Runa Vavia Fenger

Cohort Profile: The Health2006 cohort, Research Centre for Prevention and Health

Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, The Capital Region of Denmark, Denmark, National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Denmark, Danish Research Centre for Chemical Sensitivities, Gentofte University Hospital, University of Copenhagen, Copenhagen, Denmark, Hagedorn Research Institute and Steno Diabetes Centre, Gentofte, Denmark, The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark and Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

Serum 25(OH)D and incident type 2 diabetes: a cohort study.

BACKGROUND/OBJECTIVES:Mild to moderate vitamin D insufficiency has been proposed as a risk factor for several common chronic diseases including type 2 diabetes. This study aimed to examine the association between serum 25-hydroxy vitamin D (25(OH)D) and incident diabetes.SUBJECTS/METHODS:The MONICA10 cohort consists of 2656 participants (men and women aged 41–71 years) who participated in a 10-year follow-up examination during 1993–1994 as part of the MONICA 1 population survey. A total of 2571 participants free of diabetes at baseline and with successful measurement of serum 25(OH)D were included in the current study. The Danish National Diabetes register enabled identification of 288 cases of incident diabetes during follow-up (median: 16.4 years). Data were analysed by Cox proportional hazard models and associations were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs).RESULTS:Serum 25(OH)D was inversely associated with incident diabetes adjusted for potential confounders (HR per 25 nmol/l=0.83; 95% CI: 0.72–0.95; P=0.009). A statistically significant interaction was observed between 25(OH)D and waist circumference (WC) (Pinteraction=0.042) suggesting an association in persons with a high WC (HR (95%CI) per 25 nmol/l=0.74 (0.63–0.88), 218 incident cases) and not in persons with a normal WC (HR (95%CI) per 25 nmol/l=0.98 (0.78–1.24), 70 incident cases).CONCLUSIONS:Low serum 25(OH)D was associated independently with incident diabetes. The inverse association was only found in overweight-obese and not in normal weight individuals, suggesting that obesity may modify the effect of vitamin D status on the risk of diabetes.

Exploring the obesity‐asthma link: do all types of adiposity increase the risk of asthma?

Obesity and risk of asthma are linked. Different distributions of adiposity, such as visceral, subcutaneous or ectopic adiposity, may affect asthma risk differently.

Vitamin D Status, Filaggrin Genotype, and Cardiovascular Risk Factors: A Mendelian Randomization Approach

Background Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Methods Three population based studies were included, Monica10 (2,656 individuals aged 40–71 years), Inter99 (6,784 individuals aged 30–60 years), and Health2006 (3,471 individuals aged 18–69 years) conducted in 1993–94, 1999–2001, and 2006–2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Results Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Conclusion Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

Determinants of Serum Tryptase in a General Population: The Relationship of Serum Tryptase to Obesity and Asthma

Background: Recent studies indicate that mast cells are more abundant in the obese state. Total serum tryptase (ST) is a marker of mast cell numbers or activity. Since obesity and asthma have been consistently linked in epidemiological studies, a possible higher mast cell activity in obesity could be a factor between the two conditions. The aim of this study was to investigate determinants of ST and whether a potential association between obesity and allergic respiratory disease would be influenced by levels of ST in obese persons. Methods: Measurements of ST (ImmunoCAP Tryptase assay), atopy (skin prick test reactivity), methacholine bronchial hyperresponsiveness (BHR), body mass index (BMI) and serum lipids were performed in a general population of 1,216 persons aged 15–69 years. Results: ST increased significantly with increasing BMI. The median ST level increased from 3.3 µg/l in persons with BMI <25 to 4.4 µg/l in persons with BMI >30, p < 0.0001. Age (p < 0.0001), male sex (p = 0.0009) and smoking (p = 0.022) were positively associated with ST, whereas alcohol consumption (p = 0.005) was inversely associated with ST. ST was not associated with atopy, symptoms of allergic respiratory disease or BHR. A positive association between symptoms of allergic respiratory disease and obesity (OR = 1.98, 95% CI = 1.25–3.14) was not influenced by obesity-related differences in ST. Conclusions: Increasing BMI was significantly associated with increasing ST and the prevalence of symptoms of allergic respiratory disease. However, mast cell activity/burden (assessed by ST levels) did not influence the association between BMI and asthma/rhinitis symptoms.

