Identifying allergic-rhinitis-associated genes with random-walk-based method in PPI network.

Allergic rhinitis is a common allergic disease with a complex pathogenesis and many unresolved issues. Studies have shown that the incidence of allergic rhinitis is closely related to genetic factors, and research on the related genes could help further understand its pathogenesis and develop new treatment methods. In this study, 446 allergic rhinitis-related genes were obtained on the basis of the DisGeNET database. The protein-protein interaction network was searched using the random-walk-with-restart algorithm with these 446 genes as seed nodes to assess the linkages between other genes and allergic rhinitis. Then, this result was further examined by three screening tests, including permutation, interaction, and enrichment tests, which aimed to pick up genes that have strong and special associations with allergic rhinitis. 52 novel genes were finally obtained. The functional enrichment test confirmed their relationships to the biological processes and pathways related to allergic rhinitis. Furthermore, some genes were extensively analyzed to uncover their special or latent associations to allergic rhinitis, including IRAK2 and MAPK, which are involved in the pathogenesis of allergic rhinitis and the inhibition of allergic inflammation via the p38-MAPK pathway, respectively. The new found genes may help the following investigations for understanding the underlying molecular mechanisms of allergic rhinitis and developing effective treatments.

MiR-4454 in Combined Allergic Rhinitis and Asthma Syndrome (CARAS): Clinical significance and mechanistic insights into airway inflammation.

Abnormal expression of non-coding microRNA is associated with the development of combined allergic rhinitis and asthma syndrome (CARAS). However, the function of miR-4454 in CARAS is unknown. Our study aimed to reveal the clinical significance and related mechanism of miR-4454 in CARAS. Blood samples from 38 cases of CARAS and 43 cases of healthy subjects were collected to detect the expression of miR-4454. House dust mite (HDM) sensitization and challenge-induced bronchial epithelial cells to simulate the asthma state model in vitro, miR-4454 mimics and inhibitor transfection to detect the expression level of pro-inflammatory cytokines, cell survival rate and migration ability, flow cytometry and western blot (WB) Detection of cell cycle, apoptosis and inflammation-related protein levels. Compared with healthy controls, the expression of miR-4454 in the blood of CARAS patients was significantly up-regulated, and IL-6 and IL-8 were significantly up-regulated in the HDM treatment group, indicating that the model induction was successful. After overexpression of miR-4454, cell proliferation and migration in the HDM-treated group were significantly inhibited, and the levels of early apoptosis and inflammation-related proteins (IL-17, IL-17RD, TNF-α, GCSF and NF-κB) were increased High; after inhibiting miR-4454, cell proliferation and migration were significantly enhanced, and the levels of apoptosis and inflammation-related proteins were decreased. This study found that inhibiting the expression of miR-4454 can improve HDM-induced cell injury, which may be related to miR-4454 regulating the activation of IL-17/NF-кB inflammatory axis.

Identification of diagnostic signature, molecular subtypes, and potential drugs in allergic rhinitis based on an inflammatory response gene set.

Background: Rhinitis is a complex condition characterized by various subtypes, including allergic rhinitis (AR), which involves inflammatory reactions. The objective of this research was to identify crucial genes associated with inflammatory response that are relevant for the treatment and diagnosis of AR. Methods: We acquired the AR-related expression datasets (GSE75011 and GSE50223) from the Gene Expression Omnibus (GEO) database. In GSE75011, we compared the gene expression profiles between the HC and AR groups and identified differentially expressed genes (DEGs). By intersecting these DEGs with inflammatory response-related genes (IRGGs), resulting in the identification of differentially expressed inflammatory response-related genes (DIRRGs). Afterwards, we utilized the protein-protein interaction (PPI) network, machine learning algorithms, namely least absolute shrinkage and selection operator (LASSO) regression and random forest, to identify the signature markers. We employed a nomogram to evaluate the diagnostic effectiveness of the method, which has been confirmed through validation using GSE50223. qRT-PCR was used to confirm the expression of diagnostic genes in clinical samples. In addition, a consensus clustering method was employed to categorize patients with AR. Subsequently, extensive investigation was conducted to explore the discrepancies in gene expression, enriched functions and pathways, as well as potential therapeutic drugs among these distinct subtypes. Results: A total of 22 DIRRGs were acquired, which participated in pathways including chemokine and TNF signaling pathway. Additionally, machine learning algorithms identified NFKBIA, HIF1A, MYC, and CCRL2 as signature genes associated with AR's inflammatory response, indicating their potential as AR biomarkers. The nomogram based on feature genes could offer clinical benefits to AR patients. We discovered two molecular subtypes, C1 and C2, and observed that the C2 subtype exhibited activation of immune- and inflammation-related pathways. Conclusions: NFKBIA, HIF1A, MYC, and CCRL2 are the key genes involved in the inflammatory response and have the strongest association with the advancement of disease in AR. The proposed molecular subgroups could provide fresh insights for personalized treatment of AR.

