Adrenal insufficiency associated with long-term use of inhaled steroid in asthma.

BACKGROUND: We previously reported that as many as one third of hospitalized patients with asthma treated with a low to medium daily dose of inhaled steroids (ICSs) for an average of 4.5 years showed adrenal insufficiency (AI). OBJECTIVE: To re-examine this issue in consecutive outpatients with asthma because of possible subject selection bias. METHODS: One hundred twenty-one consecutive adult patients with asthma under ICS treatment for at least 6 months underwent a rapid adrenocorticotrophic hormone stimulation test. AI was defined as a morning serum cortisol level no higher than 3 µg/dL or lower than 18 µg/dL before and after administration of 250 µg of adrenocorticotrophic hormone. RESULTS: The mean durations of ICS use in the short-term (less than the median) and long-term (at least the median) users were 3.8 and 11.5 years, respectively. The proportion of subjects affected by AI tended to increase with the increasing cumulative dose of ICS (short-term users at a low to medium daily dose: mean cumulative dose 502 mg [15 of 34, 44.1%]; short-term users at a high dose of 941 mg [16 of 26, 61.5%]; long-term users at a low to medium dose of 1,077 mg [25 of 41, 61.0%]; long-term users at a high dose of 2,805 mg [13 of 20, 65.0%]), although not significantly. In short-term users, daily and cumulative ICS doses were significantly related to serum cortisol levels 60 minutes after taking adrenocorticotrophic hormone (r = -0.300 and -0.287, respectively; P < .05). CONCLUSION: A large number of patients with asthma might have AI even with low- to medium-dose ICS treatment when ICSs are administered over a long period. Thus, it is essential that patients with asthma under ICS treatment be checked for AI much more frequently.

Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Genetic variants of the gasdermin B gene associated with the development of aspirin-exacerbated respiratory diseases.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by a severe and sudden asthma attack after aspirin ingestion in patients with asthma. We studied associations with six common single nucleotide polymorphisms (SNP) of the gasdermin B gene (GSDMB). OBJECTIVE: DNA obtained from 572 patients with asthma (with AERD, n = 165; and with aspirin-tolerant asthma, n = 407) and 391 normal controls was subjected to genotyping of six SNPs of GSDMB. METHODS: An association analysis between GSDMB variants and AERD, with a fall rate of the forced expiratory volume in the first second of expiration (FEV1), was performed by using logistic and regression models. RESULTS: Two SNPs in the intron (rs870830, rs7216389) showed significant associations with AERD (minimum p = 7.00 × 10-4 in the dominant model), even after Bonferroni correction (pcorr = 0.01 for the rs870830). Regression analysis of the genetic variants with FEV1 revealed significant associations with rs870830 and the haplotype 2 (pcorr = 4.71 × 10-4 for rs870830 and pcorr = 1.14 × 10-3 for haplotype 2, respectively). CONCLUSION: We found strong associations among GSDMB polymorphisms and the presence of AERD and FEV1 in Korean patients with asthma. Our findings indicated that genetic variations of GSDMB may be associated with the development of AERD and aspirin-induced bronchospasm.

Association analysis of tapasin polymorphisms with aspirin-exacerbated respiratory disease in asthmatics.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the development of airway obstruction in asthmatic individuals following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. TAPBP (TAP-binding protein, tapasin) is upregulated by eicosanoids, which act as potent inflammatory molecules in aspirin-related reactions. Thus, functional alterations in the TAPBP gene may contribute toward AERD. OBJECTIVES: We examined the relationship between the single nucleotide polymorphisms on the TAPBP gene and AERD. MATERIALS AND METHODS: A group of asthmatic patients (n=1252) underwent the oral aspirin challenge. Oral aspirin challenge reactions were categorized into two groups as follows: 15% or greater decreases in forced expiratory volume in 1 s or naso-ocular and skin reactions (AERD), or 15% or less decreases in forced expiratory volume in 1 s without naso-ocular and skin reactions (aspirin-tolerant asthma). Five single nucleotide polymorphisms of the TAPBP gene were genotyped. RESULTS: Logistic regression analysis showed that the minor allele frequencies of TAPBP rs2071888 C>G (Thr260Arg) on exon 4 (P>0.05), which was in absolute linkage disequilibrium with rs1059288 T>C on 3'UTR, were significantly higher in the AERD group than in the aspirin-tolerant asthma group, and the P values remained significant after multiple comparisons (Pcorr=0.006, odds ratio: 1.37, 95% confidence interval: 1.11-1.69, additive model; Pcorr=0.009, odds ratio: 1.52, 95% confidence interval: 1.14-2.03, dominant model). Alpha-helical wheel plotting showed that 260Arg had greater hydrophilic helical property than 260Thr. CONCLUSION: TAPBP polymorphisms may play a role in the development of AERD.

Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population.

Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3' regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case-control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD (p = 5.11 × 10(-7); OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge (p = 2.82 × 10(-7)). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.

Association analysis of formyl peptide receptor 2 (FPR2) polymorphisms and aspirin exacerbated respiratory diseases.

Aspirin-exacerbated respiratory diseases (AERD) are associated with the metabolism of arachidonic acid. FPR2 (formyl peptide receptor2) is a high-affinity ligand receptor for potent anti-inflammatory lipid metabolites: lipoxins. Thus, functional alterations of the FPR2 may contribute to AERD. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in the FPR2 and AERD. Asthmatics were categorized into AERD <15% decreases in forced expiratory volume in one second (FEV(1)), and/or naso-ocular reactions after oral aspirin challenge (n=170) and aspirin-tolerant asthma (ATA, n=268). In all, 11 SNPs were genotyped. FPR2 protein expressions on CD14-positive monocytes in peripheral blood were measured using flow cytometric analysis. We performed RT-PCR of the FPR2 mRNA expressed by peripheral blood mononuclear cells. Logistic regression analysis showed that the minor allele frequency of FPR2 -4209T>G (rs1769490) in intron 2 was significantly lower in the AERD group (n=170) than in the ATA group (n=268) (P=0.006, P(corr)=0.04, recessive model). The decline of FEV(1) after aspirin challenge was significantly lower in the subjects with GG homozygotes of FPR2 -4209T>G than those with the other genotypes (P=0.0002). Asthmatic homozygotes for FPR2 -4209T>G minor allele exhibited significantly higher FPR2 protein expression in CD14-positive monocytes than did those with the common allele of FPR2 -4209T>G allele (P=0.01). There was no difference in the expression of the wild form and the exon 2 deleted variant form of FPR2 gene according to the genotypes of FPR2 -4209T>G. The minor allele at FPR2 -4209T>G may have a protective role against the development of AERD, via increase of FPR2 protein expression in inflammatory cells.

Association of FANCC polymorphisms with FEV1 decline in aspirin exacerbated respiratory disease.

Aspirin exacerbated respiratory disease (AERD) is a clinical condition characterized by severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. The exacerbated inflammatory response in Fancc-deficient mice has been reported to be associated with hemopoietic responses that are also related to AERD pathogenesis. To investigate associations of FANCC polymorphisms with AERD and related phenotypes, this study genotyped 25 common single nucleotide polymorphisms (SNPs) in a total of 592 Korean asthmatics including 163 AERD and 429 aspirin-tolerant asthma (ATA) subjects. Logistic analysis revealed that genetic polymorphisms of the FANCC gene might not be directly related to AERD development and nasal polyposis (P > 0.05). However, the FEV1 decline by aspirin provocation showed significant associations with FANCC polymorphisms (P = 0.006-0.04) and a haplotype (unique to rs4647416G > A, P = 0.01 under co-dominant, P = 0.006 under recessive model). In silico analysis showed that the "A" allele of rs4647376C > A, which was more prevalent in AERD than in ATA, could act as a potential branch point (BP) site for alternative splicing (BP score = 4.16). Although replications in independent cohorts and further functional evaluations are still needed, our preliminary findings suggest that FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases.

Potential association of DDR1 genetic variant with FEV1 decline by aspirin provocation in asthmatics.

