression showed SNP rs8193036 in IL17A gene, rs2569254 in IL-12 and rs1898413 in RORα weresignificantlyassociatedwith AR.Simple SNP-phenotype association analysis with genetic models demonstrated thatrs2569254 in IL-12, rs1031508 in STAT4, and rs3741809 in IL-26 were likely to be recessive, rs8193036 in IL17A allelic, rs897200in STAT4 genotypic, and rs1898413 in RORα dominant. Epistasis analyses exhibited that 83 SNPs in 23 genes were significantly interactive; of which 59 interactions/SNP pairs demonstrated OR values higher than 2 or lower than 0.5, and 12 interactions/SNP pairs OR values higher than 4 or lower than 0.25. STAT3, RORα and IL-26, involved in Th17 pathway,were the mostfrequentlyinteractive genes.ConclusionThis study suggests that interactions between several SNPs in key genes involved in effector T-cell pathways are likely to influence an individual’s susceptibility to develop AR.

Highlights

Allergic rhinitis (AR) is a serious systemic disease which, with comorbid asthma, causes major illness and disability worldwide
This study suggests that interactions between several single nucleotide polymorphisms (SNPs) in key genes involved in effector T-cell pathways are likely to influence an individual’s susceptibility to develop AR
It has been demonstrated that the commitment of peripheral T-cell clones to undergo differentiation into one of these lineages is shaped by self-reinforcing transcriptional circuitries that center on key transcriptional regulators: T-box expressed in T cells (Th1), GATA-3 (Th2), forkhead box p3 (Treg), and retinoid-related orphan receptor gt/retinoid-related orphan receptor a (Th17)[8]

Summary

Introduction

Allergic rhinitis (AR) is a serious systemic disease which, with comorbid asthma, causes major illness and disability worldwide. The immunological mechanisms underlying allergic sensitization involve functional T cell subsets including T helper 1 (Th1) and T helper 2 (Th2) cells that display polarized cytokine profiles; with a general consensus among researchers that a weak Th1 imprinting and an unrestrained Th2 response allows an increase in allergic responses[5]. Increasing evidence from studies investigating the mechanisms underlying the pathogenesis of allergic diseases has further implicated the important contributions of T regulatory (Treg) cells[6]and the newly described proinflammatoryTh17 cell lineage[7] in this process. Evidence suggests that interaction between key genes mediating signaling and transcriptional networks involving effector T-cell responses may influence an individual’s susceptibility to develop allergic rhinitis(AR)

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Results

Conclusion