Downregulation of lncRNA CDKN2B-AS1 attenuates inflammatory response in mice with allergic rhinitis by regulating miR-98-5p/SOCS1 axis.

Long non-coding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in various diseases has been verified. However, the underlying mechanism of CDKN2B-AS1 contributes to the development of allergic rhinitis (AR) remains unknown. To evaluate the impact of CDKN2B-AS1 on AR, BALB/c mice were sensitized by intraperitoneal injection of normal saline containing ovalbumin (OVA) and calmogastrin to establish an AR model. Nasal rubbing and sneezing were documented after the final OVA treatment. The concentrations of IgE, IgG1, and inflammatory elements were quantified using ELISA. Hematoxylin and eosin (H&E) staining and immunofluorescence were used to assess histopathological variations and tryptase expression, respectively. StarBase, TargetScan and luciferase reporter assays were applied to predict and confirm the interactions among CDKN2B-AS1, miR-98-5p, and SOCS1. CDKN2B-AS1, miR-98-5p, and SOCS1 levels were assessed by quantitative real-time PCR (qRT-PCR) or western blotting. Our results revealed that CDKN2B-AS1 was obviously over-expressed in the nasal mucosa of AR patients and AR mice. Down-regulation of CDKN2B-AS1 significantly decreased nasal rubbing and sneezing frequencies, IgE and IgG1 concentrations, and cytokine levels. Furthermore, down-regulation of CDKN2B-AS1 also relieved the pathological changes in the nasal mucosa, and the infiltration of eosinophils and mast cells. Importantly, these results were reversed by the miR-98-5p inhibitor, whereas miR-98-5p directly targeted CDKN2B-AS1, and miR-98-5p negatively regulated SOCS1 level. Our findings demonstrate that down-regulation of CDKN2B-AS1 improves allergic inflammation and symptoms in a murine model of AR through the miR-98-5p/SOCS1 axis, which provides new insights into the latent functions of CDKN2B-AS1 in AR treatment.

Inflammatory cytokines and risk of allergic rhinitis: A Mendelian randomization study.

BACKGROUND: Epidemiological and experimental evidences have implicated chronic inflammation in the association with allergic rhinitis (AR). However, it remains unclear whether specific circulating cytokines are the cause of AR or the consequence of bias. To examine whether genetic-predicted changes in circulating cytokine concentrations are related to the occurrence of AR, we conducted a two-sample Mendelian randomization (MR) analysis. METHODS: We investigated the causal effects of 26 circulating inflammatory cytokines on AR through MR analysis. The primary method employed in this study was the inverse variance-weighted (IVW) method. Sensitivity analyses were conducted using simple median, weighted median, penalized weighted median, and MR-Egger regression. RESULTS: Our study revealed suggestive evidence that higher levels of circulating IL-18 (OR per one standard deviation [SD] increase: 1.006; 95 % CI, 1.002 to 1.011; P = 0.006, PFDR = 0.067, random-effects IVW method) and Macrophage inflammatory protein-1α (MIP-1α) (OR per one SD increase: 1.015; 95 % CI, 1.004 to 1.026; P = 0.009, PFDR = 0.048, random-effects IVW method) were associated with an increased risk of AR. Conversely, higher levels of circulating TRAIL were associated with a decreased risk of AR (OR per one SD increase: 0.993; 95 % CI, 0.989 to 0.997; P = 4.58E-4, PFDR = 0.004, random-effects IVW method). Only the results of TRAIL exist after Bonferroni-correction (the p-value < 0.0019). Sensitivity analysis yielded directionally consistent results. No significant associations were observed between other circulating inflammatory cytokines and AR. CONCLUSION: Genetically predicted levels of IL-18, and MIP-1α are likely to associated with an increased risk of AR occurrence. Genetically predicted levels of TRAIL are statistically significant in reducing the risk of AR occurrence. However, the current research evidence does not support an impact of other inflammatory cytokines on the risk of AR. Future studies are needed to provide additional evidence to support the current conclusions.

Causal relationships of metabolites with allergic diseases: a trans-ethnic Mendelian randomization study.