BACKGROUND: The discoidin domain receptor tyrosine kinase 1 (DDR1) is positioned within the major histocompatibility complex (MHC) region which plays an important role in the immune system. In addition, DDR1 has been elucidated to be downregulated during the epithelial-mesenchymal transition of bronchial epithelium. OBJECTIVE: To investigate the potential genetic associations between DDR1 and aspirin-exacerbated respiratory disease (AERD), this study conducted association studies of DDR1 single nucleotide polymorphisms (SNPs) with AERD and the obstructive symptom of forced expiratory volume in 1 s (FEV(1)) decline after aspirin provocation. METHODS: Nine common SNPs were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) controls. The genotype distributions of all loci were in Hardy-Weinberg equilibrium (HWE; p > .05). Results. In the results of logistic analyses using age, sex, smoking status, and atopy as covariates, DDR1 rs1264320 in the intronic region showed a potent association signal with FEV(1) decline by aspirin provocation in asthmatics of this study even after corrections for multiple testing (p = .003 and corrected p = .01). However, the variants of DDR1 were not significantly associated with the AERD development (corrected p > .05). On further comparison of FEV(1) decline by aspirin provocation between AERD and ATA, the variant rs1264320 was found to be associated with the FEV(1) decline of ATA rather than AERD. CONCLUSION: Despite the need for further functional evaluations and replications, we conclude that DDR1 polymorphisms are not likely to contribute to predispositions of AERD, but may be potentially associated with FEV(1) decline by aspirin provocation in asthmatics.

Potential association of DCBLD2 polymorphisms with fall rates of FEV(1) by aspirin provocation in Korean asthmatics.

Aspirin exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyposis and aspirin hypersensitivity. The aspirin-induced bronchospasm is mediated by mast cell and eosinophilic inflammation. Recently, it has been reported that the expression of discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is up-regulated in lung cancers and is regulated by transcription factor AP-2 alpha (TFAP2A), a component of activator protein-2 (AP-2) that is known to regulate IL-8 production in human lung fibroblasts and epithelial cells. To investigate the associations between AERD and DCBLD2 polymorphisms, 12 common variants were genotyped in 163 AERD subjects and 429 aspirin tolerant asthma (ATA) controls. Among these variants, seven SNPs (rs1371687, rs7615856, rs828621, rs828618, rs828616, rs1062196, and rs8833) and one haplotype (DCBLD2-ht1) show associations with susceptibility to AERD. In further analysis, this study reveals significant associations between the SNPs or haplotypes and the percentage of forced expiratory volume in one second (FEV(1)) decline following aspirin challenge using multiple linear regression analysis. Furthermore, a non-synonymous SNP rs16840208 (Asp723Asn) shows a strong association with FEV(1) decline in AERD patients. Although further studies for the non-synonymous Asp723Asn variation are needed, our findings suggest that DCBLD2 could be related to FEV(1)-related phenotypes in asthmatics.

KIF3A, a cilia structural gene on chromosome 5q31, and its polymorphisms show an association with aspirin hypersensitivity in asthma.

INTRODUCTION: The kinesin family number 3A (KIF3A) gene on the human chromosomal 5q31-33 region, which is known as a susceptibility locus for immune diseases including asthma, plays a crucial role in generation of cilia. RESULTS: A treatment with aspirin in the human bronchial epithelial cells increased the mRNA expression level of KIF3A compared to that of the untreated control (P ≤ 0.01), and nasal polyp epithelia from aspirin-intolerant asthma (AIA) patients also showed a higher expression of KIF3A protein than aspirin-tolerant asthma controls. Further logistic analyses revealed that most polymorphisms of KIF3A were significantly associated with AIA (P = 0.0004-0.02; P(corr) = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV(1))% by aspirin provocation (P = 0.004-0.04; P(corr) = 0.03). DISCUSSION: Our findings suggest that the KIF3A gene and/or its polymorphisms might have a susceptibility effect on AIA, providing a new step toward controlling aspirin intolerance in asthmatics.

A possible association of EMID2 polymorphisms with aspirin hypersensitivity in asthma.

Aspirin-intolerant asthma (AIA) is an asthma phenotype characterized by the development of bronchoconstriction following ingestion of aspirin. Despite the well-defined pathological trigger, the underlying mechanisms of AIA are still unclear. With the biophysical characteristics of the human EMI domain-containing protein 2 (EMID2) gene in relation to the extracellular matrix deposition and epithelial-mesenchymal transition as pivotal characteristics of airway remodeling in asthma, we hypothesized that genetic polymorphisms of EMID2 might affect the development of AIA. In this study, the allelic associations of 49 single-nucleotide polymorphisms (SNPs) of the human EMID2 gene were evaluated from 163 AIA patients and 429 aspirin-tolerant asthma (ATA) subjects as controls in a Korean population. Logistic analysis showed that five SNPs (P = 0.01-0.04, but P (corr) > 0.05) and EMID2_BL2_ht2 haplotype (unique to the minor alleles of rs4727494 and rs13233066; P = 0.02; P (corr) = 0.02) were significantly associated with AIA. More interestingly, regression analysis of the decline of forced expiratory volume in one second (FEV(1)) by aspirin provocation revealed that 10 SNPs (P = 0.003-0.04) and four relevant haplotypes (P = 0.002-0.02) were significantly associated with the fall rate of FEV(1) by aspirin provocation, indicating that genetic polymorphisms of EMID2 could cause meaningful deficits in the upper and lower airways among AIA patients. These findings provide evidence that EMID2 may be a susceptible genetic factor for aspirin hypersensitivity among asthmatics in Korean population.

Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline.

Aspirin exacerbated respiratory disease (AERD) induces bronchoconstriction in asthmatic patients characterized with a clinical condition of severe decline in forced expiratory volume in one second (FEV1) after ingestion of aspirin. Two genes consisting a heterodimer, transporter 1 and 2, ATP-binding cassette, sub-family B (MDR/TAP) (TAP1 and TAP2) within the major histocompatibility complex (MHC) region, have been implicated in immunodeficiency and bronchiectasis development. To investigate the associations of TAP1 and TAP2 genetic polymorphisms with AERD and phenotypic FEV1 decline, a total of 43 common single-nucleotide polymorphisms (SNPs) including 12 SNPs of TAP1 and 31 SNPs of TAP2 were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma controls. Interestingly, regression analysis revealed that polymorphisms and haplotypes of TAP2 were associated with FEV1 decline by aspirin provocation (P=0.002-0.04), with about twofold decline rate of FEV1 in most of minor homozygotes compared with major homozygotes. In addition, nominal evidences of association between TAP2 and AERD development were observed (P=0.02-0.04). However, TAP1 polymorphisms showed no relations to both AERD and FEV1 decline after aspirin challenge (P>0.05). Although further functional evaluations and replications are required, our preliminary findings provide supporting information that variants of TAP2 might be predisposing factors for FEV1 decline-related symptoms.

Possible association of SLC22A2 polymorphisms with aspirin-intolerant asthma.

BACKGROUND: Aspirin-intolerant asthma (AIA) is a clinical syndrome characterized by acute bronchoconstriction following the ingestion of aspirin. Solute carrier family 22, member 2 (SLC22A2), also known as organic cation transporter 2 (OCT2), is predominantly expressed in the luminal membrane of airway epithelial cells and has been shown to mediate the transport of prostaglandins on the cyclooxygenase pathway which is regulated by aspirin blockage. Recently, SLC22A2-mediated uptake inhibition by several nonsteroidal anti-inflammatory drugs and decreased SLC22A2 transport activity by its genetic variants have been elucidated in asthma. METHODS: To investigate the associations between AIA and genetic polymorphisms of the SLC22A2 gene, 18 variants were genotyped in 163 AIA subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate p values for the associations of SLC22A2 polymorphisms with AIA. RESULTS: One common polymorphism in intron 5, i.e. rs316021, was significantly associated with susceptibility to AIA (p = 0.004, P(corr) = 0.05, OR = 0.60, 95% CI = 0.43-0.85 in a codominant model). The minor allele frequency of rs316021 in the AIA group was significantly lower than that in the ATA controls. In addition, a polymorphism in intron 4 (rs3912161) and a haplotype (SLC22A2-ht3) showed significantly stronger association signals with the FEV(1) fall rate induced by aspirin provocation in AIA subjects compared with ATA controls (p = 0.004, P(corr) = 0.05). CONCLUSION: Our findings suggest that SLC22A2 could be a susceptibility gene for aspirin intolerance in asthmatics.

Association analysis of RGS7BP gene polymorphisms with aspirin intolerance in asthmatic patients.

