Comorbidities associated with adult asthma: a population-based matched cohort study in Finland.

BACKGROUND: Asthma is a common chronic disease characterised by variable respiratory symptoms and airflow limitation, affecting roughly 4%-10% of the adult population. Adult asthma is associated with higher all-cause mortality compared to individuals without asthma. In this study, we investigate the comorbidities that may affect the management of asthma. METHODS: Total of 1648 adults with asthma and 3310 individuals without asthma aged 30-93 were matched with age, gender and area of residency, and followed from 1 January 1997 to 31 December 2013. Baseline information was collected with questionnaires 1997 and follow-up register data from the national discharge registry Finnish Institute for Health and Welfare. Data included diagnoses from outpatient care and day surgery of specialised health care, and data from inpatient care of specialised and primary health care. We included all main diagnoses that had at minimum 200 events and number of diagnoses based on their common appearance with adult asthma. RESULTS: The mean follow-up time varied between 14.2 and 15.1 years, and age at the time of enrolment was 53.9 years for subjects without asthma and 54.4 years for patients with asthma. Chronic obstructive pulmonary disease was 10 times more common among asthmatics. Risk of acute rhinosinusitis, chronic rhinosinusitis with nasal polyps, atopic dermatitis and vocal cord dysfunction was fourfold and risk of pneumonia, and chronic rhinosinusitis was 2.5 times more common among asthmatics. Sleep apnoea, gastro-oesophageal reflux disease, diabetes, allergic rhinitis and dysfunctional breathing were twofold and cataract nearly twofold higher in the asthmatic group. Adult asthma was also significantly associated with musculoskeletal diseases, incontinence and bronchiectasis. CONCLUSIONS: The most common and most severe comorbidity of adult asthma in this study was chronic obstructive pulmonary disease. Other common comorbidities of adult asthma include acute rhinosinusitis, chronic rhinosinusitis with nasal polyps, atopic dermatitis, allergic rhinitis, dysfunctional breathing, diabetes, pneumonia, sleep apnoea and gastro-oesophageal reflux disease.

Cluster Analysis of Finnish Population-Based Adult-Onset Asthma Patients.

BACKGROUND: Phenotypes of adult asthma have been identified in previous studies but rarely in population-based settings. OBJECTIVE: To identify clusters of adult-onset asthma in a Finnish population-based study on subjects born before 1967. METHODS: We used population-based data from 1350 asthmatics with adult-onset asthma (Adult Asthma in Finland) from Finnish national registers. Twenty-eight covariates were selected based on literature. The number of covariates was reduced by using factor analysis before cluster analysis. RESULTS: Five clusters (CLU1-CLU5) were identified, 3 clusters with late-onset adult asthma (onset ≥40 years) and 2 clusters with onset at earlier adulthood (<40 years). Subjects in CLU1 (n = 666) had late-onset asthma and were nonobese, symptomatic, and predominantly female with few respiratory infections during childhood. CLU2 (n = 36) consisted of subjects who had earlier-onset asthma, were predominantly female, obese with allergic asthma, and had recurrent respiratory infections. Subjects in CLU3 (n = 75) were nonobese, older, and predominantly men with late-onset asthma, smoking history, comorbidities, severe asthma, least allergic diseases, low education, many siblings, and childhood in rural areas. CLU4 (n = 218) was a late-onset cluster consisting of obese females with comorbidities, asthma symptoms, and low education level. Subjects in CLU5 (n = 260) had earlier onset asthma, were nonobese, and predominantly allergic females. CONCLUSIONS: Our population-based adult-onset asthma clusters take into account several critical factors such as obesity and smoking, and identified clusters that partially overlap with clusters identified in clinical settings. Results give us a more profound understanding of adult-onset asthma phenotypes and support personalized management.

Radiological score of computed tomography scans predicts revision surgery for chronic rhinosinusitis.

