Gyu Young Hur

CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients

OBJECTIVES Leukotriene receptor antagonists (LTRA), such as montelukast, have been used as a first-line treatment for patients with aspirin-intolerant asthma (AIA). This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the ALOX5, LTC4S, COX-2, CysLTR1 and TBXA2R genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population. METHODS Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA, and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year: group I (> or = 200 mg montelukast/month; n = 37), group II (5-150 mg/month; n = 25) and group III (< 5 mg/month; n = 27). Genetic polymorphisms in the arachidonic acid cascade were determined using a single-base extension method. RESULTS We found that there was a significant difference in the genotype frequency of the CysLTR1 promoter polymorphism -634C > T among the three groups (p = 0.007 for group I vs group II, p = 0.017 for group I vs group III), while there were no significant associations between LTRA requirements and polymorphisms of the other genes. The patients with the variant genotype (CT or TT) of the -634C = T CysLTR1 promoter polymorphism showed a higher expression level than those with the common genotype (CC). CONCLUSION These findings indicate that the CysLTR1 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long-term management of AIA patients.

The Clinical Characteristics of Anisakis Allergy in Korea

Anisakidae larvae can cause anisakiasis when ingested by humans. Although several groups have reported a gastrointestinal Anisakis allergy among people in Spain and Japan, our report is the first to summarize the clinical features of 10 Anisakis allergy cases in Korea. We enrolled 10 Korean patients (6 men and 4 women) who complained of aggravated allergic symptoms after ingesting raw fish or seafood. Sensitization to Anisakis was confirmed by detecting serum specific IgE to Anisakis simplex. The most common manifestation of anisakiasis was urticaria (100%), followed by abdominal pain (30%) and anaphylaxis (30%). All patients presenting with these symptoms also exhibited high serum specific IgE (0.45 to 100 kU/L) to A. simplex. Nine patients (90%) exhibited atopy and increased total serum IgE levels. The fish species suspected of carrying the Anisakis parasite were flatfish (40%), congers (40%), squid (30%), whelk (10%), and tuna (10%). Anisakis simplex should be considered as a possible causative food allergen in adult patients presenting with urticaria, angioedema, and anaphylaxis following the consumption of raw fish or seafood.

Prevalence of work-related symptoms and serum-specific antibodies to wheat flour in exposed workers in the bakery industry

BACKGROUND Although bakers asthma (BA) is a common occupational asthma, there have been few reports on this disease in Korean subjects. OBJECTIVES We evaluated the prevalence of serum-specific IgE, IgG1, and IgG4 antibodies in relation to work-related respiratory symptoms in a single industrial bakery. METHODS Three hundred and ninety-two bakery workers were administered and taken a questionnaire regarding respiratory symptoms. For symptomatic workers, the methacholine bronchial challenge test and specific bronchoprovocation tests with wheat extracts were carried out. Skin prick tests were performed and serum-specific IgE, IgG1, and IgG4 antibodies to wheat flour were detected. The IgE- and IgG4-binding components were identified by immunoblotting. RESULTS Sixty-seven workers (17.1%) complained of work-related upper and lower respiratory symptoms. The prevalence of BA based on positive bronchoprovocation test results was 1.5%. The sensitization rate to wheat flour was 5.9% by skin prick test and 6.5% by ELISA, and was closely associated with the presence of atopy and work-related lower respiratory symptoms (P<0.001 for both). IgE immunoblotting revealed six major IgE-binding components (27, 31, 36, 43, 54, and 72 kDa). The presence of wheat-specific IgG1 and IgG4 antibodies was found to be significantly associated with exposure intensity (P<0.05 for both). CONCLUSIONS The overall prevalence of wheat sensitization in a Korean bakery was 5.9%. We confirmed that an IgE-mediated response is the major pathogenic mechanism for the induction of work-related symptoms in wheat-exposed workers. Wheat-specific IgG antibodies may represent current or previous exposure to wheat dust.

Predictors of the Severity and Serious Outcomes of Anaphylaxis in Korean Adults: A Multicenter Retrospective Case Study