Association between Loss-of-Function Mutations in the Filaggrin Gene and Self-Reported Food Allergy and Alcohol Sensitivity

Background: Loss-of-function mutations of the filaggrin (FLG) gene cause an impaired skin barrier and increase the risk of atopic dermatitis. Interestingly, FLG mutations have also been found to be associated with a high risk of peanut allergy. Objective: We investigated the association of FLG mutations with self-reported food allergy, symptoms of oral allergy syndrome (OAS), and alcohol sensitivity. Methods: A total of 3,471 adults from the general population participated in a health examination. Information on food allergies, OAS and alcohol sensitivity was obtained by questionnaire. FLG mutation carriers were defined as having at least one null mutation allele of R501X or 2282del4. Primary lactose intolerance (PLI) was defined as the C/C genotype of the rs4988235 polymorphism. Results: FLG mutations were associated with a higher risk of self-reported allergy to eggs (OR 3.22 and 95% CI 1.46-7.11), milk (OR 2.10 and 95% CI 1.12-3.92), fish (OR 4.54 and 95% CI 1.88-10.96) and wheat (OR 3.59 and 95% CI 1.61-8.02), but not with symptoms of OAS (OR 1.05 and 95% CI 0.73-1.51). Serum-specific IgE was measured in a subsample and confirmed the association between FLG and IgE to milk. A significant gene-by-gene interaction between FLG and PLI was observed in relation to self-reported allergy to milk. Furthermore, FLG mutations were associated with a higher risk of alcohol sensitivity. Conclusions: We found that loss-of-function mutations in the FLG gene were significantly associated with self-reported food allergy and alcohol sensitivity, but not with OAS. These findings, if confirmed, support the idea that skin barrier functions may be involved in the pathogenesis of food allergy.

Vitamin D status and chronic obstructive pulmonary disease: A prospective general population study

Objectives Vitamin D deficiency is common among persons with chronic obstructive pulmonary disease (COPD). Whether vitamin D affects the development and deterioration of COPD or is a consequence of the disease lacks clarity. We investigated the association between vitamin D status and prevalent and incident COPD in the general population. Methods We included a total of 12,041 individuals from three general population studies conducted in 1993–94, 1999–2001, and 2006–2008, respectively, with vitamin D measurements. Information on COPD was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death. Results There were 85 prevalent and 463 incident cases of COPD (median follow-up 9.7 years). We found a statistically significant inverse association between vitamin D status and prevalent COPD with odds ratio = 0.89 (95% confidence interval, CI: 0.79, 1.0), but no statistically significant association with incident COPD with a hazard ratio = 0.98 (95% CI: 0.94, 1.0), respectively, per 10 nmol/l higher vitamin D status, when adjusted for possible confounders. Conclusions We found a statistically significant inverse cross-sectional association between vitamin D status and COPD, but no association between vitamin D status and incident COPD.

Immunoglobulin E Sensitization to Cross-Reactive Carbohydrate Determinants: Epidemiological Study of Clinical Relevance and Role of Alcohol Consumption

Background: The determinants and biologic significance of IgE-mediated sensitization to cross-reactive carbohydrate determinants (CCDs) are not entirely known. An association between alcohol consumption and CCD sensitization has been reported in studies from Spain and Portugal. Objective: To investigate the relationship of alcohol consumption with CCD sensitization, the role of alcohol dehydrogenase gene polymorphisms, and the clinical consequences of CCD sensitization. Methods: Serum-specific IgE sensitization (≧0.1 kU/l) to a CCD (the N-glycan from bromelain) was assessed in 1,197 adults participating in a population-based study in Copenhagen, Denmark. Alcohol consumption and atopic symptoms (rhinitis, asthma and oral allergy syndrome) were assessed by questionnaire. Examinations included skin prick tests (SPTs), qualitative multiallergen IgE test (Phadiatop®), methacholine bronchial hyperreactivity, eosinophil cationic protein and alcohol dehydrogenase (ADH) gene polymorphisms. Results: Alcohol consumption was significantly associated with CCD sensitization and this was particularly evident in SPT-negative individuals. The fast-metabolizing allele of the ADH1b polymorphism was significantly associated with CCD sensitization in alcohol drinkers. CCD sensitization was associated with atopic symptoms, but associations attenuated markedly when adjusting for SPT reactivity. Conclusions: Our results suggest that the positive association between alcohol consumption and CCD sensitization is universal and not specific to certain populations. The observed association between the ADH1b polymorphism and CCD sensitization may support that alcohol is causally related to the risk of CCD sensitization. The observed association between CCD sensitization and atopic phenotypes did not appear to be independent of SPT reactivity indicating limited significance of CCD sensitization per se.