BACKGROUND: Allergic diseases exert a considerable impact on global health, thus necessitating investigations into their etiology and pathophysiology for devising effective prevention and treatment strategies. This study employs a Mendelian randomization (MR) analysis and meta-analysis to identify metabolite targets potentially associated with allergic diseases. METHODS: A two-sample MR analysis was conducted to explore potential causal relationships between circulating and urinary metabolites and allergic diseases. Exposures were derived from a genome-wide association study (GWAS) of 486 circulating metabolites and a GWAS of 55 targeted urinary metabolites. Outcome data for allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma, were obtained from the FinnGen biobank in Europe (cohort 1) and the Biobank Japan in Asia (cohort 2). MR results from both cohorts were combined using a meta-analysis. RESULTS: MR analysis identified 50 circulating metabolites and 6 urinary metabolites in cohort 1 and 54 circulating metabolites and 2 urinary metabolites in cohort 2 as potentially causally related to allergic diseases. A meta-analysis of the MR results revealed stearoylcarnitine (OR 8.654; 95% CI 4.399-17.025; P = 4.06E-10) and 1-arachidonoylglycerophosphoinositol (OR 2.178; 95% CI 1.388-3.419; P = 7.15E-04) as the most reliable causal circulating metabolites for asthma and AR, respectively. Further, histidine (OR 0.734; 95% CI: 0.594-0.907; P = 0.004), tyrosine (OR 0.601; 95% CI: 0.380-0.952; P = 0.030), and alanine (OR 0.280; 95% CI: 0.125-0.628; P = 0.002) emerged as urinary metabolites with the greatest protective effects against asthma, AD, and AR, respectively. CONCLUSIONS: Imbalances in numerous circulating and urinary metabolites may be implicated in the development and progression of allergic diseases. These findings have significant implications for the development of targeted strategies for the prevention and treatment of allergic diseases.

Silencing of forkhead box C1 reduces nasal epithelial barrier damage in mice with allergic rhinitis via epigenetically upregulating secreted frizzled-related protein 5.

Allergic rhinitis (AR) is caused by immunoglobulin E (IgE)-mediated reactions to inhaled allergens, which leads to mucosal inflammation and barrier dysfunction. The transcription factor forkhead box C1 (FOXC1) has been identified to be associated with allergic inflammation. This study sought to uncover the role of FOXC1 in AR. A murine model of AR was induced by repeated intranasal ovalbumin (OVA) challenges. Results revealed that high FOXC1 expression was found in the nasal mucosal epithelium of AR mice. Nasal allergy symptoms, mucosal epithelial swelling, goblet cell hyperplasia and eosinophil infiltration in AR mice were attenuated after silencing of FOXC1. Knockdown of FOXC1 decreased the levels of T-helper 2 cytokines interleukin(IL)-4 and IL-13 in nasal lavage fluid, and serum OVA-specific IgE and histamine. Silencing of FOXC1 restored nasal epithelial integrity in AR mice by enhancing the expression of tight junctions (TJs) and adherence junction. Furthermore, knocking down FOXC1 increased tight junction expression and transepithelial electrical resistance (TEER) in IL-13-treated air-liquid interface (ALI) cultures of human nasal epithelial cells (HNEpCs). Mechanistically, silencing of FOXC1 induced DNA methylation of secreted frizzled-related protein 5 (SFRP5) promoter and increased its expression in the nasal mucosa of AR mice and IL-13-treated ALI cultures. FOXC1 overexpression transcriptionally activated DNA methyltransferase 3B (DNMT3B) in IL-13-treated ALI cultures. Knockdown of SFRP5 reversed the protection of FOXC1 silencing on epithelial barrier damage induced by IL-13. Collectively, silencing of FOXC1 reduced allergic inflammation and nasal epithelial barrier damage in AR mice via upregulating SFRP5, which may be attribute to DNMT3B-driven DNA methylation. Our study indicated that FOXC1 may represent a potential therapeutic target for AR.

Molecular characterization of allergic constitution based on network pharmacology and multi-omics analysis methods.