Objective: Evaluate computed tomography (CT) signs that predict need for revision endoscopic sinus surgery (ESS) of chronic rhinosinusitis (CRS). Methods: CRS patients (n = 48) underwent routine sinus CT scans and baseline ESS in 2006-2011. Lund-Mackay (LM) scores and 43 other CT signs were analysed blinded from both sides. Patients filled in a questionnaire during the day of CT scanning. Follow-up data were collected from hospital records until January 2018. Associations were analysed by Fisher's exact, Mann Whitney U, Kaplan-Meier method with logrank test and Cox's proportional hazard model. Results: Total LM score was not significantly associated with the need for revision ESS. The best predictive model was a sum of CT signs of non-detectable anatomy of inferior/middle turbinates, obstructed frontal recess, and previous sinus surgery. Using these CT findings, we formed a Radiological Score (RS) (min-max, 0-3 points). Having at least one RS point was significantly associated with the need for revision ESS during the average follow-up of 10.7 years (p = 0.008, Logrank test). Conclusion: We identified a radiologic score that was able to predict the need for revision ESS, which is probably useful in predicting CRS outcomes.

Risk factors for severe adult-onset asthma: a multi-factor approach.

BACKGROUND: The aim was to identify risk factors for severe adult-onset asthma. METHODS: We used data from a population-based sample (Adult Asthma in Finland) of 1350 patients with adult-onset asthma (age range 31-93 years) from Finnish national registers. Severe asthma was defined as self-reported severe asthma and asthma symptoms causing much harm and regular impairment and ≥ 1 oral corticosteroid course/year or regular oral corticosteroids or waking up in the night due to asthma symptoms/wheezing ≥ a few times/month. Sixteen covariates covering several domains (personal characteristics, education, lifestyle, early-life factors, asthma characteristics and multiple morbidities) were selected based on the literature and were studied in association with severe asthma using logistic regressions. RESULTS: The study population included 100 (7.4%) individuals with severe asthma. In a univariate analysis, severe asthma was associated with male sex, age, a low education level, no professional training, ever smoking, ≥ 2 siblings, ≥ 1 chronic comorbidity and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) (p < 0.05), and trends for association (p < 0.2) were observed for severe childhood infection, the presence of chronic rhinosinusitis with nasal polyps, and being the 1st child. The 10 variables (being a 1st child was removed due to multicollinearity) were thus entered in a multivariate regression model, and severe asthma was significantly associated with male sex (OR [95% CI] = 1.96 [1.16-3.30]), ever smoking (1.98 [1.11-3.52]), chronic comorbidities (2.68 [1.35-5.31]), NERD (3.29 [1.75-6.19]), and ≥ 2 siblings (2.51 [1.17-5.41]). There was a dose-response effect of the total sum of these five factors on severe asthma (OR [95% CI] = 2.30 [1.81-2.93] for each one-unit increase in the score). CONCLUSIONS: Male sex, smoking, NERD, comorbidities, and ≥ 2 siblings were independent risk factors for self-reported severe asthma. The effects of these factors seem to be cumulative; each additional risk factor gradually increases the risk of severe asthma.

Diseases with oral manifestations among adult asthmatics in Finland: a population-based matched cohort study.

OBJECTIVES: Many comorbidities are associated with adult asthma and may exacerbate the asthma burden of disease. This study aims to investigate the risk for major oral diseases or oral-manifesting diseases in asthmatic compared with non-asthmatic adults. DESIGN: We conducted a population-based matched cohort study with a 13.8-year follow-up. SETTING: A baseline questionnaire was completed by participants in 1997 and follow-up data were extracted from the national hospital discharge registry of the National Institute for Health and Welfare in Finland from 1997 to 2014. PARTICIPANTS: A total of 1394 adults with asthma were matched with 2398 adults without asthma based on sex, age and area of residence. Asthmatic adults were identified from the Drug Reimbursement Register of the Finnish Social Insurance Institution based on a special drug reimbursement right resulting from asthma. Participants without asthma were identified from the Population Register. MAIN OUTCOMES AND MEASURES: Oral health-related primary diagnoses were retrieved using codes from the International Classification of Diseases, 10th edition and divided into groups of diseases. Cox's proportional hazards models stratified by matching unit and models matched and adjusted for pack-years, education level and body mass index (when possible) were used to evaluate the matched and further adjusted HRs for diseases comparing asthmatic and non-asthmatic cohorts. RESULTS: Adult asthma was associated with a higher risk for any oral-manifesting disease (adjusted HR 1.41, 95% CI 1.11 to 1.80), herpes zoster (adjusted HR 6.18, 95% CI 1.21 to 31.6), benign tumours of the oral cavity and pharynx (matched HR 1.94, 95% CI 1.05 to 3.56) and dermatological diseases (pemphigus, pemphigoid, dermatitis herpetiformis, psoriasis and lichen planus, HR 1.67, 95% CI 1.01 to 2.78). CONCLUSIONS: In this study, adult asthmatics experienced a higher risk for a major oral disease or oral-manifesting disease.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Maternal smoking during pregnancy affects adult onset of asthma in offspring: a follow up from birth to age 46†years.

