Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma.
ABSTRACT: We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype.We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped.In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P?=?0.001-0.004, OR?=?0.59-0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P?=?0.033), but the other four SNPs in hapblock2 were not.To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition.
Project description:Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often in the form of a severe and sudden attack. Due to time consuming and laborious oral aspirin challenge (OAC) for diagnosis of AERD, non-invasive biomarkers have been searched. Therefore, we scrutinize AERD-associated exonic SNPs and examine the diagnostic potential of combination of these candidate SNPs to predict AERD DNA obtained from 164 AERD subjects, 397 subjects with aspirin-tolerant asthma (ATA), 398 normal controls and 10 null samples were subjected to Exome Chip assay of 240K SNPs. 1023 model (210-1) were generated from combination of the top 10 SNPs selected by p-values. The area under the curve (AUC) value of receiver operating characteristic (ROC) curves was calculated for each model. SNP functional Portal and PolyPhen-2 was used to validate the functional significance of the candidate SNPs
Project description: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.
Project description:Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p?=?3.40×10-8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.
Project description:PURPOSE: The human WD repeat-containing protein 46 (WDR46; also known as C6orf11), located at the disease-relevant centromere side of the class II major histocompatibility complex region, is hypothesized to be associated with risk of aspirin-exacerbated respiratory disease (AERD) as well as a decline in forced expiratory volume in the first second (FEV1), an important diagnostic marker of asthma. METHODS: To investigate the association between WDR46 and AERD, five single-nucleotide polymorphisms (SNPs) were genotyped in 93 AERD cases and 96 aspirin-tolerant asthma controls of Korean ethnicity. Three major haplotypes were inferred from pairwise comparison of the SNPs, and one was included in the association analysis. Differences in the frequency distribution of WDR46 SNPs and haplotype were analyzed using logistic and regression models via various modes of genetic inheritance. RESULTS: Depending on the genetic model, the logistic and regression analyses revealed significant associations between rs463260, rs446735, rs455567, rs469064, and WDR46_ht2 and the risk of AERD (P=0.007-0.04, P(corr)=0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, P(corr)=0.01-0.03). Furthermore, functional analysis in silico showed that the G>A allele of rs463260 located in the 5' untranslated region potentially matched a nucleotide sequence within an upstream open reading frame of WDR46. CONCLUSIONS: These findings show for the first time that WDR46 is an important genetic marker of aspirin-induced airway inflammation and may be useful for formulating new disease-management strategies.
Project description:PURPOSE:Aspirin exacerbated respiratory disease (AERD) results in a severe asthma attack after aspirin ingestion in asthmatics. The filamin A interacting protein 1 (FILIP1) may play a crucial role in AERD pathogenesis by mediating T cell activation and membrane rearrangement. We investigated the association of FILIP1 variations with AERD and the fall rate of forced expiratory volume in one second (FEV1). METHODS:A total of 34 common FILIP1 single nucleotide polymorphisms (SNPs) were genotyped in 592 Korean asthmatic subjects that included 163 AERD patients and 429 aspirin-tolerant asthma (ATA) controls. RESULTS:This study found that 5 SNPs (P=0.006-0.01) and 2 haplotypes (P=0.01-0.03) of FILIP1 showed nominal signals; however, corrections for the multiple testing revealed no significant associations with the development of AERD (P(corr)>0.05). In addition, association analysis of the genetic variants with the fall rate of FEV1, an important diagnostic marker of AERD, revealed no significant evidence (P(corr)>0.05). CONCLUSIONS:Although further replications and functional evaluations are needed, our preliminary findings suggest that genetic variants of FILIP1 might be not associated with the onset of AERD.