Purpose Differences in definitions of the condition, relevant triggers, and the geographical locations of study centers, cause estimates of the prevalence of anaphylaxis to vary. Recent epidemiological data indicate that the incidence of anaphylaxis is rising. Methods To investigate the causes and clinical features of anaphylaxis in Korean adults, factors associated with the severity of the condition, and serious outcomes, a retrospective medical record review was performed on adult patients diagnosed with anaphylaxis between 2007 and 2011 in 15 University Hospitals of South Korea. Results A total of 1,806 cases (52% male, age 16-86 years) were reported. Cutaneous symptoms (84.0%), combined with respiratory (53.9%) and/or cardiovascular (55.4%) symptoms, were the most frequent presentations. Using a recognized grading system, 1,776 cases could be classified as either mild, 340; moderate, 690; or severe, 746. Although eliciting factors varied significantly by age, gender, and regional and seasonal factors, drugs (46.5%; including nonsteroidal anti-inflammatory drugs, antibiotics, and radiocontrast media) were the most common cause of anaphylaxis, followed by foods (24.2%), insect stings (16.4%), exercise (5.9%), and unknown etiology (7.0%). All of age, multi-organ involvement, a history of allergic disease, and drug-induced anaphylaxis, were significant predictors of serious outcomes requiring hospital admission or prolongation of hospital stay. Epinephrine auto-injectors were prescribed for 7.4% of reported cases. Conclusions The principal causes of anaphylaxis in Korean adults were drugs, food, and insect stings. Drug-associated anaphylaxis, a history of allergic disease, multi-organ involvement, and older age, were identified as predictors of serious outcomes.

Asthma-Like Symptoms are Increased in the Metabolic Syndrome

Background. The prevalence of obesity and asthma has been increasing during the last several decades. Obesity has been reported to be associated with asthma. Obesity, especially abdominal obesity, is the main component of the metabolic syndrome. Objectives. We thus hypothesized that metabolic syndrome is an important contributing factor for the development of asthma-like symptoms. Methods. The Korean Health and Genome Study started in 2001 as an ongoing population-based study of Korean adults 40 to 69 years of age. The prevalence of asthma-like symptoms in the previous 12 months was obtained by a questionnaire, and spirometric testing was conducted. Results. Among the 10,038 participants, the data from 9,942 individuals (4,716 men and 5,226 women) was available. Asthma-like symptoms (wheeze [p = 0.0006], resting dyspnea [p = 0.0062], and post-exercise dyspnea [p < 0.0001]) were increased in the subjects of the metabolic syndrome group. Subjects with asthma-like symptoms had a decreased lung function compared to subjects without asthma-like symptoms. Among the components of the metabolic syndrome, abdominal obesity and hypertension were the risk factors for asthma-like symptoms. Conclusions. Metabolic syndrome is associated with asthma-like symptoms. Among the components of metabolic syndrome, abdominal obesity and hypertension are the risk factors for asthma-like symptoms.

Thymidylate synthase and ERCC1 as predictive markers in patients with pulmonary adenocarcinoma treated with pemetrexed and cisplatin

Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to antifolate drugs such as pemetrexed. Excision repair cross-complementation group 1 (ERCC1) is a predictive marker for platinum-based chemotherapy. This study evaluated whether the expression of TS and ERCC1 proteins is associated with clinical outcomes of the patients with pulmonary adenocarcinoma who were treated with pemetrexed/cisplatin as first-line chemotherapy. The expressions of TS and ERCC1 were evaluated by immunohistochemistry in biopsy specimens obtained from patients with pulmonary adenocarcinoma who had received pemetrexed/cisplatin as first-line treatment. Patients were categorized according to median H-score. Response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively. Both low TS and ERCC1 expressions were significantly associated with better RR (p = 0.037 and p = 0.015, respectively) and longer PFS (p < 0.001 and p = 0.004, respectively). Low ERCC1 expression was also associated with longer OS (p = 0.003) while TS only showed a trend (p = 0.105). TS expression was independent predictor for the better PFS in multivariate analysis (hazard ratio [HR] = 0.32, 95% confidence interval [CI]: 0.14-0.76). Combining the two markers, the low TS/low ERCC1 group showed significantly longer PFS (HR = 0.48, 95% CI: 0.26-0.75) and OS (HR = 0.57, 95% CI: 0.36-0.89) compared with high TS/high ERCC1 group. Protein expressions of TS and ERCC1 were associated with clinical outcomes in patients with pulmonary adenocarcinoma who were treated with pemetrexed/cisplatin as first-line chemotherapy. TS and ERCC1 protein expressions can be potential predictive markers in this setting.

The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype is a risk factor for toluene diisocyanate-induced occupational asthma.