RATIONALE: Environmental tobacco smoke (ETS) exposure increases asthma risk in children. There is limited knowledge of prenatal ETS for adult-onset asthma. OBJECTIVES: To determine the association between prenatal ETS and adult onset asthma. MEASUREMENTS AND MAIN RESULTS: The questionnaire and clinical data of 5200 people, free of physician-diagnosed asthma by 31 years of age, who were included in the Northern Finland Birth Cohort 1966 Study was used. The association of maternal smoking during the last 3 months of pregnancy with onset of physician-diagnosed asthma and with lung function in adult offspring was studied using adjusted multivariate regression analyses. The cumulative incidence of physician-diagnosed asthma between the ages of 31 and 46 years was 5.1% among men and 8.8% among women. Gestational smoke exposure was associated with adult-onset asthma among offspring (adjusted OR 1.54, 95% CI 1.04-2.29), namely among offspring who reported either past non-diagnosed asthma (OR 9.63, 95% CI 2.28-40.67) or past cough with wheeze (3.21, 95% CI 1.71-6.05). A significant association was detected between gestational smoke exposure and the offspring's forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio at 31 years of age. In offspring with the haplotype rs11702779-AA of RUNX1, gestational smoke exposure was associated with adult-onset asthma (5.53, 95% CI 2.11-14.52, adjusted p-value for interaction 0.10). CONCLUSION: Maternal smoking during pregnancy is associated with the cumulative incidence of asthma in offspring between the ages of 31 and 46 years. The association was accentuated in offspring who at age 31, reported having past respiratory problems and/or who had haplotype rs11702779-AA. A reduction in FEV1/FVC ratio was also observed at age 31 years in offspring with gestational smoke exposure. These results could reflect the early vulnerability of offspring's airways to ETS and its putative long-term effects.

TNF-α-induced protein 3 is a key player in childhood asthma development and environment-mediated protection.

BACKGROUND: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-α-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, mediates environmentally induced asthma protection. OBJECTIVE: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. METHODS: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective" farms or LPS. NF-κB signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. RESULTS: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P < .05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-κB signaling-associated gene expression toward an anti-inflammatory state (P < .001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. CONCLUSION: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.

Risk of adult-onset asthma increases with the number of allergic multimorbidities and decreases with age.

BACKGROUND: The aim was to study the association between allergic multimorbidity and adult-onset asthma considering the number of allergic diseases and the age effect. METHODS: We used population-based data from Finnish national registers including 1205 adults over 30 years of age with recently diagnosed asthma (age range: 30-93), matched for gender, age, and living region with one or two controls (n = 2050). Allergic rhinitis (AR), allergic conjunctivitis (AC), and allergic dermatitis (AD) were defined from self-completed questionnaire. Conditional logistic regression adjusted on potential confounders (smoking, growing in countryside, childhood hospitalized infection/pneumonia, parental asthma/allergy, parental smoking, education level, professional training, number of siblings, and birth order) was applied to estimate the asthma risk associated with allergic multimorbidity. RESULTS: A total of 1118 cases with asthma and 1772 matched controls were included [mean (SD, min-max) 53 (11, 31-71) years, 37% men)]. AR, AC, and AD were reported by 50.2%, 39.6%, and 33.8%, respectively, among subjects with asthma and 26.1%, 20.0%, and 23.5%, respectively, among controls. Compared to nonatopics, adult-onset asthma increased with the number of allergic diseases; adjusted OR for asthma [95% CI] associated with 1, 2, and 3 allergic diseases was 1.95 [1.52-2.49], 2.87 [2.19-3.77], and 4.26 [3.07-5.90], respectively. The association between adult-onset asthma and ≥ 1 allergic multimorbidity decreased with increasing age (3.52 [2.51-4.94], 2.44 [1.74-3.42], and 1.68 [1.04-2.71]) in subjects < 50 years, 50-62 years, and > 62 years, respectively (p for age*≥1 allergic multimorbidity interaction, 0.002). CONCLUSIONS: Adult-onset asthma was positively associated with the number of allergic diseases, and this association decreases with age.