The objective of this study was to identify critical pathways associated with allergic constitution. Shared genes among allergic rhinitis (AR), asthma (AA), and atopic dermatitis (AD) were extracted from the GWAS catalog. RNA-seq data of AR, AA, and AD from gene expression omnibus (GEO) database were preprocessed and subjected to differential gene expression analysis. The differentially expressed genes (DEGs) were merged using the Robust Rank Aggregation (RRA) algorithm. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules associated with allergies. Components of Guominkang (GMK) were obtained from 6 databases and activate components were identified by SwissADME website. Utilizing the SwissTarget Prediction, PharmMapper, SymMap, and HERB, the targets of GMK were predicted and subsequently validated using gene chip data from our team previous study. Differentially expressed proteins (DEPs) related to the allergic constitution were also extracted based on a previous study. Pathway enrichment analysis was performed using KOBAS-i on the GWAS, RRA, WGCNA modules, DEPs, and GMK targets. P values from multi-omics datasets were combined by meta-analysis, and Bonferroni correction was applied. The significant pathways were further validated using Gene Set Enrichment Analysis (GSEA) with intervention data of GMK. The GWAS results yielded 172 genes. Four datasets AR1, AA1, AD1, and AD2 were acquired from GSE75011, GSE125916, and GSE184237. The RRA algorithm identified 19 upregulated and 20 downregulated genes. WGCNA identified 5 significant modules, with the blue and turquoise modules displaying a moderate correlation with allergies. By performing network pharmacology analysis, we identified 127 active ingredients of GMK and predicted 618 targets. Validation using gene chip data confirmed 107 GMK targets. Single-omics pathway analysis was conducted using KOBAS-i, and 39 significant pathways were identified across multiple omics datasets. GSEA analysis using GMK intervention data identified 11 of 39 significant pathways as the final key pathways associated with the allergic constitution. Through multi-omics integrated pathway analysis, we identified 11 critical pathways of allergic constitution, including TH1 and TH2 cell differentiation, TLR cascade, and TH17 cell differentiation. Identifying these pathways suggests that the observed alterations at the pathway level may play significant roles in the molecular characteristics of the allergic constitution.

Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy.

BACKGROUND: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR. METHODS: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s). RESULTS: Treatment with dupilumab (normalized enrichment score [NES] = -1.73, p = .002) or SCIT + dupilumab (NES = -2.55, p < .001), but not SCIT alone (NES = +1.16, p = .107), significantly repressed the AR disease signature. Dupilumab (NES = -2.55, p < .001), SCIT (NES = -2.99, p < .001), and SCIT + dupilumab (NES = -3.15, p < .001) all repressed the NAC gene signature. CONCLUSION: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression.

Single-cell RNA sequencing reveals the landscape of biomarker in allergic rhinitis patient undergoing intracervical lymphatic immunotherapy and related pan-cancer analysis.

INTRODUCTION: Allergic rhinitis (AR) is one of the leading allergic diseases worldwide. Allergen immunotherapy (AIT) induces persistent specific allergen tolerance to achieve remission of the symptoms in AR patients. We creatively conducted the intra-cervical lymphatic immunotherapy (ICLIT) for AR patients. However, the underlying molecular mechanism of immune cell response of AIT in AR remains elusive. METHOD: To investigate the transcriptome profile in AR patients who underwent ICLIT, we comprehensively investigated the transcriptional changes in B cells from peripheral blood mononuclear cells of AR patient by single-cell RNA sequencing. Immunoglobulins and relative key gene, which influences the B cell differentiation, was demonstrated. The biomarkers' association with different types of tumors was investigated. RESULTS: Naive B cells, germinal center B cells, activated memory B cells, and memory B cells constituted the B cells subsets. The expression of IGHE, IGHGs, IGHA, IGHD, and IGHM from memory B cells was validated. Pseudotime analysis further indicated the dynamic change from the expression of the immunoglobulins in the memory B cells, suggesting that ITGB1 may contribute to the differentiation procedure of memory B cells. The cell-cell communication among these immune cells demonstrated the significantly enhanced CD23, BTLA signaling after ICLIT in AR patient. ITGB1 was upregulated in 13 tumors and downregulated in six others. High ITGB1 expression was linked to poor prognosis in eight types of tumors. ITGB1 expression showed correlations with tumor mutation burden, tissue purity, and microsatellite instability in different types of tumors. DISCUSSION: ITGB1 was demonstrated as a potential biomarker for AR patients after ICLIT and is significant in identifying immune infiltration in tumor tissue and predicting tumor prognosis.

Allergic Diseases and Chronic Adenotonsillar Diseases: A Mendelian Randomization Study.

