ABSTRACT
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a syndrome characterised by chronic rhinosinusitis, nasal polyps, asthma and aspirin intolerance. An imbalance of eicosanoid metabolism with anover-production of cysteinyl leukotrienes (CysLTs) has been associated with AERD. However, the precise mechanisms underlying AERD are unknown. OBJECTIVE: To establish the transcriptome of the nasal polyp airway epithelial cells derived from AERD patients to discover gene expression patterns in this disease. METHODS: Nasal airway epithelial cells were isolated from 12 AERD polyps and 8 AERD non-polyp nasal mucosa samples as controls from the same subjects. Utilising the Illumina HiSeq 2500 platform, RNA samples were sequenced. Potential gene candidate DMRT3 was selected from the differentially-expressed genes for validation. RESULTS: Comparative transcriptome profiling of nasal epithelial cells was accomplished in AERD. A total of 20 genes had twofold mean regulation expression differences or greater. In addition, 8 genes were upregulated, including doublesex and mab-3 related transcription factor 3 (DMRT3), and 12 genes were downregulated. Differentially regulated genes comprised roles in inflammation, defence and immunity. Metabolic process and embryonic development pathways were significantly enriched. Enzyme-linked immune sorbent assay (ELISA) results of DMRT3 in AERD patients were significantly upregulated compared to controls (p = 0.03). Immunohistochemistry (IHC) of AERD nasal polyps localised DMRT3 and was predominantly released in the airway epithelia. CONCLUSION: Findings suggest that DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps. However, further studies are imperative to confirm the exact mechanism of polyp formation in AERD patients.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Nasal Polyps/metabolism , Respiration Disorders/drug therapy , Respiration Disorders/metabolism , Transcription Factors, TFII/metabolism , Transcriptome , Adult , Aspirin/adverse effects , Asthma, Aspirin-Induced/genetics , Asthma, Aspirin-Induced/metabolism , Chronic Disease , Epithelial Cells/metabolism , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Leukotrienes/metabolism , Male , Middle Aged , Nasal Lavage , Nasal Polyps/immunology , RNA-Seq , Sinusitis/immunology , Sinusitis/metabolism , Skin TestsABSTRACT
AIM: To evaluate the association of three single nucleotide polymorphisms in TNF and one in LTA in Mexican patients with aspirin-exacerbated respiratory disease (AERD) and the correlation of those single nucleotide polymorphisms with serum levels of TNF-α. PATIENTS & METHODS: Case-control study including 133 patients with AERD, 135 patients with asthma (aspirin-tolerant asthmatics) and 182 healthy subjects. RESULTS: GA genotype of rs1800629 in TNF was found to be associated with the risk of developing AERD (p < 0.05; odds ratio = 2.36) and by dominant model (p < 0.05; odds ratio = 2.51). Furthermore, there was a difference in the serum levels between the aspirin-tolerant asthmatics group and the other groups (p < 0.001). CONCLUSION: The GA genotype of rs1800629 is associated with genetic susceptibility to AERD, but it does not correlate to protein serum levels.
Subject(s)
Asthma, Aspirin-Induced/genetics , Genetic Predisposition to Disease , Genotype , Polymorphism, Single Nucleotide , Tumor Necrosis Factor-alpha/genetics , Adult , Asthma, Aspirin-Induced/epidemiology , Asthma, Aspirin-Induced/ethnology , Case-Control Studies , Female , Humans , Male , Mexico/epidemiology , Mexico/ethnology , Middle AgedABSTRACT
INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma rhinosinusitis and poliposis; ingestion of aspirin or other non-steroid anti-inflammatory drugs exacerbate asthma-like symptoms. The pathogenesis of AERD is unknown, and genetic and environmental factors contribute to the disease. Our objective is identifying polymorphisms associated with susceptibility in a Mexican mestizo population. METHODS: Primarily we performed custom Illumina goldengate array-based genotyping of 1512 SNPs, carefully selected from a variety of acute/chronic inflammatory lung conditions previously reported. Four SNPs in TRPM3 gene showed the lowest p-values (rs10780946, rs7025694, rs1889915, and rs7047645). We further selected rs10780946 and rs7025694 for validation using Taqman genotyping (n = 743; 288 AERD, 272 ATA, and 183 HC). RESULTS: rs10780946 showed association when compared between AERD and ATA groups under co-dominant (p = 0.006), dominant (p = 0.002), overdominant (p = 0.01), and log-additive (p = 0.03) genetic models. AERD showed increased heterozygous TC (rs10780946-rs7025694) haplotype compared to ATA and HC (p < 0.05). We could not confirm any association between rs7025694 and AERD. CONCLUSION: rs10780946 TRPM3 polymorphism is associated with AERD susceptibility.