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.

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Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10−5 to 4.0×10−5). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR  = 2.63; 95% CI  = 1.64–4.21; P = 6.0×10−5). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV1) by aspirin provocation than other variants (P = 3.0×10−5). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.

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.

Because genetic characteristics vary among subjects, the therapeutic effects of a certain drug differ among patients with the same disease. For this reason, special interest has focused on tailored treatments. Although it is well known that sex is genetically determined, little attention has been paid to sex differences in the clinical features and treatment of asthma. Females are more likely to suffer allergic asthma, to have difficulty controlling asthma symptoms, and to show adverse effects to drugs. As asthma symptoms show cyclic changes depending on female hormone levels in many women of child-bearing age, the use of contraceptives may specifically help to treat female patients with asthma such as those with perimenstrual asthma and severe asthma. Generally, testosterone seems to suppress asthma, and dehydroepiandrosterone (DHEA), a less virilizing androgen, may be effective for treating asthma. Evidence exists for a therapeutic and steroid-sparing effect of DHEA. However, further studies on the optimal dose and route of DHEA for each sex are needed. Monitoring of the serum DHEA-S level is necessary for patients with asthma on inhaled steroid treatment, and at minimum, replacement therapy for patients with a low level of DHEA may be helpful for treating their asthma.

Background: Most studies on the effects of temperature and humidity on exercise-induced bronchospasm (EIB) in asthmatics have been carried out under indoor conditions. However, any asthmatic patient is exposed to varying climatic conditions. Objective: To investigate whether temperature or relative humidity plays a more important role in determining the degree of EIB in asthmatics under naturally exposed climate conditions. Methods: To exclude the effects of pollen on EIB, we enrolled 69 subjects with perennial asthma (mean ± SD: 20.1 ± 1.5 years). The subjects performed outdoor free running tests. They were divided into winter (n = 25), spring/autumn (n = 22), and summer (n = 22) groups according to the season when they performed the tests. Initial spirometry and skin prick tests were performed. Methacholine bronchial challenge testing and, one day later, the free running tests were done. Results: There were significant differences in temperature and relative humidity among the three groups: However, the relative humidity in winter did not differ from that in spring/autumn. There were no differences in pulmonary functions, airway responsiveness, and atopy score among the three groups. The percentage of cases of positive EIB – fall in forced expiratory volume in 1s FEV₁ of >15% from baseline – in winter (84%, p < 0.05) or spring/autumn (86.4%, p < 0.05) was higher than that in summer (50%). However, the percentage of subjects with a positive EIB in winter did not differ from that in spring/autumn. The maximal percent fall in FEV₁ after exercise in winter did not differ from that in spring/autumn. Conclusions: The occurrence of EIB is associated with environmental temperature and humidity. Under such climatic conditions as in Korea, relative humidity may be a more important factor than temperature in contributing to EIB in patients with perennial asthma.

It has been suggested that airway eosinophilic inflammation is associated with the severity of exercise-induced bronchospasm (EIB). Blood eosinophils are known to be an indirect marker of airway inflammation in asthma. The aim of this study is to investigate that a simple and easy blood test for blood eosinphil counts may predict the severity of EIB in asthma. Seventy-seven men with perennial asthma (age range 18-23 years) were included. Lung function test, skin prick test, and blood tests for eosinophils counts and total IgE levels were performed. Methacholine bronchial provocation test and, 24 h later, free running test were carried out. EIB was defined as a 15% reduction or more in post-exercise FEV1 compared with pre-exercise FEV1 value. Atopy score was defined as a sum of mean wheal diameters to allergens. EIB was observed in 60 (78%) of 77 subjects. Asthmatics with EIB showed significantly increased percentages of eosinophils (P<0.01), log eosinophil counts (P<0.001), and atopy scores (P<0.05) and decreased log PC20 values (P < 0.05) compared with asthmatics without EIB. Asthmatics with eosinophils of > 700 microl(-1) (36.9 +/- 12.7%) had significantly greater maximal % fall in FEV1 after exercise than asthmatics with eosinophils of < 350 microl(-1) (24.7 +/- 16.6%, P <0.05). Blood eosinophil counts > 350 microl(-1) yielded the specificity of 88% and positive predictive value of 93% for the presence of EIB. When a multiple regression analysis of maximal % fall in FEV1 according to log eosinophil counts, log PC20, log IgE and atopy score was performed, only blood eosinophil counts were significant factor contributing to the maximal % fall in FEV1 after exercise. These findings not only suggest that a simple blood test for eosinophils may be useful in the prediction of the severity of EIB, but also reinforce the view that airway eosinophilic inflammation may play a major role in EIB in asthma.

In a study conducted 1 year ago, we found that Th1 immune enhancement following Bacille Calmette-Guérin (BCG) vaccination effectively suppressed human asthma. To investigate whether revaccination would further improve lung function, BCG vaccine was given again. Current lung function tended to improve in the Repeated BCG group (n = 9), but not in the Single BCG group (previously the placebo group) (n = 11), compared with that 1 year ago. The BCG vaccination improved lung function in both groups, and the Repeated BCG group showed a significant increase in the peripheral blood interferon gamma/interleukin 4 ratio. These findings suggest that repeated BCG vaccinations might be effective in asthma therapy.