OBJECTIVE: The existing epidemiological evidence regarding the intricate relationship between allergic diseases and chronic adenotonsillar diseases (CATD) remains inconclusive. Herein, the objective of our study is to explore the causal association using Mendelian randomization (MR). METHODS: Employing data from large genome-wide association studies, a comprehensive two-sample bidirectional MR study was conducted. The studied traits encompassed allergic rhinitis (cases n = 9707, controls n = 331173), allergic asthma (cases n = 8525, controls n = 193857), allergic conjunctivitis (cases n = 18321, controls n = 324178), atopic dermatitis (cases n = 11964, controls n = 306909), and CATD (cases n = 38983, controls n = 258553). All the patients were of European descent and participants in cohort studies. The primary analysis was executed using inverse-variance-weighted MR. Furthermore, six additional MR methods (MR-Egger, weighted median, simple mode, weighted mode, MR pleiotropy residual sum and outlier, MR robust adjusted profile score) were employed to ensure the reliability and detect potential horizontal pleiotropy within the results. The estimates obtained from the MR analysis were factored into the overall effect calculation. RESULTS: Genetically anticipated outcomes demonstrated a significant association between CATD risk and allergic rhinitis (OR = 1.141, p = 6.30E-06), allergic asthma (OR = 1.115, p = 8.31E-05), allergic conjunctivitis (OR = 1.197, p = 8.69E-07), and a suggestive association with atopic dermatitis (OR = 1.053, p = 0.040). However, no substantial correlation was observed in the reverse direction. CONCLUSIONS: Findings of our study provide evidence supporting a causal role of allergic diseases in the development of CATD, whereas the converse relationship does not appear to hold true. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2653-2658, 2024.

Allergic rhinitis phenotypes with distinct transcriptome profiles in children: A birth cohort.

BACKGROUND: Allergic rhinitis (AR) phenotypes in childhood are unclear. OBJECTIVES: This study sought to determine AR phenotypes and investigate their natural course and clinical and transcriptomic characteristics. METHODS: Latent class trajectory analysis was used for phenotyping AR in 1050 children from birth through 12 years using a birth cohort study. Blood transcriptome analyses were performed to define the underlying mechanisms of each phenotype. RESULTS: Five AR phenotypes were identified: early onset (n = 88, 8.4%), intermediate transient (n = 110, 10.5%), late onset (n = 209, 19.9%), very late onset (n=187, 17.8%), and never/infrequent (n = 456, 43.4%). Children with early-onset AR were associated with higher AR severity and sensitizations to foods at age 1 year and inhalants at age 3 years and asthma symptoms, but not with bronchial hyperresponsiveness (BHR). Children with late-onset AR phenotype associated with sensitizations to various foods at age 1 year but not from age 3 years, and to inhalants from age 7 years and with asthma with BHR. Children with very late-onset AR phenotype associated with sensitizations to foods throughout preschool age and to inhalants at ages 7 and 9 years and with asthma with BHR. Transcriptome analysis showed that early-onset AR was associated with viral/bacterial infection-related defense response, whereas late-onset AR was associated with T cell-related immune response. CONCLUSIONS: Early-onset AR phenotype was associated with sensitization to foods and inhalants at an early age and asthma symptoms, but not with BHR, whereas very late- and late-onset AR phenotypes were positively associated with sensitization to inhalants and asthma with BHR. Transcriptomic analyses indicated that early- and late-onset AR phenotypes had distinct underlying mechanisms related to AR as well.

No causal association between allergic rhinitis and migraine: a Mendelian randomization study.

PURPOSE: Allergic rhinitis (AR) and migraine are among the most common public health problems worldwide. Observational studies on the correlation between AR and migraine have reported inconsistent results. This study aimed to investigate the causal relationship of AR with migraine and its subtypes, including migraine with aura (MA) and migraine without aura (MO). METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was performed with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The inverse variance-weighted method was selected for primary analysis and was supplemented with the weighted median, weighted mode, and MR-Egger methods. The causal analysis using summary effect estimates (CAUSE) were further performed to verify the causality. Several sensitivity tests, including the leave-one-out, Cochran's Q, MR-Egger intercept, and MR-PRESSO tests, were performed to assess the robustness of the results. RESULTS: AR did not exhibit a significant causal correlation with the elevated risk of any migraine (odd ratio (OR), 0.816; 95% confidence interval (CI), 0.511-1.302; P = 0.394), MA (OR, 0.690; 95% CI 0.298-1.593; P = 0.384), or MO (OR, 1.022; 95% CI 0.490-2.131; P = 0.954). Consistently, reverse MR analysis did not reveal causal effects of any migraine or its subtypes on AR. Almost all sensitivity analyses supported the robustness of the results. CONCLUSIONS: This MR study did not reveal a clear causal association between AR and migraine risk. More research is warranted to reveal the complex association between AR and migraine.

Serum microRNA-223 as a potential biomarker for allergic rhinitis and its correlation to eosinophil-derived neurotoxin.