Risk factors for repetitive doctor's consultations due to cough: a cross-sectional study in a Finnish employed population.

OBJECTIVES: Cough is the most common symptom prompting people to consult a doctor, thus representing a huge cost to the healthcare. This burden could be reduced by decreasing the number of repetitive consultations by the same individuals. Therefore, it would be valuable to recognise the factors that associate with repetitive doctor's consultations due to cough. DESIGN: A cross-sectional, email survey. SETTING: Public service employees in two Finnish towns. PARTICIPANTS: The questionnaire was sent to 13 980 subjects; 3695 (26.4 %) participated. INTERVENTIONS: The questionnaire sought detailed information about participant characteristics, all disorders diagnosed by a doctor, various symptoms and doctor's consultations. Those with current cough were inquired about cough characteristics and filled in the Leicester Cough Questionnaire (LCQ). PRIMARY OUTCOME: Repetitive (≥3) doctor's consultations due to cough during the previous 12 months. RESULTS: There were 205 participants (5.5% of the participants) with repetitive consultations. They accounted for 848 out of the 1681 doctor's consultations (50.4%) due to cough. Among all participants, repetitive consultations were mainly related to the presence of asthma (adjusted OR (aOR) 2.90 (2.01 to 4.19)) and chronic rhinosinusitis (aOR 2.40 (1.74 to 3.32)). Among the 975 participants with current cough, repetitive consultations were mainly related to a low LCQ total score (aOR 3.84 (2.76 to 5.34) per tertile). Comorbidity, depressive symptoms and smoking were also associated with repetitive consultations. CONCLUSIONS: A modest proportion of subjects with repetitive consultations is responsible for every second doctor's consultation due to cough. The typical features of these subjects could be identified. These findings can help to focus on certain subpopulations in order to plan interventions to reduce the healthcare burden attributable to cough.

Kuopio birth cohort - design of a Finnish joint research effort for identification of environmental and lifestyle risk factors for the wellbeing of the mother and the newborn child.

BACKGROUND: A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. METHODS: KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omics; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. DISCUSSION: This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.

The association between gestational diabetes mellitus and postpartum depressive symptomatology: A prospective cohort study.

BACKGROUND: The literature suggests an association between type 2 diabetes mellitus and depression, but data on the association between gestational diabetes mellitus (GDM) and postpartum depressive symptomatology (PPDS) are scarce. METHODS: Altogether, 1066 women with no previous mental health issues enrolled in the Kuopio Birth Cohort (KuBiCo, www.kubico.fi) were selected for this study. GDM was diagnosed according to the Finnish Current Care Guidelines. Depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS) during the third trimester of pregnancy and eight weeks after delivery. Additionally, a subgroup of women (n = 505) also completed the EPDS during the first trimester of pregnancy. RESULTS: The prevalence rates of GDM and PPDS in the whole study population were 14.1% and 10.3%, respectively. GDM was associated with an increased likelihood of belonging to the PPDS group (OR 2.23, 95% CI 1.23-4.05; adjusted for maternal age at delivery, BMI in the first trimester, smoking before pregnancy, relationship status, nulliparity, delivery by caesarean section, gestational age at delivery, neonatal intensive care unit admission and third-trimester EPDS scores). A significant association between GDM and PPDS was found in the subgroup of women with available data on first-trimester depression (n = 505). LIMITATIONS: The participation rate of the KuBiCo study was relatively low (37%). CONCLUSIONS: Women with GDM may be at increased risk of PPDS. Future studies should investigate whether these women would benefit from a closer follow-up and possible supportive interventions during pregnancy and the postpartum period to avoid PPDS.