Specific IgE positivity against inhalant allergens and development of autoimmune disease.

Abstract Background: Allergic and autoimmune diseases have been suggested to be inversely associated. We investigated the association between atopy and development of any and specific types of autoimmune disease. Methods: We included a total of 14 849 individuals from five population-based studies with measurements of atopy defined as specific IgE positivity against inhalant allergens. We followed the participants by linkage to the Danish National Patient Register (median follow-up time 11.2 years). Hazard ratio (HR) and 95% confidence interval (CI) of autoimmune disease were estimated by Cox regression. Results: The risk for atopics versus non-atopics was: for any autoimmune disease (HR = 0.99, 95% CI: 0.83, 1.18), thyrotoxicosis (HR = 0.69, 95% CI: 0.34, 1.37), type 1 diabetes (HR = 1.16, 95% CI: 0.84, 1.60), multiple sclerosis (HR = 1.97, 95% CI: 0.95, 4.11), iridocyclitis (HR = 0.82, 95% CI: 0.38, 1.74), Crohn’s disease (HR = 1.03, 95% CI: 0.47, 2.25), ulcerative colitis (HR = 0.93, 95% CI: 0.52, 1.69), psoriasis vulgaris (HR = 1.50, 95% CI: 0.86, 2.62), seropositive rheumatoid arthritis (HR = 0.74, 95% CI: 0.48, 1.14) and polymyalgia rheumatica (HR = 0.79, 95% CI: 0.44, 1.44). Conclusions: We found no statistically significant associations between atopy and autoimmune disease, but we cannot exclude relatively small to moderate effects - protective or promotive - of atopy on autoimmune disease.

IgE sensitization to inhalant allergens and the risk of airway infection and disease: A population-based study

Background Immunoglobulin E (IgE) sensitization, which is the propensity to develop IgE antibodies against common environmental allergens, is associated with a lymphocyte T-helper type 2 (Th2) skewed immune response and a high risk of allergic respiratory disease. Little is known about whether IgE sensitization confers an increased risk of respiratory infections in adults. We investigated the association between IgE sensitization and the incidence of acute airway infections, other infections and chronic lower airway disease events as recorded in nation-wide registries. Methods We included 14,849 persons from five population-based studies with measurements of serum specific IgE positivity against inhalant allergens. Participants were followed by linkage to Danish national registries (median follow-up time 11.3 years). The study-specific relative risks were estimated by Cox regression analysis, meta-analysed, and expressed as hazard ratios, HRs (95% confidence intervals, CIs). Results The relative risks for IgE sensitized vs. non-sensitized were: for pneumonia (HR = 1.20, 95% CI: 1.01, 1.41), other acute airway infection (HR = 0.86, 95% CI: 0.60, 1.22), infection (HR = 1.06, 95% CI: 0.90, 1.24), asthma (HR = 2.26, 95% CI: 1.79, 2.86), and other chronic lower airway disease (HR = 1.31, 95% CI: 1.08, 1.58). In never smokers, the higher risk of pneumonia (HR = 1.73, 95% CI: 1.23, 2.44) and asthma (HR = 3.17, 95% CI: 2.10, 4.76) among IgE sensitized was more pronounced. Conclusions IgE sensitization was associated with a higher risk of asthma, other chronic lower airway diseases, and pneumonia. However, the association between IgE sensitization and pneumonia may be explained by undiagnosed asthma causing the pneumonia. Further studies are needed for confirmation.