Background: Although the pathogenesis of toluene diisocyanate (TDI)-induced occupational asthma (TDI-OA) is incompletely understood, several studies have suggested immunologic mechanisms, including specific IgE responses. A few studies have suggested human leukocyte antigen (HLA) associations with TDI-induced asthma in Western countries, but this is the first investigation of associations between HLA class I and II alleles and TDI-induced asthma patients in Asia, using high-resolution analysis. Methods: Patients with TDI-OA (n = 84), asymptomatic exposed controls (AECs, n = 47) and unexposed normal controls (NCs, n = 127) were enrolled. HLA class I and II genotyping was performed by the direct DNA sequencing analysis. Specific serum IgE antibodies to the vapor type TDI-albumin conjugate were measured by ELISA. Results: There was no significant association between the allele frequencies and the phenotype of TDI-OA. However, the frequency of the HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype was significantly higher in TDI-OA patients (19%) than in AEC (2.1%, p = 0.007, OR 4.429, CI 1.497–13.103) or NC (3.1%, p < 0.001, OR 7.235, CI 2.236–22.510) subjects, with statistical significance persisting after correction for multiple comparisons. DQB1*0402 was significantly associated with the presence of specific IgE to TDI-albumin conjugates in serum (p = 0.006, OR 4.552, CI 1.540–13.449). This p value remained significant after correction for multiple comparison. Conclusion: The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype may be a genetic marker for the development of TDI-induced asthma in Koreans. Several HLA alleles that enhance specific IgE sensitization in exposed subjects are indicated.

Serum ferritin and transferrin levels as serologic markers of methylene diphenyl diisocyanate-induced occupational asthma

BACKGROUND Although methylene diphenyl diisocyanate (MDI) may induce occupational asthma in the workplace, the pathogenic mechanisms are unclear. OBJECTIVES By using bronchoalveolar lavage fluid, we sought to identify proteins that were differentially expressed between subjects with MDI-induced occupational asthma (MDI-OA) and asymptomatic exposed controls (AECs). METHODS To find proteins that were differentially expressed between the MDI-OA and AEC groups, 2-dimensional electrophoresis was performed by using bronchoalveolar lavage fluid obtained from subjects after MDI-specific inhalation challenge. The selected protein spots were then identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The clinical relevance of the differentially expressed spots was compared by ELISA using sera from the MDI-OA/eosinophilic bronchitis, AEC, and unexposed healthy control groups. Receiver operating characteristic curves were then plotted, and the sensitivity and specificity were determined. RESULTS Twenty-three protein spots were identified that distinguished the subjects with MDI-OA from those in the AEC group. Among them, ferritin expression was downregulated whereas transferrin expression was upregulated in subjects with MDI-OA compared with AEC; these results were validated by ELISA using sera from the MDI-OA/EB and AEC groups. To identify subjects with MDI-OA, the optimal serum cutoff levels were 69.84 ng/mL for ferritin and 2.48 microg/mL for transferrin. When these 2 parameters were combined, the sensitivity was 71.43% and the specificity was 85.71%. CONCLUSION Serum ferritin and transferrin levels are associated with the phenotype of MDI-OA.

Pharmacogenetics of aspirin-intolerant asthma

Leukotriene overproduction is the major characteristic of aspirin-intolerant asthma (AIA). Most studies examining the molecular genetic mechanisms of AIA have focused on leukotriene-related genes, including ALOX5, LTC4S, TXA2R and prostanoid-receptor genes. One study suggested that the human leukocyte antigen (HLA) allele DPB1*0301 may be a genetic marker for the AIA phenotype in European and Asian populations, and HLA-DPB1*0301 has been suggested as a useful genetic marker for predicting more favorable responders to leukotriene-receptor antagonists for long-term management of AIA. Although several reports have indicated possible associations between genetic polymorphisms and variable responses to leukotriene modifiers in nonaspirin sensitive asthmatic patients, few have suggested relationships between such genetic polymorphisms and variable responses to asthma drugs in AIA patients.

Tissue Transglutaminase Can Be Involved in Airway Inflammation of Toluene Diisocyanate-Induced Occupational Asthma

BackgroundThis study was conducted to evaluate whether tissue transglutaminase (tTG) may be involved in airway inflammation of toluene diisocyanate-induced occupational asthma (TDI-OA).MethodsWe enrolled 93 patients with TDI-OA, 177 asymptomatic exposed subjects, 43 patients with allergic asthma, and 70 unexposed normal controls. The prevalence of serum immunoglobulin G (IgG) to tTG in the TDI-OA group (20.2%) was significantly higher than that in the three other groups (P < 0.001).ResultsTDI-OA patients with serum IgG to tTG had significantly lower methacholine PC20 values (P < 0.02) and significantly higher prevalence of specific immunoglobulin E to vapor type TDI–human serum albumin conjugate (P < 0.01; r2 = 0.411, P < 0.05). TDI exposure could increase tTG activity via reactive oxygen species (ROS) production, which was found to cross-link with cytokeratin 19 on immunoblot analysis.ConclusionTherefore, TDI exposure may activate tTG via ROS-mediated mechanism in the airway epithelium leading to persistent airway inflammation in TDI-OA patients.