BACKGROUND: Signal-regulated palmitoylation of RGS7BP(regulator of G-protein-signaling 7-binding protein) initiates the activation of G-protein-coupled receptors (GPCRs), including muscarinic receptors, which contribute to the development of asthma and its subphenotypes. OBJECTIVE: To determine the association of RGS7BP gene polymorphisms with the development of aspirin-exacerbated respiratory disease (AERD). METHODS: We evaluated the association of RGS7BP gene polymorphisms with response to oral aspirin challenge and with responsiveness to methacholine challenge. RGS7BP messenger RNA splice variants in peripheral blood platelets from patients with different single-nucleotide polymorphisms were analyzed by reverse-transcription polymerase chain reaction. RESULTS: Logistic regression analysis of RGS7BP gene polymorphisms in patients with AERD (n = 102) and aspirin-tolerant asthma (n = 429) revealed that a haplotype of block 3 consisting of rare alleles +98092 C>G, +98853 C>T, and +104450 T>G of the RGS7BP gene was associated with AERD. Multiple linear regression analysis showed that asthmatic patients carrying ht2/ht2 in block 3 were more responsive to aspirin challenge than those not carrying ht2 (P = .008 in a codominant model). The log-transformed provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% for methacholine was significantly dependent on the BL3-ht2 haplotype. No significant differences in platelet expression of different RGS7BP messenger RNA splice variants were detected between those with and without the BL3-ht2 haplotype. CONCLUSION: BL3-ht2 of RGS7BP may be an important genetic variant associated with AERD. The haplotype of block 3 may play a protective role against aspirin hypersensitivity in asthma, perhaps by altering the responsiveness of muscarinic receptors.

Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma.

BACKGROUND/AIMS: Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. METHODS: This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. RESULTS: Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). CONCLUSION: Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.

Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean population.

Aspirin-intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin-intolerant asthma (AIA) and 429 aspirin-tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; P(corr)= 0.03), rs557881 (non-synonymous C10R, P= 0.007; P(corr)= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; P(corr)= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV(1) by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population.

Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity.

OBJECTIVE: Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels. METHODS: Aspirin-intolerant (AIA, n=103) and aspirin-tolerant asthmatics (n=270) were genotyped and functional promoter assays were performed. RESULTS: Of 15 SNPs tested, seven (-589T>C (rs2243250) in promoter, -33T>C (rs2070874) in the 5'-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P=0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T>C T and -33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and -589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins ß and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors. CONCLUSION: Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity.

Association of CACNG6 polymorphisms with aspirin-intolerance asthmatics in a Korean population.

BACKGROUND: Aspirin-intolerant asthma (AIA) occurs in the lower and upper airways through excessive production of leukotrienes upon administration of non-steroidal anti-inflammatory drugs (NSAIDs). One of the three symptoms of AIA is nasal polyposis, a chronic inflammatory disease that is related to the function of calcium ion in recruitment of immune cells during airway inflammation. It has been implicated that bronchodilation in the airway is related to Ca(2+) regulation. The calcium channel, voltage-dependent, gamma subunit 6 (CACNG6) gene encodes a protein that stabilizes the calcium channel. METHODS: To study the associations between AIA and polymorphisms in CACNG6 gene, eight variants were genotyped in 102 AIA cases and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate the associations of CACNG6 polymorphisms with AIA. RESULTS: Statistical analyses revealed that a single nucleotide polymorphism (SNP; rs192808C > T; P = 0.0004, Pcorr = 0.0029, OR = 2.88 in co-dominant model; P = 0.0005, Pcorr = 0.0036, OR = 2.99 in dominant model) in intron and a haplotype unique to this variant (CACNG6_BL1_ht6; P = 0.003, Pcorr = 0.02, OR = 2.57 in co-dominant model, P = 0.001, Pcorr = 0.0087, OR = 2.81 in dominant model) were significantly associated with the risk of AIA. CONCLUSIONS: Our results suggest that the CACNG6 variants might be associated with the risk of AIA in a Korean population.

Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics.

BACKGROUND: Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. OBJECTIVE: To verify our hypothesis that SMAP1L could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the SMAP1L gene and AIA. METHODS: We conducted an association study between 19 SNPs of the SMAP1L gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of SMAP1L and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. RESULTS: Logistic analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (p = .003, p(corr) = .004, OR = 0.24, 95% CI = 0.09-0.62 for rs2982510 and rs2294752; p = .008, p(corr) = .03, OR = 0.44, 95% CI = 0.24-0.80 for rs446738, in the recessive model). In addition, rs2982510 and rs2294752 were significantly associated with the fall of forced expiratory volume in 1 s (FEV1) by aspirin provocation (p = .001, p(corr) = .04 in the recessive model for both SNPs). CONCLUSIONS: Our findings suggest that SMAP1L might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.

Positive association between aspirin-intolerant asthma and genetic polymorphisms of FSIP1: a case-case study.

BACKGROUND: Aspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by alpha disintegrin and metalloproteinase 33 (ADAM33), which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium. OBJECTIVES: Aim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes. METHODS: We conducted association study between 66 single nucleotide polymorphisms (SNPs) of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates. RESULTS: Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics. CONCLUSION: Although our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.