Hyunna Choi

Effect of Toll-like receptor 4 gene polymorphisms on work-related respiratory symptoms and sensitization to wheat flour in bakery workers

BACKGROUND Bakery workers are exposed to flour allergens and endotoxins, which interact to induce allergic responses and respiratory symptoms. We hypothesized that Toll-like receptor 4 (TLR4) may be involved in the development of work-related respiratory symptoms and sensitization to wheat flour. OBJECTIVE To investigate the genetic contribution of TLR4 to respiratory symptoms and sensitization to wheat flour in bakery workers, we performed a genetic association study of TLR4 in Korean bakery workers. METHODS A total of 381 workers completed a questionnaire regarding work-related symptoms. Skin prick tests with common and occupational allergens were done, and specific antibodies to wheat flour were measured by enzyme-linked immunosorbent assay. Two single-nucleotide polymorphisms (SNPs) of the TLR4 gene (-2027A>G and -1608T>C) were genotyped, and the functional effects of the polymorphisms were analyzed using the luciferase reporter and electrophoretic mobility shift assay. RESULTS Homozygotes for the -2027G and -1608C alleles exhibited a lower prevalence of work-related lower respiratory symptoms than carriers of the -2027AA/AG (P = .007) and -1608TT/TC (P =.021) genotypes. Furthermore, haplotype analysis indicated that workers with the haplotype 2, ht2 [GC], had fewer work-related lower respiratory symptoms (P = .021). The ht2 [GC] construct showed lower promoter activity than the haplotype 1, ht1[AT], in both BEAS-2B (P = .001) and U937 cells (P = .007). CONCLUSION Bakery workers carrying the TLR4 variants are at lower risk of developing work-related chest symptoms. This finding suggests that the TLR4 gene may be involved in allergic sensitization to wheat flour as well as endotoxin-induced respiratory symptoms in endotoxin-allergen-exposed workers and that carriers of TLR4 variants are less affected by environmental exposure.

The SNP rs3128965 of HLA-DPB1 as a genetic marker of the AERD phenotype.

Background Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population. Methods A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups. Results The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively). Conclusions This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.

Effect of interleukin-18 gene polymorphisms on sensitization to wheat flour in bakery workers.

Lower respiratory symptoms in bakery workers may be induced by wheat flour and endotoxins. We hypothesized that endotoxins from wheat flour may stimulate innate immunity and that interleukin-18 (IL-18) gene polymorphisms may affect their regulatory role in innate immune responses to endotoxins. To investigate the genetic contribution of IL-18 to sensitization to wheat flour, we performed a genetic association study of IL-18 in Korean bakery workers. A total of 373 bakery workers undertook a questionnaire regarding work-related symptoms. Skin prick tests with common and occupational allergens were performed and specific antibodies to wheat flour were measured by ELISA. Three polymorphisms of the IL-18 gene (-607A/C, -137G/C, 8674C/G) were genotyped, and the functional effects of the polymorphisms were analyzed using the luciferase reporter assay. Genotypes of -137G/C (GC or CC) and haplotype ht3 [ACC] showed a significant association with the rate of sensitization to wheat flour. Luciferase activity assay indicated ht3 [AC] as a low transcript haplotype. In conclusion, the regulatory role of IL-18 in lipopolysaccharide-induced responses in bakery workers may be affected by this polymorphism, thus contributing to the development of sensitization to wheat flour and work-related respiratory symptoms.

A Retrospective Study of Clinical Response Predictors in Subcutaneous Allergen Immunotherapy With House Dust Mites for Allergic Rhinitis

Purpose House dust mites (HDM) are major allergens that cause allergic rhinitis (AR). Allergen-specific subcutaneous immunotherapy (SCIT) has been shown to be clinically beneficial in many clinical trials. Such trials, however, are not reflective of all patient populations. The aim of this study was to describe the efficacy and safety of SCIT in routine clinical practice in Korean adults with AR sensitized to HDM. Methods We reviewed medical records of 304 patients with AR treated at an allergy clinic of a tertiary hospital using SCIT with aluminum hydroxide-adsorbed allergen extract targeting HDM alone or with pollens for at least 1 year from 2000 to 2012. Patients with asthma were excluded. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Specific immunoglobulin E (IgE) levels to HDM were categorized into 6 classes. Results The mean time until achieving remission was 4.9±0.1 years, and the cumulative incidence of remission from AR was 76.6%. Severe AR (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.23-0.69; P=0.001), specific IgE levels to HDM ≥17.5 kU/L (OR, 1.85; 95% CI, 1.01-3.37; P=0.045), and duration of immunotherapy ≥3 years (OR, 7.37; 95% CI, 3.50-15.51; P<0.001) were identified as significant predictors of clinical remission during SCIT for patients with AR sensitized to HDM. Overall, 73 patients (24.0%) experienced adverse reactions to SCIT, and only 1 case of anaphylaxis (0.3%) developed. Conclusions SCIT with HDM was found to be effective and safe for patients with AR. Specific IgE levels to HDM and a duration of SCIT ≥3 years may be predictors of clinical responses to SCIT in AR patients.

Subcutaneous Immunotherapy for Allergic Asthma in a Single Center of Korea: Efficacy, Safety, and Clinical Response Predictors

Allergen-specific immunotherapy is the only causal treatment for allergic diseases. However, the efficacy of immunotherapy may vary around the world due to differences in climate, the nature of aero-allergens and their distribution. The aim of this study was to describe the effects of subcutaneous immunotherapy (SCIT) in Korean adults with allergic asthma (AA). As a retrospective cohort study, we reviewed medical records for 627 patients with AA in Korea who were sensitized to house dust mite (HDM) and/or pollens and who underwent SCIT with aluminum hydroxide adsorbed allergen extract from 2000 to 2012. Rates of remission, defined as no further requirement of maintenance medication, over time were determined by means of life tables and extension of survival analysis. Herein, 627 asthmatic patients achieved remission within a mean of 4.7 ± 0.2 years. The cumulative incidence rates of remission from AA were 86.9% upon treatment with SCIT. Baseline forced expiratory volume in the first second (FEV1) ≥ 80% (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.79–5.39; P < 0.001), and maintenance of immunotherapy for more than 3 years (HR, 1.82; 95% CI, 1.21–2.72; P = 0.004) were significant predictors of asthma remission during SCIT. In 284 patients on SCIT with HDM alone, initial specific immunoglobulin E (IgE) levels to Dermatophagoides pteronyssinus and Dermatophagoides farinae did not show significant difference between remission and non-remission group after adjusting demographic variables. In conclusion, SCIT was effective and safe treatment modality for patients with AA. Initial FEV1 ≥ 80% and immunotherapy more than 3 years were found to be associated with favorable clinical responses to SCIT.