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Immunoglobulin E (IgE) is one of the central players in asthma and allergic diseases. Although the serum IgE level, a useful endophenotype, is generally increased in patients with asthma, genetic factors influencing IgE regulation in asthma are still not fully understood. To identify the genetic variations associated with total serum and mite-specific IgEs in asthmatics, a genome-wide association study (GWAS) of 657,366 single nucleotide polymorphisms (SNPs) was performed in 877 Korean asthmatics. This study found that several new genes might be associated with total IgE in asthmatics, such as CRIM1 (rs848512, P = 1.18×10(-6); rs711254, P = 6.73×10(-6)), ZNF71 (rs10404342, P = 7.60×10(-6)), TLN1 (rs4879926, P = 7.74×10(-6)), and SYNPO2 (rs1472066, P = 8.36×10(-6); rs1038770, P = 8.66×10(-6)). Regarding the association of specific IgE to house dust mites, it was observed that intergenic SNPs nearby to OPRK1 and LOC730217 might be associated with Dermatophagoides pteronyssinus (D.p.) and Dermatophagoides farinae (D.f.) in asthmatics, respectively. In further pathway analysis, the phosphatidylinositol signaling system and adherens junction pathways were estimated to play a role in the regulation of total IgE levels in asthma. Although functional evaluations and replications of these results in other populations are needed, this GWAS of serum IgE in asthmatics could facilitate improved understanding of the role of the newly identified genetic variants in asthma and its related phenotypes.

Nasal polyps are abnormal lesions arising mainly from the nasal mucosa and paranasal sinuses. Since the human class II, major histocompatibility complex, transactivator (CIITA) is a positive regulator of class II, major histocompatibility complex gene transcription, the CIITA gene is thought to be involved in the presence of nasal polyps in asthma and aspirin hypersensitive patients. To investigate the association between CIITA and nasal polyposis, 18 single nucleotide polymorphisms (SNPs) were genotyped in 467 asthmatics who were classified into 158 aspirin-exacerbated respiratory disease (AERD) and 309 aspirin-tolerant asthma (ATA) subgroups. Differences in the frequency distribution of CIITA variations between polyp-positive cases and polyp-negative controls were determined using logistic analyses. Initially, a total of 9 CIITA variants were significantly associated with the presence of nasal polyps in the overall asthma, AERD and ATA groups [P=0.001-0.05, odds ratio (OR)=0.53-2.35 in the overall asthma group; P=0.01-0.02, OR=2.45-2.66 in the AERD group; P=0.001‑0.05, OR=0.45-2.61 in the ATA group using various modes of genetic inheritance]. One the variations (rs12932187) retained this association after multiple testing corrections (Pcorr=0.01) in the overall asthma group. In addition, two variations (rs12932187 and rs11074938) were associated with the presence of nasal polyps following multiple testing corrections (Pcorr=0.02 and 0.04, respectively) in the ATA group. These novel findings suggest that rs12932187 and rs11074938 may constitute susceptibility markers of inflammation of the nasal passages in asthma patients.

Background: Nasal polyps are abnormal lesions that cause airway obstruction and can occur along with other respiratory diseases. On account of its association with aspirin exacerbated respiratory disease (AERD), the human discoidin, CUB and LCCL domain containing 2 (DCBLD2) is hypothesized to be a candidate gene for the development of nasal polyps in asthma patients., Methods: A total of 12 single-nucleotide polymorphisms (SNPs) were genotyped in 467 Korean asthma patients who were stratified further into 108 AERD and 353 aspirin-tolerant asthma (ATA) subgroups. Five major haplotypes were inferred from pairwise comparison of the polymorphisms. The patients were matched to control for confounds, and differences in the frequency distribution of DCBLD2 SNPs and haplotypes were analyzed using logistic models via various modes of genetic inheritance., Results: Results reveal significant association of rs828618 and DCBLD2_ht1 with nasal polyposis in the overall asthma patients group (P = 0.006, P(corr) = 0.05). Interestingly, the strength of association were maintained in the ATA subgroup (P = 0.007, P(corr) = 0.06), and moderate correlation was detected in the AERD subgroup (P = 0.04-0.05, P(corr) > 0.05)., Conclusions: Although further replication and validation are needed, these findings suggest that DCBLD2 could be a potential marker and drug target for treatment of nasal polyposis in Korean asthma patients.

