Genetic heterogeneity of asthma phenotypes identified by a clustering approach.

The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account. Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474). The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p<1.25 × 10(-7)) were observed between "active adult-onset nonallergic asthma" and rs9851461 flanking CD200 (3q13.2) and between "inactive/mild nonallergic asthma" and rs2579931 flanking GRIK2 (6q16.3). Borderline significant results (2.5 × 10(-7) < p <8.2 × 10(-7)) were observed between three single nucleotide polymorphisms (SNPs) in the ALCAM region (3q13.11) and "active adult-onset nonallergic asthma". These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the "active allergic asthma" phenotype. Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.

Early age at menarche, lung function, and adult asthma.

RATIONALE: hormonal and metabolic status appears to influence lung health in women, and there are findings suggesting that early menarche may be related to asthma, cardiovascular disease, diabetes, and breast cancer. OBJECTIVES: this study investigates whether age at menarche is related to adult lung function and asthma. METHODS: among participants in the European Community Respiratory Health Survey II, 3,354 women aged 27-57 years from random population samples in 21 centers responded to a questionnaire concerning women's health (1998-2002). Of these women, 2,873 had lung function measurements, 2,136 had measurements of bronchial hyperreactivity, and 2,743 had IgE measurements. Logistic, linear, and negative binomial regression analyses included adjustment for age, height, body mass index, education, smoking, family size, and center. MEASUREMENTS AND MAIN RESULTS: FEV(1) and FVC were lower and asthma was more common in women with early menarche. Women reporting menarche at age 10 years or less, as compared with women with menarche at age 13 years (reference category), had lower FEV(1) (adjusted difference, -113 ml; 95% confidence interval [CI], -196 to -33 ml) and FVC (-126 ml; 95% CI, -223 to -28 ml); also lower FEV(1) expressed as a percentage of the predicted value (-3.28%; 95% CI, -6.25 to -0.30%) and FVC expressed as a percentage of the predicted value (-3.63%; 95% CI, -6.64 to -0.62%). Women with early menarche more often had asthma symptoms (odds ratio, 1.80; 95% CI, 1.09-2.97), asthma with bronchial hyperreactivity (odds ratio, 2.79; 95% CI, 1.06-7.34), and higher asthma symptom score (mean ratio, 1.58; 95% CI, 1.12-2.21). CONCLUSIONS: women with early menarche had lower lung function and more asthma in adulthood. This supports a role for metabolic and hormonal factors in women's respiratory health.

Oral contraception, body mass index, and asthma: a cross-sectional Nordic-Baltic population survey.

BACKGROUND: Emerging evidence suggests that sex steroid hormones may influence airways obstruction, and that metabolic status may modify potential effects. OBJECTIVE: This study investigated the association between use of oral contraceptive pills (OCPs) and asthma in a Nordic-Baltic population-based study, while taking into account possible interplay with body mass index (BMI). METHODS: Postal questionnaires were sent to subjects in Denmark, Estonia, Iceland, Norway, and Sweden from 1999 to 2001 (response rate in women, 77%). Pregnant women, women using hormone replacement therapy, and women >45 years were excluded. Analyses included 5791 women 25 to 44 years old, of whom 961 (17%) used OCP. Logistic regression analyses included adjustment for smoking, irregular menstruation, BMI, age, type of dwelling, and center. RESULTS: Oral contraceptive pills were associated with increased risk for asthma (odds ratio, 1.42; 95% CI, 1.09-1.86), asthma with hay fever (1.48; 1.08-2.03), wheeze with shortness of breath (1.27; 1.02-1.60), hay fever (1.25; 1.06-1.48), and >/=3 asthma symptoms (1.29; 1.05-1.58). The findings were consistent between centers. The associations were present only among normal weight women (BMI 20-25 kg/m(2), asthma: 1.45; 1.02-2.05) and overweight women (BMI >25kg/m(2): 1.91; 1.20-3.02), but not among lean women (BMI <20 kg/m(2): 0.41; 0.12-1.40). Interaction between BMI and OCP in association with asthma was significant (P(interaction) < .05). CONCLUSIONS: Women using oral contraceptive pills had more asthma. This was found only in normal weight and overweight women, indicating interplay between sex hormones and metabolic status in effect on the airways. The findings originate from a cross-sectional postal survey and should be interpreted with caution; it is recommended that asthma symptoms are included in clinical trials of oral contraception.

