Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults.

OBJECTIVE: A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population. METHODS: We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index ≥ 25kg/m2) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation. RESULTS: In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72-0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09-1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI:1.05-2.38) for obesity. CONCLUSIONS: In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered.

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.

[Prevalence of adult asthma and allergic rhinitis in Kamishihoro, Hokkaido -trends from 2006 through 2011-].

PURPOSE: To investigate changes in the prevalence of adult asthma and allergic rhinitis from 2006 to 2011 in Kamishihoro, a town in Hokkaido, Japan. METHODS: The Japanese edition of the European Community Respiratory Health Survey questionnaire was completed by 1472 residents aged from 20 to 81 years old. (718 men, 749 women). The age and gender distribution of respondents matched that of respondents in 2006. RESULTS: Response rates were 98.1% in 2011 and 95.8% in 2006. Wheezing in the last 12 months was reported by 10.7% of men and 8.3% of women in 2011, compared to 12.9% and 9.8%, respectively, in 2006. The questions "Have you ever had asthma?" followed by "Was this confirmed by a doctor?" both received positive answers from 7.9% of men and 7.5% of women in 2011, compared to 5.7% and 6.3%, respectively, in 2006. The rate of current smoking was 34.8% in men and 14.7% in women in 2011, compared to 42.8% and 17.2%, respectively, in 2006. A "Yes" answer to the questionnaire item, "Do you have any nasal allergies, including hay fever?" (defining allergic rhinitis) was given by 23.2% of men and 25.4% of women in 2011, compared to 17.6% and 23.0%, respectively, in 2006. The prevalence of allergic rhinitis was increased, particularly among younger respondents. CONCLUSION: Rates of current asthma and allergic rhinitis increased, whereas the rate of wheezing in the past 12 months decreased from 2006 to 2011. Optimal treatment of asthma might be related to these trends.

Association of the CAT-262C>T polymorphism with asthma in smokers and the nonemphysematous phenotype of chronic obstructive pulmonary disease.

BACKGROUND: Catalase (CAT) is a part of the active antioxidant defense system and has been studied with regard to its association with asthma and chronic obstructive pulmonary disease (COPD), which are heterogeneous obstructive pulmonary diseases characterized by chronic airway inflammation. We hypothesized that the CAT gene might be involved in the common pathogenesis underlying asthma and COPD. OBJECTIVE: To evaluate the association of CAT polymorphisms with specific phenotypes of asthma and COPD to identify the common underlying pathophysiologic mechanisms of these 2 diseases. METHODS: The -262C>T and -21A>T polymorphisms in the CAT gene were genotyped in 493 individuals with asthma, 265 with COPD, and 1,076 healthy controls. Asthmatic patients were categorized according to smoking status (smokers and nonsmokers) and age at onset (early onset and adult onset) as part of a case-control study. In patients with COPD, visual scoring (computed tomographic score) was assessed to determine emphysema severity, which was used to evaluate associations with CAT gene polymorphisms. RESULTS: Overall, the -262C>T and -21A>T polymorphisms were not associated with asthma. However, the -262CT+TT genotype was significantly associated with adult-onset asthma in smokers (P = .005), and a significant interaction between smoking status and the effect of -262C>T genotype on asthma were observed (P = .01). In patients with COPD, this genotype was significantly associated with a low computed tomographic score (P = .03), which indicates a nonemphysematous type of COPD. CONCLUSION: The present study indicates that the CAT gene is involved in the common pathogenesis underlying adult-onset asthma in smokers and the nonemphysematous type of COPD.

The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma.

