Yukiko Maeda

Genetic polymorphisms at FCER1B and PAI-1 and asthma susceptibility

Background We previously detected a promoter polymorphism (−109C/T) in the gene for the β‐chain of the high‐affinity receptor for IgE (FCER1B), which was associated with total serum IgE levels but not with asthma in a Japanese population. A genetic interaction is biologically plausible between FcεRI‐β and the plasminogen activator inhibitor 1 (PAI‐1), which is highly expressed in mast cells in asthmatics and plays an essential role in airway remodelling. We hypothesized that FCER1B promoter polymorphisms, by modifying the intensity of mast cell activation signals, modulate the genetic effects of a functional 4G/5G polymorphism in the PAI‐1 gene on asthma.

A functional polymorphism (-603A → G) in the tissue factor gene promoter is associated with adult-onset asthma.

Tissue factor (TF) is important for initiation of coagulation and for the increased thrombin activity observed at sites of inflammation. Thrombin activity is induced by allergen challenge in asthmatic airways and is involved in the pathogenesis of asthma. A −603A → G polymorphism (rs1361600) in the promoter region of the TF gene has been associated with serum TF levels and with the development of cardiovascular diseases. The aim of this study was to determine whether the functional −603A → G polymorphism has genetic influences on the development of asthma. Case–control analysis was performed of the association between six common single-nucleotide polymorphisms (SNPs), including the −603A → G polymorphism, at the TF gene, and the development of asthma, using two unrelated Japanese populations. In the primary population (n=826), the GG genotype at the −603A → G polymorphism was associated with adult-onset asthma (onset at ⩾21 years of age) (odds ratio (OR) 2.886, P=0.0231). A second population showed a similar tendency (n=1654, OR 1.602, P=0.064). Transcriptional activity of promoters with −603A → G genotypes were examined using luciferase promoter assays. The −603G allele was associated with higher promoter activity (P<0.05). The association between the functional polymorphism (−603A → G) in the TF gene promoter and adult-onset asthma indicates that TF is a candidate gene contributing to asthma susceptibility.

Genetic Impact of Functional Single Nucleotide Polymorphisms in the 3′-UTR Region of the Chemoattractant Receptor Expressed on Th2 Cells (CRTH2) Gene on Asthma and Atopy in a Japanese Population

Background: The human chemoattractant receptor expressed on Th2 cells (CRTH2), the receptor for prostaglandin D2, induces cell migration in eosinophils, basophils, and Th2 cells. The gene encoding CRTH2 is located on chromosome 11q13. Several groups, including ours, have reported significant associations between this region and various traits associated with allergic diseases such as asthma and atopy. Two single nucleotide polymorphisms in the 3′-UTR of the CRTH2 gene (1544G→C and 1651G→A) are associated with the mRNA stability of the gene; they have also been associated with asthma in both African American and Chinese populations. Methods: Because CRTH2 is a biologically important candidate gene on chromosome 11q13, we conducted a case-control analysis using 787 Japanese subjects (384 asthmatics and 403 controls) to evaluate the genetic impact of the CRTH2 gene on asthma and asthma-related traits. Four polymorphisms [1544G→C (rs11571288), 1651G→A (rs545659), 11336T→C (rs2074422), and 12375G→T (rs561285)] were studied. Results: The allele, genotype, or haplotype frequencies for 2 functional polymorphisms in our Japanese population were significantly different from those in the Chinese or African American populations. No association was found between any polymorphisms or haplotypes in the CRTH2 gene and asthma, atopy, or total serum IgE levels in a Japanese population. Conclusions: Our data failed to support previous associations of functional polymorphisms at the 3′-UTR of the CRTH2 gene implicated in asthma. We did show a significant difference in the allele and genotype frequencies as well as different haplotype frequencies among African American, Chinese, and Japanese populations, suggesting that the genetic impacts of these functional polymorphisms on asthma and asthma-related phenotypes may vary in different populations.

Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population.

Background Secreted phosphoprotein 1 (SPP1) is a cytokine with pleiotrophic immunological activities, including activation of macrophage chemotaxis and T‐helper type 1 (Th1) immune responses. SPP1 gene polymorphisms have been shown to be associated with several immune inflammatory diseases including multiple sclerosis (MS), which is characterized by fewer allergic symptoms and lower numbers of allergen sensitizations.

Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma

RATIONALE Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. METHODS We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. MEASUREMENTS AND MAIN RESULTS Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. CONCLUSIONS This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).