Background: Since subepithelial fibrosis and protruded extracellular matrix are among the histological characteristics of polyps, the emilin/multimerin domain-containing protein 2 (EMID2) gene is speculated to be involved in the presence of nasal polyps in asthma and aspirin-hypersensitive patients., Methods: To investigate the association between EMID2 and nasal polyposis, 49 single-nucleotide polymorphisms (SNPs) were genotyped in 467 asthmatics of Korean ancestry who were stratified further into 114 aspirin exacerbated respiratory disease (AERD) and 353 aspirin-tolerant asthma (ATA) subgroups. From pairwise comparison of the genotyped polymorphisms, 14 major haplotypes (frequency > 0.05) were inferred and selected for association analysis. Differences in the frequency distribution of EMID2 variations between polyp-positive cases and polyp-negative controls were determined using logistic analyses., Results: Initially, 13 EMID2 variants were significantly associated with the presence of nasal polyps in the overall asthma group (P = 0.0008-0.05, OR = 0.54-1.32 using various modes of genetic inheritance). Although association signals from 12 variants disappeared after multiple testing corrections, the relationship between EMID2_BL1_ht2 and nasal polyposis remained significant via a codominant mechanism (P corr = 0.03). On the other hand, the nominal associations observed between the genetic variants tested for the presence of nasal polyps in AERD (P = 0.003-0.05, OR = 0.25-1.82) and ATA (P = 0.01-0.04, OR = 0.46-10.96) subgroups disappeared after multiple comparisons, suggesting lack of associations., Conclusions: These preliminary findings suggest that EMID2_BL1_ht2 may be a susceptibility marker of inflammation of the nasal passages among Korean asthma patients.

Background: Nasal polyps, part of the aspirin triad symptoms, are edematous protrusions arising from the mucosa of the nasal sinuses. Although the causative factors and pathogenesis of the polyps are unknown, the significant effect of human leukocyte antigen-DR (HLA-DR) expression in nasal polyps and genetic associations of the major histocompatibility complex class II, DR alpha (HLA-DRA) with immune-mediated diseases have been revealed., Methods: To investigate the associations of HLA-DRA polymorphisms with nasal polyposis in asthmatic patients and in aspirin-hypersensitive subgroups, 22 single nucleotide polymorphisms (SNPs) were genotyped in a total of 467 asthmatic patients including 158 nasal polyp-positive and 309 polyp-negative subjects., Results: Statistical analysis showed that four SNPs (p = 0.0005-0.02; Pcorr = 0.009-0.033) and one haplotype (p = 0.002; Pcorr = 0.029) were significantly associated with the presence of nasal polyposis in asthmatic patients. In further analysis, although significant signals disappeared after corrections for multiple testing, two HLA-DRA polymorphisms (rs9268644C>A, rs3129878A>C) were found to be potential markers for nasal polyp development in aspirin-tolerant asthma (p = 0.005 and 0.007, respectively) compared with the aspirin-exacerbated respiratory disease (p > 0.05) subgroup. In silico analysis predicted major "C" allele of rs14004C>A in 5'-untranslated region as a potential binding site for regulatory glucocorticoid receptor. In addition, sequence nearby rs1051336G>A is suspected to be a pyrimidine-rich element that affects mRNA stability., Conclusion: Despite the need for replication in larger cohorts and/or functional evaluations, our findings suggest that HLA-DRA polymorphisms might contribute to nasal polyposis susceptibility in patients with asthma.