BACKGROUND: Clara cell secretory protein (CC16) is expressed primarily in the respiratory tract and is a potent anti-inflammatory agent that protects the airway from inflammation. The associations of the A38G polymorphism in this gene with asymptomatic airway hyper-responsiveness (AHR), which is considered a risk factor for future asthma in adults, and the development of adult-onset asthma are unclear. OBJECTIVE: To evaluate the association of the CC16 A38G polymorphism with asymptomatic AHR in healthy young adults and the development of adult-onset asthma and the association between plasma CC16 level according to this genotype and asymptomatic AHR. METHODS: Nonspecific AHR was measured in 154 asymptomatic, young, healthy adults using a continuous methacholine inhalation method. The cumulative dose values of inhaled methacholine measured at the inflection point at which respiratory conductance started to decrease (Dmin) were used as an index of AHR. Case-control analysis was performed for the association between this polymorphism and the development of asthma in 1,086 unrelated Japanese subjects (504 subjects with asthma and 582 healthy subjects). RESULTS: The 38AA + AG genotype was associated with lower Dmin values and lower plasma CC16 levels (P = .012 and .020). There was a significant positive correlation between Dmin values and plasma CC16 levels (P = .012). In the case-control study, the 38AA + AG genotype was significantly associated with late-onset asthma (onset at >40 years; odds ratio, 1.63; P = .016). CONCLUSION: These results suggest that the CC16 A38G polymorphism may play a role in asymptomatic AHR and contribute to the development of late-onset asthma.

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis.

BACKGROUND: Mannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with sarcoidosis. METHODS: Nine single nucleotide polymorphisms (SNPs), encompassing the MRC1 gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls. RESULTS: Suggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (P = 0.001). CONCLUSIONS: These results suggest that MRC1 is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in MRC1, a major member of the C-type lectin, contribute to the development of sarcoidosis.

The role of atopy in the clinical course of pulmonary sarcoidosis in the Japanese population.

Sarcoidosis is a multisystem disorder characterized by a T-helper 1 (Th1)-mediated immune response. Conversely, atopy is characterized by the presence of a specific immunoglobulin E (IgE) E response in association with a Th2-type immune response. Several epidemiological studies have shown that atopic status influences disease activity and clinical course for several Th1-mediated diseases. The aim of this study was to evaluate associations between atopic status and clinical findings of sarcoidosis. We further evaluated the impact of atopic status on the clinical course of pulmonary sarcoidosis. We defined atopy as a positive specific IgE response to at least one common inhaled allergen (multiple antigen simultaneous test scores, lumicount of >1.01). Subjects comprised 134 patients given a diagnosis of sarcoidosis between 2000 and 2006, divided into atopic and nonatopic groups. Several clinical findings were compared between the two groups. Furthermore, 100 subjects observed 2 years after diagnosis were divided into resolving and persistent clinical course groups according to chest radiography and associations with atopic status were evaluated. Atopy was more prevalent among men than women (p = 0.009) and subjects with atopy were younger (p = 0.002) and showed less frequent lung parenchymal lesions (stages II and III; p = 0.018) compared with subjects without atopy. The prevalence of atopy was higher in the resolving clinical course group than in the persistent clinical course group (p = 0.002) and this association was independent of sex, age, presence of lung parenchymal lesions, and presence of extrapulmonary lesions (p = 0.037). Classification of sarcoidosis based on atopic status might be useful for predicting the clinical course of pulmonary sarcoidosis.

[Evaluating total serum IgE levels and peripheral eosinophil count in asthma and rhinitis].

BACKGROUND: Total serum immunoglobulin (Ig)E levels and peripheral blood eosinophil counts are widely examined to evaluate patients with various allergic diseases. Asthma and allergic rhinitis often coexist. However, the significance of these indices for asthma and rhinitis under consideration of the status of co-existence has not been fully elucidated and was therefore examined in the present study. METHODS: Subjects comprised 347 adult residents in Kamishihoro town, Hokkaido. Relationships between two indices and asthma, rhinitis and their coexistence were analyzed. RESULTS: Serum IgE (sIgE) levels were significantly higher in asthma with (p<0.01) or without (p<0.01) rhinitis, regardless of atopic status, but not in rhinitis alone. Peripheral eosinophil counts were significantly higher only in asthma with rhinitis (p<0.005). CONCLUSION: Compared with rhinitis, non-antigen-specific IgE production may contribute more to elevated levels of sIgE in asthma. In addition, the significance of sIgE and peripheral eosinophil count as indices of evaluating asthma and rhinitis might differ.