Allergic rhinitis (AR) is a global health problem. It is an inflammatory condition defined by a malfunction of the immune system's regulatory mechanism. MicroRNA-223 (miRNA-223) has been linked to the modulation of AR in the last few years. The goal of this study was to determine whether miR-223 can be utilized as a potential biomarker for diagnosis of AR, and whether it correlates with the total nasal symptom score (TNSS) along with serum interleukin-17 (IL-17), interleukin-4 levels (IL-4) and eosinophil-derived neurotoxin (EDN). This study included 76 adult participants, consisted of 38 AR patients and 38 apparently healthy controls. Serum levels of miR-223 were assayed using real-time PCR. The levels of EDN, IL-17 and IL-4 in the serum were determined using an enzyme-linked immunosorbent assay. The optimal cutoff value for the analyzed factors to diagnose AR was determined using a receiver operating characteristic curve analysis (ROC). The demographic features (age and gender) of the two study groups were matched. Patients with pollen-induced AR had significantly higher levels of miR-223 in their serum compared to the controls (median = 3.82; median = 1.03, respectively, p < 0.001). In AR cases, a significant positive association was observed between miR-223 expression level and TNSS (r = 0.492, p = 0.002), EDN serum level (r = 0.427, p = 0.008), IL-4 serum level (r = 0.341, p = 0.036) and IL-17 serum level (r = 0.324, p = 0.047). MiR-223, at a cutoff value of 1.18, had a sensitivity and specificity of 94.9 % and 92.5%, respectively. In conclusion, miR-223 expression is significantly greater in blood of AR patients. There is a significant association between miR-223 and clinical severity of AR, each of IL-17 and IL-4 as well as EDN. Therefore, miR-223 may be employed as an effective biomarker for AR diagnosis.

LncRNA FGD5-AS1 Alleviates Inflammation in Allergic Rhinitis through the miR-223-3p/COX11 Axis.

INTRODUCTION: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of allergic rhinitis (AR). The current investigation is focused on elucidating the functional impact of a specific lncRNA, FGD5 antisense RNA 1 (FGD5-AS1), on the development and progression of AR through its interaction with miR-223-3p. METHODS: An experimental framework for AR was constructed in both cellular and animal models. Quantitative assessment of FGD5-AS1, miR-223-3p, and COX11 mRNA expression was conducted using real-time quantitative reverse transcription PCR. The expression of inflammatory factors, immunoglobulin E, LTC4, and ECP, was examined using ELISA. Apoptosis in human nasal epithelial cells was assessed by the flow cytometry method. The protein expression of COX11 was examined using Western blotting. Nasal mucosal function was further evaluated by hematoxylin and eosin staining. Furthermore, bioinformatics evaluations, dual-luciferase reporter assays, and a series of experimental procedures unveiled a putative competitive endogenous RNA regulatory mechanism. RESULTS: We found the expression of lncRNA FGD5-AS1 was decreased in AR. In vitro lncRNA FGD5-AS1 attenuated the production of inflammatory cytokines in nasal epithelial cells. Furthermore, elevated FGD5-AS1 expression significantly alleviated AR symptoms by reducing nasal epithelial apoptosis and inflammation. MiR-223-3p was identified as a direct target of FGD5-AS1. Moreover, miRNA-223-3p directly downregulated the expression of COX11 mRNA. Subsequent experiments confirmed that FGD5-AS1 regulated AR through the miR-223-3p/COX11 axis, thereby inhibiting inflammation. CONCLUSION: The FGD5-AS1/miR-223-3p/COX11 axis plays a pivotal role in the pathogenesis of AR, suggesting that FGD5-AS1 could serve as a potential diagnostic biomarker and therapeutic target for AR.

Association between allergic rhinitis and hypertension risk: A bidirectional 2-sample mendelian randomization study.