Lung function, respiratory symptoms, and the menopausal transition.

BACKGROUND: There is limited information on potential changes in respiratory health when women enter the menopausal transition. OBJECTIVE: We sought to investigate whether the menopausal transition is related to lung function and asthma and whether body mass index (BMI) modifies associations. METHODS: Four thousand two hundred fifty-nine women from 21 centers (ECRHS II, 2002) responded to a questionnaire concerning women's health. Women aged 45 to 56 years not using exogenous sex hormones (n = 1274) were included in the present analysis. Lung function measurements (n = 1120) and serum markers of hormonal status (follicle-stimulating hormone, luteinizing hormone, and estradiol; n = 710) were available. Logistic and linear regression analyses were adjusted for BMI, age, years of education, smoking status, center, and height. RESULTS: Women not menstruating for the last 6 months (n = 432, 34%) had significantly lower FEV(1) values (-120 mL [95% CI, -177 to -63]), lower forced vital capacity values (-115 mL [95% CI, -181 to -50]), and more respiratory symptoms (odds ratio [OR], 1.82 [95% CI, 1.27-2.61]) than those menstruating regularly. Results were similar when restricting analyses to those who never smoked. Associations were significantly stronger in women with BMIs of less than 23 kg/m(2) (respiratory symptoms: OR, 4.07 [95% CI, 1.88-8.80]; FEV(1) adjusted difference: -166 [95% CI, -263 to -70]) than in women with BMIs of 23 to 28 kg/m(2) (respiratory symptoms: OR, 1.10 [95% CI, 0.61-1.97], P(interaction): .04; FEV(1) adjusted difference, -54 [95% CI, -151 to 43], P(interaction) = .06). CONCLUSIONS: Menopause is associated with lower lung function and more respiratory symptoms, especially among lean women.

Validation of maternal reported pregnancy and birth characteristics against the Medical Birth Registry of Norway.

Studies using mothers' self-reported information on birth and pregnancy characteristics are common, but the validity of such data is uncertain. We evaluated questionnaire data from the RHINE III study on reproductive health provided by 715 mothers from Bergen, Norway, about their 1629 births between 1967 and 2010, using the Medical Birth Registry of Norway (MBRN) as gold standard. Validity of dichotomous variables (gender, preterm birth [<37 weeks' gestation], postterm birth [>42 weeks' gestation], induction of labour, forceps delivery, vacuum delivery, caesarean section, were assessed by sensitivity, specificity, positive and negative predictive values (PPV and NPV) and Cohen's kappa. Paired t-test, Pearson's correlation coefficient and Bland-Altman plots were used to validate birthweight, stratified by mother's level of education, parity, birth year and child's asthma status. Child's gender and caesarean section showed high degree of validity (kappa = 0.99, sensitivity and specificity 100%). Instrumental delivery and extremely preterm birth showed good agreement with sensitivity 75-92%. Preterm birth and induction of labour showed moderate agreement. Post-term delivery was poorly reported. The validity appeared to be independent of recall time over 45 years, and of the child's asthma status. Maternally reported birth and pregnancy information is feasible and cheap, showed high validity for important birth and pregnancy parameters, and showed similar risk-associations compared to registry data.

Respiratory Health in Cleaners in Northern Europe: Is Susceptibility Established in Early Life?