Genetic Impact of a Butyrophilin-like 2 (BTNL2) Gene Variation on Specific IgE Responsiveness to Dermatophagoides farinae (Der f) in Japanese

BACKGROUND Dermatophagoides farinae (Der f) is one of the most frequently implicated allergens in several allergic diseases. Several genome-wide screens have identified a linkage between chromosome 6p21 and mite-specific IgE responsiveness. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily and, on the basis of its homology to B7-1, has been implicated as a costimulatory molecule involved in T-cell activation. BTNL2 resides in the HLA region on chromosome 6p21, and significant associations between BTNL2 gene polymorphisms and several inflammatory diseases have been reported. OBJECTIVE The aim of this study was to examine whether BTNL2 gene polymorphisms are associated with specific IgE responses to Der f. METHODS Three single nucleotide polymorphisms (SNPs), including 2 coding SNPs and 1 intron SNP, were studied. One of the coding SNPs was the rs2076530 A > G, which has a functional consequence. A total of 863 unrelated Japanese subjects (447 positive and 416 negative for IgE to Der f) were recruited for a case-control study. RESULTS Controlling for gender, age, smoking, and the presence of asthma, multiple logistic regression analyses showed that homozygosity of the rs2076530 A allele, which has been reported to be a risk allele for sarcoidosis, was associated with a risk of sensitization towards Der f (Odds ratio; 1.55, p = 0.0060). CONCLUSIONS Although an association which may be due to the linkage disequilibrium with other genes in 6p21 needs to be ruled out, the present findings suggest that the BTNL2 gene might be one of the candidate genes that is responsible for the pathogenesis of Der f-specific IgE responsiveness.

Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma

Rationale: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. Objectives: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. Methods: We recruited a total of 127 subjects with severe asthma, including 59 current or ex‐smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2‐day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Results: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. Conclusions: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

Contrasting associations of body mass index and measles with asthma and rhinitis in young adults.

Asthma and allergic rhinitis often coexist and are increasing worldwide, particularly among the younger generation. Although the prevalences of adult asthma and allergic rhinitis and their risk factors have been reported, there have been few studies focusing on young adults. The aim of this study was to evaluate the prevalences of asthma and allergic rhinitis and their associated factors in Japanese young adults. A questionnaire survey of new students at Hokkaido University about the presence of current wheeze and rhinitis and a history of several viral infections during childhood was conducted in 2008 and 2010. The prevalences of wheeze and rhinitis and their associated factors were evaluated. Of 4076 nonsmoking subjects aged 18-25 years, 261 (6.4%) had current wheeze and 1373 (33.7%) had allergic rhinitis. On multivariate analyses, current wheeze was associated with high body mass index (BMI), atopic dermatitis, allergic rhinitis, food allergy, and a history of measles infection. In contrast, allergic rhinitis was associated with low BMI, current wheeze, atopic dermatitis, food allergy, and no history of measles. When subjects were classified into four groups by the presence or absence of wheeze and rhinitis, both high BMI and a history of measles were positively associated with wheeze without rhinitis but negatively associated with rhinitis without wheeze. High BMI and past measles infection showed contrasting associations with asthma and allergic rhinitis in nonsmoking young adults. It is important to not only recognize the common pathophysiological characteristics of asthma and allergic rhinitis but also to understand their differences.

Enhanced Expression of Interleukin-18 Receptor α Chain by CD4+ T Cells in Sarcoidosis

Study objectives To investigate the expression of interleukin-18 receptor α chain (IL-18Rα) in BAL and peripheral blood (PB) T cells in patients with sarcoidosis compared with control subjects, to evaluate the relationship between the expression and clinical manifestations, and to clarify the mechanisms of altered expression. Subjects and methods The study subjects consisted of 21 patients with sarcoidosis and 8 normal control subjects. The expression of IL-18Rα was examined by flow cytometry. Results The proportions of BAL CD4+ and PB CD4+ T cells expressing IL-18Rα were significantly increased in patients with sarcoidosis compared to control subjects. BAL CD4+ T cells expressed IL-18Rα in a higher proportion than did paired CD8+ T cells in patients with sarcoidosis but not in control subjects. Greater proportions of BAL CD4+ T cells and BAL CD8+ T cells than of their PB counterparts expressed IL-18Rα in both patients and control subjects. CD4+ T cells were more sensitive to the induction of IL-18Rα by cytokines in vitro, such as interleukin (IL)-2, IL-12, and tumor necrosis factor-α than were CD8+ T cells. Increased expression of IL-18Rα by BAL T cells commonly observed in patients and control subjects was associated with the expansion of CD45RO+ cells in BAL T cells. However, there were no significant correlations between the expression of IL-18Rα by any cell populations and BAL findings, serum angiotensin-converting enzyme activities, radiograph stages, or clinical courses. Conclusion The overexpression of IL-18Rα predominantly by CD4+ T cells in sarcoidosis emphasizes crucial roles played by T-helper type 1 cells in the IL-18/IL-18Rα system in sarcoidosis.