The human ubiquitin protein ligase E3C (UBE3C) regulates airway inflammatory responses and is hypothesized to be associated with the presence of nasal polyps in asthma-related diseases. A total of 24 UBE3C single-nucleotide polymorphisms (SNPs) were genotyped in a 467 Korean asthma cohort that was stratified into more homogenous phenotypes of 114 aspirin-exacerbated respiratory disease subgroup and 353 aspirin-tolerant asthma (ATA) subjects. Association analysis revealed that 16 UBE3C SNPs were significantly associated with presence of nasal polyps in the overall asthma group (P=0.0008 and P(corr)=0.01; odds ratio (OR)=0.60). The strength of association from 10 polymorphisms was increased in the ATA subgroup (P=0.0002 and P(corr)=0.003; OR=0.49). In addition, UBE3C_ht1 was found to be consistently associated with nasal polyps in the overall asthmatics group (P=0.006) and the ATA phenotype (P=0.002; P(corr)=0.02) via a codominant mechanism. Our findings provide evidence that variations in UBE3C are potent genetic markers of nasal polyps development in Korean asthmatics and may contribute novel insights into the clinical relevance and potential involvement of UBE3C in respiratory deficiencies.

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.

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.

The human chromosomal 5q31-33 region has been implicated as a susceptibility locus for several immune-mediated diseases including asthma in several populations. Recently, the extraneuronal GABAergic system has been implicated as a new link to airway obstruction in asthma. In addition, the SLC6A7 gene, which is positioned at 5q31-32 and encodes the transporter for an excitatory neurotransmitter of L-proline, has never been studied for its association with asthma. In this study, resequencing of all exon, promoter region (2 kb), and exon-intron boundary regions in the SLC6A7 gene found a total of 33 single nucleotide polymorphisms (SNPs) in 24 Korean asthmatic patients. After the initial SNP survey, a total of 17 common SNPs with minor allele frequency (MAF) over 10% were genotyped in 498 asthmatic patients and 303 normal controls. Logistic analyses revealed significant associations between genetic variants of the SLC6A7 gene and asthma (P-value up to 6.0 x 10(-4); P(corr) value up to 0.009). In further regression analyses, minor alleles of intronic +11431T>C, +12213C>T and +12927A>G in linkage disequilibrium block 2 and +20113T>C in 3'UTR significantly increased the bronchodilator response in asthmatics (P-value of recessive model up to 0.008; which are not significant after multiple correction). Therefore, our findings suggest that SLC6A7 could be a susceptible gene for asthma.

BACKGROUND:The functional role of the human diffuse panbronchiolitis critical region 1 (DPCR1) gene, located in the major histocompatibility complex class I, has not been widely investigated. However, this gene is a well known genetic marker for diffuse panbronchiolitis, a disease affecting human respiratory bronchioles. In this study we explored the association between polymorphisms in DPCR1 and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype. METHODS: Genotyping of 6 polymorphisms was carried out in a total of 189 Korean asthmatic patients stratified into 93 AERD cases and 96 aspirin tolerant asthma controls. Subjects who exhibited significant decrease of FEV1 by aspirin provocation were identified as AERD subjects. Logistic and regression analyses were performed to investigate the association between DPCR1 polymorphisms and the risk of AERD as well as FEV1 decline. RESULTS: Initial analysis revealed significant association of rs2517449 with AERD, with a P value of .03 via a recessive model; however, the association signal disappeared after multiple testing corrections. In addition, rs2517449 and rs2240804 also showed association signals with decline of FEV1 after aspirin provocation (P = .007 and .03, respectively, in a recessive model). After testing for multiple comparisons, only the association signal from rs2517449 was retained (Pcorr = .04), while other polymorphisms showed no associations with the risk of AERD and FEV1 decline. CONCLUSIONS: Our results show that polymorphisms in DPCR1 are not associated with the risk of AERD. [ABSTRACT FROM AUTHOR]

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 = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV)% by aspirin provocation ( P = 0.004-0.04; P = 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. [ABSTRACT FROM AUTHOR]

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, pcorr = .004, OR = 0.24, 95% CI = 0.09-0.62 for rs2982510 and rs2294752; p = .008, pcorr = .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, pcorr = .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. [ABSTRACT FROM AUTHOR]