Previous studies have suggested a potential association between allergic rhinitis (AR) and hypertension, but the genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between AR and hypertension. Using a large-scale genome-wide association study (GWAS) public database, we conducted meticulous screening to acquire the most up-to-date GWAS data on single nucleotide polymorphisms (SNPs) relevant to AR and hypertension, with a significance threshold of P < 5 × 10-8. Then, we investigated the causal association between AR and hypertension through mendelian randomization (MR) analysis. We also performed reverse MR analysis to assess the possibility of reverse causality. Sensitivity analyses encompassed various factors, including horizontal pleiotropy, heterogeneity testing, and stepwise exclusion sensitivity checks. To investigate the causal relationship between AR and hypertension, we utilize the odds ratio (OR) and 95% confidence interval (CI) as our evaluative metric. This study leveraged a database comprising 112583 samples for AR and 461880 samples for hypertension. After meticulous screening, we identified 32 SNPs as instrumental variables. By employing the aforementioned 2-sample Mendelian randomization approaches, the estimated causal effects showed striking concordance. A discernible causal association between AR and hypertension was found using the IVW method (OR = 0.91, 95% CI: 0.86-0.98, P = .008), with horizontal pleiotropy and heterogeneity tests supporting the validity of our MR study. MR-Egger regression findings provided reassurance against bias stemming from genetic pleiotropy (intercept = -0.0006802, P = .6947). Interestingly, "leave-one-out" analysis yielded no evidence of nonspecific SNP influences, further consolidating our findings. Moreover, our reverse MR analysis yielded no indication of reverse causality from hypertension to AR, effectively discounting any influence from the latter on the former. Our study found evidence of a causal association between AR and hypertension in individuals of European ancestry. It demonstrated that AR reduced the risk of hypertension, suggesting a protective effect on hypertension due to the negative correlation with AR.

Exploring causal relationships between inflammatory cytokines and allergic rhinitis, chronic rhinosinusitis, and nasal polyps: a Mendelian randomization study.

Objectives: Previous research has suggested connections between specific inflammatory cytokines and nasal conditions, including Allergic Rhinitis (AR), Chronic Rhinosinusitis (CRS), and Nasal Polyps (NP). However, a lack of robust research establishing the causal underpinnings of them. This Mendelian Randomization (MR) study aims to evaluate the causal relationships between 41 inflammatory cytokines and the incidence of AR, CRS and NP. Methods: This study employed a two-sample MR design, harnessing genetic variations derived from publicly accessible genome-wide association studies (GWAS) datasets. AR data was sourced from a GWAS with 25,486 cases and 87,097 controls (identifier: ukb-b-7178). CRS data originated from a GWAS encompassing 1,179 cases and 360,015 controls (identifier: ukb-d-J32). NP data was extracted from a GWAS involving 1,637 cases and 335,562 controls (identifier: ukb-a-541). The data for 41 inflammatory cytokines were obtained from an independent GWAS encompassing 8,293 participants. Inverse variance weighted (IVW), MR Egger regression and Weighted median were used to evaluate the causalities of exposures and outcomes. A range of sensitivity analyses were implemented to assess the robustness of the results. Results: The results revealed significant associations between elevated circulating levels of MIP-1α (odds ratio, OR: 1.01798, 95% confidence interval, CI: 1.00217-1.03404, p = 0.02570) and TNF-α (OR: 1.01478, 95% CI: 1.00225-1.02746, p = 0.02067) with an augmented risk of AR in the IVW approach. Heightened levels of circulating IL-2 exhibited a positive correlation with an increased susceptibility to NP in the IVW approach (OR: 1.00129, 95% CI: 1.00017-1.00242, p = 0.02434), whereas elevated levels of circulating PDGF-BB demonstrated a decreased risk of NP (OR: 0.99920, 95% CI: 0.99841-0.99999, p = 0.047610). The MR analysis between levels of 41 inflammatory cytokines and the incidence of CRS yielded no positive outcomes. Conclusion: This investigation proposes a potential causal association between elevated levels of MIP-1α and TNF-α with an elevated risk of AR, as well as an increased risk of NP linked to elevated IL-2 levels. Furthermore, there appears to be a potential association between increased levels of circulating PDGF-BB and a reduced risk of NP.

CircMIRLET7BHG, upregulated in an m6A-dependent manner, induces the nasal epithelial barrier dysfunction in allergic rhinitis pathogenesis.