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 >or=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 variants in the mannose receptor gene (MRC1) are associated with asthma in two independent populations.

Mannose receptor is a member of the C-type lectin receptor family involved in pathogen molecular pattern recognition and thought to be critical in shaping host immune responses and maintaining homeostasis. The aim of this study was to investigate potential associations of genetic variants in the MRC1 gene with asthma in two independent populations. Seven single-nucleotide polymorphisms (SNPs; rs2477637, rs2253120, rs2477631, rs2477664, rs692527, rs1926736, and rs691005) in the MRC1 gene locus were genotyped and evaluated regarding association with asthma in 870 unrelated Japanese subjects (446 asthmatics, 424 controls). The same markers were validated in 176 unrelated African-American subjects (86 asthmatics, 90 controls). Suggestive evidence of association between five SNPs (rs2477637, rs2253120, rs2477664, rs692527, and rs1926736) and asthma was observed in the analysis of the Japanese population independent of sex, age, smoking status, and atopic status. SNPs rs692527 and rs691005 showed significant association with asthma in the African-American population. Haplotypes containing two linked SNPs (rs692527 and rs1926736) were significantly associated with asthma in both Japanese and African-American populations. Our results suggest that sequence variations in the MRC1 gene are associated with the development of asthma in two independent and ethnically diverse populations.

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.

[Prevalence of adult asthma and allergic rhinitis in Kamishihoro town, Hokkaido--association with smoking habit and obesity].

PURPOSE: To investigate the prevalence of adult asthma and allergic rhinitis, and to analyze associations between smoking habit, obesity and disease in Kamishihoro town, Hokkaido. METHODS: The Japanese edition of the European Community Respiratory Health Survey (ECRHS) Questionnaire was completed by 3096 residents (men: 1520, women: 1576) who ranged in age from 18 to 81. RESULTS: Among the respondents, 12.9% of the males and 9.8% of the females responded "Yes" to the questionnaire item, "Wheezing at any time in the last 12 months" (defined as having asthma) and 17.6% of the males and 23.0% of the females responded "Yes" to the question, "Do you have any nasal allergies including hay fever?" (defined as having allergic rhinitis). This prevalence tended to be higher among younger respondents. Smoking habit and obesity were significantly associated with wheezing over the last 12 months, but not with allergic rhinitis. CONCLUSION: Smoking habit and obesity are significantly associated with asthma in Kamishihoro town, located in a rural area of Hokkaido, Japan.

[The Arg16Glybeta2-adrenergic receptor polymorphism influences long term clinical responses to beta2-agonist].

BACKGROUND: The coding region variant Arg16Gly at the beta2-adrenoceptor gene (ADRB2) is functionally relevant, and is common in Japanese. Longer term clinical responses to short-acting and long-acting beta2 agonists have been influenced by the Arg16Gly polymorphism. The purpose of the present study is to assess the clinical effects of real life usage of beta2-agonist (long-acting beta2-agonist, regular use of short-acting beta2 agonist, or oral beta2-agonist), as an add-on medication to inhaled steroids, in Arg/Arg and Gly/Gly patients with asthma. METHODS: In a retrospective analysis of outpatient records, 27 patients with Arg/Arg and 35 patients with Gly/Gly had regular usage of beta2-agonist, whereas 37 patients with Arg/Arg and 29 patients with Gly/Gly had as-needed usage of beta2-agonist. During the follow-up periods at Hokkaido University Hospital, long term bronchodilator responses were assessed using 3 indexes: 1) improvement in FEV1 (DeltaFEV1 [ml]), 2) DeltaFEV1/FEV1 at an initial visit, 3) DeltaFEV1/predicted FEV1. RESULTS: In patients with Gly/Gly genotype, compared with as-needed usage of beta2-agonist, the regular usage of beta2-agonist was associated with greater improvement in FEV1 in every index (p=0.027-0.041). In contrast, in patients with Arg/Arg genotype, the regular usage of beta2-agonist showed no greater improvement in FEV1 compared with as-needed beta2-agonist usage. CONCLUSION: Gly/Gly and Arg/Arg genotype responses to regular usage of beta2-agonists may differ in patients with asthma.