RATIONALE: There is some evidence that maternal smoking increases susceptibility to personal smoking's detrimental effects. One might question whether early life disadvantage might influence susceptibility to occupational exposure. OBJECTIVES: In this cross-sectional study we investigated respiratory symptoms, asthma and self-reported chronic obstructive pulmonary disease (COPD) as related to working as a cleaner in Northern European populations, and whether early life factors influenced susceptibility to occupational cleaning's unhealthy effects. METHODS: The RHINE III questionnaire study assessed occupational cleaning in 13,499 participants. Associations with respiratory symptoms, asthma and self-reported COPD were analysed with multiple logistic regressions, adjusting for sex, age, smoking, educational level, parent´s educational level, BMI and participating centre. Interaction of occupational cleaning with early life disadvantage (maternal smoking, severe respiratory infection <5 years, born during winter months, maternal age at birth >35 years) was investigated. MAIN RESULTS: Among 2138 ever-cleaners the risks of wheeze (OR 1.4, 95% CI 1.3-1.6), adult-onset asthma (1.5 [1.2-1.8]) and self-reported COPD (1.7 [1.3-2.2]) were increased. The risk increased with years in occupational cleaning (adult-onset asthma: ≤1 year 0.9 [0.7-1.3]; 1-4 years 1.5 [1.1-2.0]; ≥4 years 1.6 [1.2-2.1]). The association of wheeze with cleaning activity ≥4 years was significantly stronger for those with early life disadvantage than in those without (1.8 [1.5-2.3] vs. 1.3 [0.96-1.8]; pinteraction 0.035). CONCLUSIONS: Occupational cleaners had increased risk of asthma and self-reported COPD. Respiratory symptom risk was particularly increased in persons with factors suggestive of early life disadvantage. We hypothesize that early life disadvantage may increase airway vulnerability to harmful exposure from cleaning agents later in life.

Excessive costs of COPD in ever-smokers. A longitudinal community study.

AIM: We aimed to estimate the societal treatment-related costs of COPD in hospital- and population-based subjects with spirometry defined COPD, relative to a control group. METHODS: 81 COPD cases and 132 controls without COPD were randomly recruited from a general population, as were 205 COPD patients from a hospital register. All participants were ever-smokers of at least 40 years of age, followed for 12 months. Data on comorbid conditions and spirometry were collected at baseline. Standardized telephone interviews every third month gave information on use of healthcare services and exacerbations of respiratory symptoms. RESULTS: The increased (excessive) median annual costs per case having stage II, stage III and stage IV COPD were € (95% CI) 400 (105-695), 1918 (1268-2569) and 1870 (1031-2709), respectively, compared to the population-based controls. Costs increased with €81 (95% CI 50-112) per exacerbation of respiratory symptoms and €461 (95% CI 354-567) per comorbid condition. Excessive costs for hospital COPD patients were threefold that of the population-based COPD cases. CONCLUSION: The excessive treatment-related cost of COPD stage II+ in ever-smokers of at least 40 years was estimated to €105 million for Norway. Comorbidity was a dominant predictor of excessive cost in COPD.

Case-control studies on risk factors for chronic obstructive pulmonary disease: how does the sampling of the cases and controls affect the results?

INTRODUCTION: Sampling is regarded as crucial to the validity of case-control studies. Ideally, cases and controls should be selected from the same source population, but deviations from this approach are often seen. OBJECTIVE: Our objective was to examine how exposure-disease relationships in a study on chronic obstructive pulmonary disease (COPD) were affected by the sampling sources of cases and controls. METHODS: A Norwegian case-control study on COPD including 1909 subjects used three sources of recruitment for cases (general population, hospital registry and volunteers) and two sources for controls (general population and volunteers). This resulted in six sampling combinations of cases and controls (groups A-F). We examined how the risk factors gender, age, smoking, educational level and comorbidity were associated with COPD in these six sampling groups. RESULTS: Several exposure-disease associations were dependent on variation in sampling source, thereby demonstrating the possibility of selection bias. The theoretically most ideal sampling group is likely group A, where both cases and controls are recruited from a general population. When using group A as a reference, the groups containing either voluntary controls and/or hospital-based cases deviated the most, suggesting higher susceptibility to selection bias in these groups. CONCLUSION: Recruitment from several sources made our study design vulnerable to selection bias. Our findings should bring about increased awareness to the sampling process, and encourage sampling of cases and controls from the same source population in future studies.