Self-Reported Allergic Rhinitis and/or Allergic Conjunctivitis Associate with IL13 rs20541 Polymorphism in Finnish Adult Asthma Patients.

BACKGROUND: Our aim was to observe factors associated with IL13 rs20541 polymorphism and other factors with or without allergic comorbidities such as subject-reported allergic rhinitis (AR) and/or allergic conjunctivitis (AC) symptoms in adult asthmatics. METHODS: A population-based sample of Finnish adult asthma patients (n = 1,156) and matched controls (n = 1,792) filled in a questionnaire. Asthma was diagnosed based on a typical history of asthma symptoms and lung function tests. Skin prick tests with 17 aeroallergens and blood tests including analysis of interleukin 13 (IL13) rs20541 (G/A) genotypes were performed for a subsample (n = 193). RESULTS: The proportion of asthmatics reporting AR was 61.9% and reporting AC was 40.7%. After adjustments, the presence of the IL13 rs20541A- allele (OR 3.06, 95% CI 1.42-6.58, p = 0.004) or multisensitization (adjusted OR 4.59, 95% CI 1.48-14.26, p = 0.008) was associated with AR/AC asthma. Nasal polyps and acetylsalicylic acid-exacerbated respiratory disease was also associated with AR/AC asthma. CONCLUSIONS: Adult AR/AC asthma could putatively be a phenotype, characterized by the presence of atopic and/or eosinophilic factors and a high prevalence of the IL13 rs20541A- allele. Studies on the mechanisms behind this and in other populations are needed.

Heterozygous Vangl2Looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair.

Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising. The planar cell polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly because of the perinatal lethality of many PCP mouse mutant lines. Here, we investigate heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage, including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in emphysema. In vitro, disruption of VANGL2 impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking on lung function. Finally, we show that PCP genes VANGL2 and SCRIB are significantly downregulated in lung tissue from patients with emphysema. Our data reveal an important novel role for the PCP pathway in adult lung homeostasis and repair and shed new light on the genetic factors which may modify destructive lung diseases such as emphysema.

Comparison of questionnaire data and analyzed dioxin concentrations as a measure of exposure in soft-tissue sarcoma studies.

Soft-tissue sarcoma is one of the few specific tumors thought to be caused by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and specifically TCDD. Evidence is, however, based on questionnaire-based case-control studies, and on very few cancer cases in cohort studies at high occupational exposures to chlorophenols or chlorophenoxy acid herbicides with dioxin impurities. Recall bias has been suspected to influence the reporting of exposure, but this possibility has never been adequately put to test. In the present study 87 cancer patients and 308 controls answered a questionnaire asking their exposure to wood preservatives, fungicides and herbicides, and insecticides, and their PCDD/F concentrations were also measured. After matching for age and area 67-69 sarcoma patients and 153-156 controls were available for the study depending on the chemical group, 1-3 controls for each sarcoma patient. Sarcoma patients reported exposure to these chemicals significantly more often than controls did, odds ratios were 6.7 for wood preservatives (p=0.02), 16 for fungicides and herbicides (p=0.01), and 4.9 for insecticides (p=0.06). There was no association, when the analysis was based on measured PCDD/F concentrations (odds ratios close to 1). Although it is not possible to exclude the role of the main chemical as the cause with certainty, the results indicate that recall bias is very likely in previous studies. Thus the causality between contaminant PCDD/Fs and soft tissue sarcoma cannot be considered proven.

Enhanced T helper 1 and 2 cytokine responses at birth associate with lower risk of middle ear infections in infancy.

BACKGROUND: Respiratory tract infections and their symptoms are frequent during early childhood, but their risk factors, including the effect of early immune regulation, are less known. The aim of the study was to analyze whether stimulated cord blood cytokine production is associated with the frequency of respiratory tract infection symptoms or infections during the first year of life. METHODS: The study population consisted of children of mothers from farm or non-farm rural environment from Austria, Finland, Germany, and Switzerland who participated in a prospective birth cohort study (PASTURE: Protection against Allergy-Study in Rural Environments) (N = 550). Cord blood samples were stimulated with the combination of phorbol ester and ionomycin (P/I) for 24 h, and the production of IL-5, IL-10, TNF-α, and IFN-γ was determined using ELISA. Information about infectious morbidity was collected using weekly diaries. RESULTS: P/I-stimulated production of IL-5 (adjusted risk ratio (aRR) for ≤median production, 0.37; 95% confidence interval (CI), 0.25-0.55, aRR for >median production, 0.41; 95% CI, 0.27-0.61 vs. production median production, 0.39; 95% CI, 0.25-0.62 vs. production

Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA.

RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. OBJECTIVES: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5 x 10(-8)) and three variants reported as suggestive (P<5× 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. MAIN RESULTS: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4 × 10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. CONCLUSIONS: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.

Few associations between high-sensitivity C-reactive protein and environmental factors in 4.5-year-old children.

BACKGROUND: Low-grade inflammation in early childhood might protect from allergic diseases later in life. Our aim was to examine the effects of different environmental factors on low-grade inflammation measured with serum high-sensitivity C-reactive protein (hsCRP) at the age of 4.5 years. METHODS: The high-sensitivity CRP values (n = 653) and serum-specific IgE concentrations were measured from 4.5-year-old children in rural areas in five European countries (Austria, Finland, France, Germany, and Switzerland). Children belonged to the prospective multi-center PASTURE birth cohort. Data on early and current farming environment and domestic animal exposure were collected by questionnaires. RESULTS: Females as well as obese or very obese children at age of 4.5 years had higher hsCRP values than males (aOR 1.84 95% CI 1.27-2.66) and healthy weight children (aOR 4.47 95% CI 1.94-10.31), respectively. Levels were lowest in the summer. Few associations were detected between hsCRP values and farm environmental factors or atopic sensitization. However, there was evidence of children with low levels of hsCRP (below the detection limit) who had increased prevalence of sensitization to inhaled and seasonal allergens. Among non-sensitized children, spending time in stables was associated with reduced hsCRP (15 min-10 h aOR 0.40 95% CI 0.16-0.96 and ≥10 h aOR 0.25 95% CI 0.07-0.90), and among sensitized children, maternal smoking was associated with higher hsCRP values (aOR 2.51 95% CI 1.12-5.59). CONCLUSION: We found few associations between early environmental farming factors and hsCRP levels, and between hsCRP levels and atopic sensitization in 4.5-year-old children. However, our results suggest that the role played by the environmental factors in low-grade inflammation may differ between sensitized and non-sensitized children.

Associations between pre-pregnancy obesity and asthma symptoms in adolescents.

BACKGROUND: The high prevalence of children's asthma symptoms, worldwide, is unexplained. We examined the relation between maternal pre-pregnancy weight and body mass index (BMI), and asthma symptoms in adolescents. METHODS: Data from 6945 adolescents born within the Northern Finland Birth Cohort 1986 were used. Prospective antenatal and birth outcome data, including maternal pre-pregnancy weight and BMI, and asthma symptoms in adolescent offspring at age 15-16 years, were employed. Logistic regression analyses were performed to examine the associations between relevant prenatal factors and asthma symptoms during adolescence. RESULTS: Current wheeze (within the past year) was reported by 10.6% of adolescents, and physician-diagnosed asthma by 6.0%. High maternal pre-pregnancy BMI was a significant predictor of wheeze in the adolescents (increase per kilogram per square metre unit; 2.7%, 95% CI 0.9 to 4.4 for ever wheeze; 3.5%, 95% CI 1.3 to 5.8 for current wheeze), and adjusting for potential confounders further increased the risk (2.8%, 95% CI 0.5 to 5.1; 4.7%, 95% CI 1.9 to 7.7, respectively). High maternal pre-pregnancy weight, in the top tertile, also significantly increased the odds of current wheeze in the adolescent by 20% (95% CI 4 to 39), and adjusting for potential confounders further increased the risk (OR=1.52, 95% CI 1.19 to 1.95). Results were similar for current asthma. Furthermore, these significant associations were observed only among adolescents without parental history of atopy but not among those with parental history of atopy. CONCLUSIONS: The association demonstrated here between maternal pre-pregnancy overweight and obesity, and asthma symptoms in adolescents suggests that increase in asthma may be partly related to the rapid rise in obesity in recent years.