Project description:Member RAS oncogene family (RAB1A), a member of the RAS oncogene family, cycles between inactive GDP-bound and active GTP-bound forms regulating vesicle transport in exocytosis. Thus, functional alterations of the RAB1A gene may contribute to aspirin intolerance in asthmatic sufferers. To investigate the relationship between single-nucleotide polymorphisms (SNPs) in the RAB1A gene and aspirin-exacerbated respiratory disease (AERD), asthmatics (n=1197) were categorized into AERD and aspirin-tolerant asthma (ATA). All subjects were diagnosed as asthma on the basis of the Global Initiative for Asthma (GINA) guidelines. AERD was defined as asthmatics showing 15% or greater decreases in forced expiratory volume in one second (FEV(1)) or naso-ocular reactions by the oral acetyl salicylic acid (ASA) challenge (OAC) test. In total, eight SNPs were genotyped. Logistic regression analysis identified that the minor allele frequency of +14444 T>G and +41170 C>G was significantly higher in the AERD group (n=181) than in the ATA group (n=1016) (p=0.0003-0.03). Linear regression analysis revealed a strong association between the SNPs and the aspirin-induced decrease in FEV(1) (p=0.0004-0.004). The RAB1A gene may play a role in the development of AERD in asthmatics and the genetic polymorphisms of the gene have the potential to be used as an indicator of this disease.
Project description:The tyrosine-protein kinase Tec (TEC) is a member of non-receptor tyrosine kinases and has critical roles in cell signaling transmission, calcium mobilization, gene expression, and transformation. TEC is also involved in various immune responses, such as mast cell activation. Therefore, we hypothesized that TEC polymorphisms might be involved in aspirin-exacerbated respiratory disease (AERD) pathogenesis. We genotyped 38 TEC single nucleotide polymorphisms in a total of 592 subjects, which comprised 163 AERD cases and 429 aspirin-tolerant asthma controls. Logistic regression analysis was performed to examine the associations between TEC polymorphisms and the risk of AERD in a Korean population. The results revealed that TEC polymorphisms and major haplotypes were not associated with the risk of AERD. In another regression analysis for the fall rate of forced expiratory volume in 1 second (FEV1) by aspirin provocation, two variations (rs7664091 and rs12500534) and one haplotype (TEC_BL2_ht4) showed nominal associations with FEV1 decline (p = 0.03-0.04). However, the association signals were not retained after performing corrections for multiple testing. Despite TEC playing an important role in immune responses, the results from the present study suggest that TEC polymorphisms do not affect AERD susceptibility. Findings from the present study might contribute to the genetic etiology of AERD pathogenesis.
Project description:Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.
Project description:BACKGROUND:Aspirin desensitization followed by daily aspirin provides therapeutic benefits to patients with aspirin-exacerbated respiratory disease (AERD). It is not well understood how eicosanoid levels change during aspirin treatment. OBJECTIVE:To investigate associations between clinical outcomes of aspirin treatment and plasma eicosanoid levels in patients with AERD. METHODS:Thirty-nine patients with AERD were offered aspirin treatment (650 mg twice daily) for 4 weeks. Respiratory parameters and plasma levels of multiple eicosanoids were recorded at baseline and after 4 weeks of aspirin therapy using the Asthma Control Test and Rhinoconjunctivitis Quality of Life Questionnaire. Respiratory function was evaluated using the FEV1 and nasal inspiratory peak flow. RESULTS:After aspirin treatment, respiratory symptoms improved in 16 patients, worsened in 12 patients, and did not change in 4 patients. Seven patients were unable to complete the desensitization protocol. Patients with symptom improvement had higher baseline plasma 15-hydroxyeicosatetraenoic acid (15-HETE) levels than did patients with symptom worsening: 7006 pg/mL (interquartile range, 6056-8688 pg/mL) versus 4800 pg/mL (interquartile range, 4238-5575 pg/mL), P = .0005. Baseline 15-HETE plasma levels positively correlated with the change in Asthma Control Test score (r = 0.61; P = .001) and in FEV1 after 4 weeks of aspirin treatment (r = 0.49; P = .01). It inversely correlated with Rhinoconjunctivitis Quality of Life Questionnaire score (r = -0.58; P = .002). Black and Latino patients were more likely to have symptom worsening on aspirin or fail to complete the initial desensitization than white, non-Latino patients (P = .02). CONCLUSIONS:In patients with AERD, low baseline 15-HETE plasma levels and black or Latino ethnicity are associated with worsening of respiratory symptoms during aspirin treatment.
Project description:BACKGROUND:Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood. OBJECTIVE:We aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA). METHODS:A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of ORMDL3 SNP (rs7216389) was performed. RESULTS:Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTE4 (all P<0.05). The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC (P = 0.033, r = -0.274; P = 0.019, r = -0.299, respectively). Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030). CONCLUSION & CLINICAL RELEVANCE:This is the first study that shows the dysregulated de novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.