OBJECTIVE: Allergic rhinitis (AR) remains a frequent aspiratory allergic inflammatory disorder with a high incidence. Circular RNAs (circRNAs) have been revealed to participate in the pathogenesis of AR. This study investigated the biological function of circMIRLET7BHG (hsa_circ_0008668) in AR progression. METHODS: Ovalbumin (OVA)-exposed human nasal epithelial cell line (HNEpC) and mice were adopted as the in vitro and in vivo models of AR. Immunofluorescence staining was used to determine epithelial tight junction protein expression. Target molecule levels were assessed by RT-qPCR and Western blotting. Localization of circMIRLET7BHG and IGF2BP1 was observed by RNA-FISH and immunofluorescence. Epithelial barrier damage was determined by transepithelial electrical resistance and fluorescein isothiocyanate-dextran (FD4) permeability. Serum concentrations of IgE, sIgE, IFN-γ, IL-4, and IL-5 were detected by ELISA. Apoptosis, pathological changes, and eosinophil infiltration in nasal mucosa tissues were evaluated by TUNEL, H&E, and Sirius red staining, respectively. Molecular mechanism was analyzed by RNA pull-down, RIP, and MeRIP assays. RESULTS: An increased expression of circMIRLET7BHG was found in AR patients and experimental models. Down-regulation of circMIRLET7BHG attenuated OVA-induced allergic symptoms via relieving epithelial thicknesses, eosinophil infiltration, apoptosis, and inflammatory response in mice. Subsequently, circMIRLET7BHG deficiency prevented OVA-induced epithelial barrier dysfunction by reducing epithelial permeability, and inhibiting tight junction proteins. Mechanistically, methyltransferase-like 3 (METTL3) enhanced circMIRLET7BHG expression via m6A methylation, which enhanced ADAM10 mRNA stability via interaction with IGF2BP1. CONCLUSION: METTL3-mediated m6A modification increased circMIRLET7BHG expression that consequently raised ADAM10 mRNA stability via interplay with IGF2BP1, thereby promoting AR by inducing epithelial barrier dysfunction.

Association of LOX gene G473A polymorphism with the occurrence of allergic rhinitis and efficacy of montelukast sodium in children.

Allergic rhinitis (AR) is very common in adolescents, and current treatment options are complex and unsatisfactory. The objective of this study was to analyze the association of lysyl oxidase (LOX) gene G473A polymorphism with susceptibility to AR in children. In addition, we analyzed the therapeutic effect of montelukast sodium on AR. Forty-five children with AR (research group, 8.16±2.88 years old) and 51 healthy children (control group, 8.22±3.87 years old) during the same period were selected. The LOX gene G473A polymorphism was detected with polymerase chain reaction (PCR)-restriction fragment length polymorphism method. The effect of G473A polymorphism in the occurrence of AR was assessed by logistic regression analysis. In addition, the levels of C-reactive protein (CRP), Interleukin (IL-6), and IL-8 were measured to observe the relationship between G473A polymorphism and inflammatory factors. Finally, montelukast sodium was given to children with AR to investigate the effect of G473A polymorphism on clinical outcomes. The number of G473A polymorphisms in the research group was not significantly different from the control group for GA-type (P = 0.521). However, the number of GG-type polymorphisms was less while the number of type AA was more than the control group (P = 0.044 and 0.046). Children carrying the AA gene had an approximately 4-fold increased risk of AR, while those carrying the GG gene had a decreased risk (P < 0.001). Moreover, children carrying the GG gene had lower levels of CRP, IL-6, and IL-8 and better clinical outcomes, while those carrying the AA gene had higher levels of inflammatory factors and worse outcomes (P<0.05). LOX gene G473A polymorphism is closely associated with AR pathogenesis and may have an important research value in antagonizing the therapeutic effect of montelukast sodium.

Potential causal association between aspirin use and the reduced risk of hayfever or allergic rhinitis: a Mendelian randomization study.

Background: The evidence from observational studies on the association between the use of aspirin and the risk of hayfever or allergic rhinitis is conflicting, with a dearth of high-quality randomized controlled trials. Objective: This study aims to investigate the causal relationship between aspirin use and the risk of hayfever or allergic rhinitis. Methods: We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We utilized publicly available summary statistics datasets from genome-wide association studies (GWAS) meta-analyses on aspirin use in individuals of European descent (n = 337,159) as the exposure variable, and a GWAS on doctor-diagnosed hayfever or allergic rhinitis in individuals from the UK Biobank (n = 83,529) as the outcome variable. Results: We identified 7 single nucleotide polymorphisms (SNPs) at genome-wide significance from the GWASs associated with aspirin use as instrumental variables (P<5×10-8; linkage disequilibrium r2 <0.1). The IVW method provided evidence supporting a causal association between aspirin use and reduced risk of hayfever or allergic rhinitis (ß = -0.349, SE = 0.1356, P = 0.01008). MR-Egger regression indicated no causal association between aspirin use and hayfever or allergic rhinitis (ß = -0.3742, SE = 0.3809, P = 0.371), but the weighted median approach yielded evidence of a causal association (ß = -0.4155, SE = 0.1657, P = 0.01216). Cochran's Q test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy. Conclusion: The findings of the MR analysis support a potential causal relationship between aspirin use and the reduced risk of hayfever or allergic rhinitis.