Dataset Information

Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics.

ABSTRACT: PURPOSE:Endoplasmic reticulum (ER) stress has recently been observed to activate NF-kappaB and induce inflammatory responses such as asthma. Activating transcription factor 6? (ATF6B) is known to regulate ATF?-mediated ER stress response. The aim of this study is to investigate the associations of ATF6B genetic variants with aspirin-exacerbated respiratory disease (AERD) and its major phenotype, % decline of FEV1 by aspirin provocation. METHODS:Four common single nucleotide polymorphisms (SNPs) of ATF6B were genotyped and statistically analyzed in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) as controls. RESULTS:Logistic analysis revealed that 2 SNPs (rs2228628 and rs8111, P=0.008; corrected P=0.03) and 1 haplotype (ATF6B-ht4, P=0.005; corrected P=0.02) were significantly associated with % decline of FEV1 by aspirin provocation, whereas ATF6B polymorphisms and haplotypes were not associated with the risk of AERD. CONCLUSIONS:Although further functional and replication studies are needed, our preliminary findings suggest that ATF6B may be related to obstructive phenotypes in response to aspirin exposure in adult asthmatics.

SUBMITTER: Park TJ

PROVIDER: S-EPMC3936043 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics.

Park Tae-Joon TJ Kim Jeong-Hyun JH Pasaje Charisse F CF Park Byung-Lae BL Bae Joon Seol JS Uh Soo-Taek ST Kim Yong-Hoon YH Kim Mi-Kyeong MK Choi Inseon S IS Choi Byoung Whui BW Shin Hye-Rim HR Park Jong-Sook JS Koh Insong I Park Choon-Sik CS Shin Hyoung Doo HD

Allergy, asthma & immunology research 20131128 2

<h4>Purpose</h4>Endoplasmic reticulum (ER) stress has recently been observed to activate NF-kappaB and induce inflammatory responses such as asthma. Activating transcription factor 6β (ATF6B) is known to regulate ATFα-mediated ER stress response. The aim of this study is to investigate the associations of ATF6B genetic variants with aspirin-exacerbated respiratory disease (AERD) and its major phenotype, % decline of FEV1 by aspirin provocation.<h4>Methods</h4>Four common single nucleotide polymo ...[more]

PMID: 24587951

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Project description:Background Aspirin exacerbated respiratory disease (AERD) is a syndrome characterized by chronic hyperplastic rhinosinusitis, nasal polyposis, asthma and aspirin sensitivity. The mechanisms by which produce these manifestations of intolerance are not fully defined, the current research involve alterations in the metabolism of arachidonic acid, cyclooxygenase 1 (COX-1) inhibition and its deviation from substrate to the lipoxygenase (LO) pathway, inducing increased synthesis of leukotrienes (LT). Biological plausibility of this fact has led to the search for polymorphisms in genes responsible for LT synthesis however others factors such as genetics polymorphisms in pro-inflammatory cytokines like, IL1B and IL8 could be associated. Methods 78 patients with AERD, 135 aspirin-tolerant asthma (ATA) and 134 healthy control subjects participated. All participants who underwent a simple spirometry, methacholine challenge and nasal challenge with Lysine-aspirin (L-ASA), both tests performed according to international guidelines. Peripheral blood was drawn by venipuncture, genomic DNA was obtained using the commercial BDtract DNA isolation kit. We selected 2 polymorphisms in 2 genes related to chronic inflammation rs16944 in IL1B, and rs4073 in IL8, Allelic discrimination of SNPs was performed by Real Time PCR (PCR-RT) on a 7300 Real Time PCR Systems. Statistical analysis was performed between groups of cases (AERD and ATA) versus control group with Epi-info v.6.04 by ?2 test to identify the difference between the allele and genotype frequencies of each polymorphism made, considering a significant P value <0.05, in addition to the calculation of odds ratios and confidence intervals of 95%. Results We find no association between IL1B (rs16944) to GG and GA genotypes in ATA patients versus control group neither AERD versus control group. Interestingly, the AA genotype showed increased frequency in the AERD patients versus the ATA patients (FG = 0.19 versus 0.07), this association remained significant (P = 0.018, OR 2.98, CI, 1.17-7.82). Conclusions This is the first observation that IL1B polymorphisms are involved in AERD, suggest that patients carrying out the IL1B-511 polymorphism (rs16944 AA genotype) may show enhanced susceptibility to develop AERD.