[Evaluation of atopy by antigen specific IGE antibody].

BACKGROUND: Atopy is usually defined as the genetic propensity to produce IgE antibodies (Abs) specific to common environmental allergens. The aim of this study was to evaluate impacts of the number of allergens examined on prevalence of atopy. METHODS: Subjects comprised 116 healthy controls, 104 patients with asthma, 294 patients with COPD, 64 patients with sarcoidosis and 218 residents of Kamishihoro town. Total serum immunoglobulin E and antigen-specific IgE antibody levels for 26 common allergens were examined. Atopy was defined as positive IgE Abs specific to > or =1 allergen. We serially increased the number of allergens to define atopy from the most common allergens in order of frequency, and changes in prevalence of atopy were evaluated. In residents of Kamishihoro, betula pollen antigen was also examined, as this antigen is very common in the town. RESULTS: The increasing prevalence of atopy was dramatically reduced relative to the number of allergens examined. Among residents of Kamishihoro town, 5 cases displayed specific IgE Abs to this allergen alone and prevalence of atopy was increased 2.3 percents. CONCLUSION: When atopy was defined as the production of specific IgE Abs to common allergens, roughly 10 of the most common allergens may cover common environmental allergens.

Retrograde radiographic development in pulmonary sarcoidosis.

A 48-year-old man with dyspnea, cough, and fever was found to have a diffuse ground-glass pulmonary lesion without lymphadenopathy on chest X-ray. The lesion shifted to the peripheral lung zones 2 months later when transbronchial biopsy demonstrated noncaseating granulomas with Langhans type giant cells. After 6 more months, prominent bilateral hilar lymphadenopathy and highly elevated serum angiotensin-converting enzyme confirmed the diagnosis of pulmonary sarcoidosis. Such a course is quite rare in that it goes the opposite way of the conventional staging system.

[Total serum IgE levels in eosinophilic lung diseases].

BACKGROUND: We previously reported elevated levels of total serum IgE in patients with asthma, regardless of their atopic status. We hypothesized that certain factors inherent to asthma may contribute to this non-specific elevation of total serum IgE. In the current study, to evaluate the role of eosinophils in the regulation of total serum IgE, we examined whether peripheral blood eosinophil count is associated with total serum IgE level in patients with eosinophilic lung diseases. METHODS: Ninety-nine healthy controls, 277 patients with asthma, 15 patients with acute eosinophilic pneumonia, 21 patients with chronic eosinophilic pneumonia were studied for total serum IgE levels and peripheral blood eosinophil counts. RESULTS: Patients with acute or chronic eosinophilic pneumonia had significantly increased total serum IgE levels compared with healthy controls regardless as atopic status (p<0.001). In non-atopic subjects with eosinophilic lung diseases, total serum IgE level was significantly correlated with peripheral blood eosinophil count (r=0.42, p<0.001, n=57). CONCLUSION: Our findings suggest that, in addition to antigen-specific IgE production, non-specific IgE production may contribute to elevated levels of total serum IgE in patients with asthma or eosinophilic pneumonia. An increased number of activated eosinophils may underlie an increased total serum IgE level in these conditions.

Inflammatory pseudotumor of the mesentery causing portal venous thrombosis and cavernomatous transformation.

A 32-year-old man was admitted to our hospital complaining of abdominal pain in the left upper quadrant. A mass was palpable on the left side of the umbilicus. Laboratory data revealed anemia, elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and prolonged prothrombin time. Computed tomography demonstrated a soft tissue mass in the mesentery of the jejunum, portal venous thrombosis, and cavernomatous transformation in the porta hepatis. The patient was eventually diagnosed by laparoscopic partial resection as having inflammatory pseudotumor of the mesentery. Four months later, all of his symptoms and abnormal laboratory findings completely disappeared without any therapy. Inflammatory pseudotumor should be kept in mind as a cause of portal venous thrombosis, and/or cavernomatous transformation although it is rare.