Aspects of healthcare utilisation in self-reported obstructive lung disease.

INTRODUCTION: Utilisation of healthcare resources because of pulmonary diseases have previously been presented according to lung function or symptom severity. We aimed to compare the associations of symptoms and lung function to healthcare and social service utilisation in subjects with self-reported obstructive lung diseases (OLDs) (asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema). MATERIALS AND METHODS: Of 2819 participants aged 27-82 years in the Hordaland County Respiratory Health Survey, 200 subjects (7.1%) self-reported OLD. They answered 13 questions on respiratory symptoms and 5 questions on use of healthcare and social services. Altogether, 161 participants (81%) completed post-bronchodilation spirometry. RESULTS: Use of anti-asthmatic drugs, regular physician's appointment, sick leave payment for the last 12 months, hospital admission for the last 12 months and disability pension were reported by 68%, 63%, 18%, 8% and 7% of those with self-reported OLD, respectively. Twenty per cent of subjects with self-reported OLD had not received any healthcare or social services. In adjusted multivariate logistic regression analyses, increase in the respiratory symptom score was significantly associated with more healthcare and social services. Lower forced expiratory volume in 1 s in % predicted, however, was not significantly associated with more use of healthcare and social services. CONCLUSION: The majority (80%) of subjects in a general population with self-reported OLD received healthcare services. The utilisation of healthcare and social services was strongly associated to the burden of respiratory symptoms, and, to a lesser degree, to the level and pattern of lung function.

Menstrual irregularity and asthma and lung function.

BACKGROUND: Oligomenorrhea was associated with more asthma (Respiratory Health in Northern Europe study), but a possible association with lung function has not been investigated previously. OBJECTIVE: To investigate whether oligomenorrhea was related to lung function and asthma, and whether body mass index and physical activity modified associations. METHODS: Women age 28 to 44 years (n = 1631) participating in the European Community Respiratory Health Survey were included. Women who were taking exogenous sex hormones, were pregnant, or had recently given birth were excluded. RESULTS: Long or irregular menstrual cycles were reported by 313 women (19%). Oligomenorrhea was significantly associated with more asthma symptoms (odds ratio [OR], 1.76; 95% CI, 1.29-2.40), allergic asthma (OR, 2.46; 95% CI, 1.43-4.23), and lower forced vital capacity (FVC; adjusted difference, 63 mL; 95% CI, -124 to -1). When excluding women using asthma medication, very lean women, or women exercising daily, these associations remained significant. Effects of oligomenorrhea were additive to those of body mass index (BMI) on asthma and FVC. Asthma symptoms increased significantly with BMI. FVC and FEV(1) increased with BMI until 25 kg/m(2) and thereafter decreased with increasing BMI. Excluding women exercising daily, asthma symptoms increased significantly with decreasing physical activity (OR, 1.09; 95% CI, 1.001-1.19) per category of physical activity) independently of oligomenorrhea. Among women exercising daily, oligomenorrhea predicted very high risk for asthma symptoms (OR, 12.6; 95% CI, 3.7-43). CONCLUSION: Women with oligomenorrhea have reduced lung function and more asthma, particularly allergic asthma, independent of BMI and physical activity. Airways pathology may have not only a hormonal but also a metabolic component. CLINICAL IMPLICATIONS: Women with oligomenorrhea should be investigated with regard to asthma and lung function. Underlying metabolic disturbance should be considered in asthma.