Project description:Few studies have investigated the significance of decreased FEV(1) in non-COPD, nonasthmatic healthy subjects. We hypothesized that a lower FEV(1) in these subjects is a potential marker of an increased susceptibility to obstructive lung disease such as asthma and COPD. This was a cross-sectional analysis of 1505 Japanese adults. We divided the population of healthy adults with no respiratory diseases whose FEV(1)/FVC ratio was ? 70% (n = 1369) into 2 groups according to their prebronchodilator FEV(1) (% predicted) measurements: < 80% (n = 217) and ? 80% (n = 1152). We compared clinical data - including gender, age, smoking habits, total IgE levels, and annual decline of FEV(1) - between these 2 groups. In addition, as our group recently found that TSLP variants are associated with asthma and reduced lung function, we assessed whether TSLP single nucleotide polymorphisms (SNPs) were associated with baseline lung function in non-COPD, nonasthmatic healthy subjects (n = 1368). Although about half of the subjects with lower FEV(1) had never smoked, smoking was the main risk factor for the decreased FEV(1) in non-COPD, nonasthmatic subjects. However, the subjects with lower FEV(1) had a significantly higher annual decline in FEV(1) independent of smoking status. Airflow obstruction was associated with increased levels of total serum IgE (P = 0.029) and with 2 functional TSLP SNPs (corrected P = 0.027-0.058 for FEV(1)% predicted, corrected P = 0.015-0.033 for FEV(1)/FVC). This study highlights the importance of early recognition of a decreased FEV(1) in healthy subjects without evident pulmonary diseases because it predicts a rapid decline in FEV(1) irrespective of smoking status. Our series of studies identified TSLP variants as a potential susceptibility locus to asthma and to lower lung function in non-COPD, nonasthmatic healthy subjects, which may support the contention that genetic determinants of lung function influence susceptibility to asthma.

Project description:BackgroundAsthma is a respiratory tract disorder characterized by airway hyper-reactivity and chronic inflammation. Allergic asthma is associated with the production of allergen-specific IgE and expansion of allergen-specific T-cell populations. Progression of allergic inflammation is driven by T-helper type 2 (Th2) mediators and is associated with alterations in the levels of lipid mediators.ObjectivesResponses of the respiratory system to birch allergen provocation in allergic asthmatics were investigated. Eicosanoids and other oxylipins were quantified in the bronchoalveolar lumen to provide a measure of shifts in lipid mediators associated with allergen challenge in allergic asthmatics.MethodsEighty-seven lipid mediators representing the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via LC-MS/MS following off-line extraction of bronchoalveolar lavage fluid (BALF). Multivariate statistics using OPLS were employed to interrogate acquired oxylipin data in combination with immunological markers.ResultsThirty-two oxylipins were quantified, with baseline asthmatics possessing a different oxylipin profile relative to healthy individuals that became more distinct following allergen provocation. The most prominent differences included 15-LOX-derived ?-3 and ?-6 oxylipins. Shared-and-Unique-Structures (SUS)-plot modeling showed a correlation (R(2) = 0.7) between OPLS models for baseline asthmatics (R(2)Y[cum] = 0.87, Q(2)[cum] = 0.51) and allergen-provoked asthmatics (R(2)Y[cum] = 0.95, Q(2)[cum] = 0.73), with the majority of quantified lipid mediators and cytokines contributing equally to both groups. Unique structures for allergen provocation included leukotrienes (LTB(4) and 6-trans-LTB(4)), CYP-derivatives of linoleic acid (epoxides/diols), and IL-10.ConclusionsDifferences in asthmatic relative to healthy profiles suggest a role for 15-LOX products of both ?-6 and ?-3 origin in allergic inflammation. Prominent differences at baseline levels indicate that non-symptomatic asthmatics are subject to an underlying inflammatory condition not observed with other traditional mediators. Results suggest that oxylipin profiling may provide a sensitive means of characterizing low-level inflammation and that even individuals with mild disease display distinct phenotypic profiles, which may have clinical ramifications for disease.

Dataset Information

Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics.

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Polymorphisms of ATF6B Are Potentially Associated With FEV1 Decline by Aspirin Provocation in Asthmatics.

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