Asthma in farm children is more determined by genetic polymorphisms and in non-farm children by environmental factors.

BACKGROUND: The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. METHODS: Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single-nucleotide polymorphisms (SNPs) were selected from a genome-wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. RESULTS: Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57-0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61-0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62-0.78]). CONCLUSIONS: Asthma in farm children is more likely predicted by other factors as compared to non-farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance.

Correction to: Prevalence of wheezing and atopic diseases in Austrian schoolchildren in conjunction with urban, rural or farm residence.

Correction: Wien Klin Wochenschr 2014 https://doi.org/10.1007/s00508-014-0571-z The disclosure needs to additionally mention the following:Erika von Mutius is listed as inventor on the following patents: Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis ….

Bacterial microbiota of the upper respiratory tract and childhood asthma.

BACKGROUND: Patients with asthma and healthy controls differ in bacterial colonization of the respiratory tract. The upper airways have been shown to reflect colonization of the lower airways, the actual site of inflammation in asthma, which is hardly accessible in population studies. OBJECTIVE: We sought to characterize the bacterial communities at 2 sites of the upper respiratory tract obtained from children from a rural area and to relate these to asthma. METHODS: The microbiota of 327 throat and 68 nasal samples from school-age farm and nonfarm children were analyzed by 454-pyrosequencing of the bacterial 16S ribosomal RNA gene. RESULTS: Alterations in nasal microbiota but not of throat microbiota were associated with asthma. Children with asthma had lower α- and ß-diversity of the nasal microbiota as compared with healthy control children. Furthermore, asthma presence was positively associated with a specific operational taxonomic unit from the genus Moraxella in children not exposed to farming, whereas in farm children Moraxella colonization was unrelated to asthma. In nonfarm children, Moraxella colonization explained the association between bacterial diversity and asthma to a large extent. CONCLUSIONS: Asthma was mainly associated with an altered nasal microbiota characterized by lower diversity and Moraxella abundance. Children living on farms might not be susceptible to the disadvantageous effect of Moraxella. Prospective studies may clarify whether Moraxella outgrowth is a cause or a consequence of loss in diversity.

Identification of fungal candidates for asthma protection in a large population-based study.

BACKGROUND: Exposure to molds has been related to asthma risk both positively and negatively, depending on the environmental setting. The pertinent results are based on generic markers or culturing methods although the majority of present fungi cannot be cultured under laboratory conditions. The aim of the present analysis was to assess environmental dust samples for asthma-protective fungal candidates with a comprehensive molecular technique covering also non-cultivable and non-viable fungi. METHODS: Mattress dust samples of 844 children from the GABRIELA study were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) of the fungus-specific internal transcribed spacer (ITS) region. Known asthma candidate species were tested for their associations with asthma, and further gel positions were sought to explain the above. As a second, data-driven, analysis, we tested the association of each individual gel position with asthma. RESULTS: In the hypothesis-driven approach, Penicillium chrysogenum emerged with an odds ratio of 0.80 (95% confidence interval 0.66-0.96; p = 0.020). The effect size was changed by 39% toward the null when adjusting for the two bands 683 (DNA of Metschnikowia sp., Aureobasidium spp.) and 978 (DNA of Epicoccum spp., Galactomyces spp., uncultured Penicillium). The data-driven approach yielded an additional band (containing DNA of Pseudotaeniolina globosa) with reduced risk of asthma (OR = 0.80 [0.66-0.96], p = 0.012). CONCLUSIONS: A large population-based study revealed several fungal taxa with inverse associations with childhood asthma. Molds produce a variety of bioactive compounds with detrimental but also beneficial immunoregulatory capacities, which renders them promising targets for further asthma research.

Diagnosis and management of asthma - Statement on the 2015 GINA Guidelines.

This statement was written by a group of pulmonologists and pediatric pulmonologists belonging to the corresponding professional associations ÖGP (Austrian Society for Pulmonology) and ÖGKJ (Austrian Society for pediatric and adolescent medicine) to provide a concise overview of the latest updates in the 2015 GINA Guidelines and to include aspects that are specific to Austria.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Prevalence of wheezing and atopic diseases in Austrian schoolchildren in conjunction with urban, rural or farm residence.

BACKGROUND: A large number of studies have consistently shown that children growing up on a farm have a reduced prevalence of allergic disorders. The GABRIEL Advanced Study was conducted in five rural areas of southern Germany, Switzerland, Austria and Poland to shed light on the protective 'farm effect' on asthma and atopic disease. Whereas, the GABRIEL Advanced Study focussed on rural children only, the present study incorporates data from Innsbruck town children also. METHODS: A screening questionnaire was developed to identify children with and without atopic disease within their living environment. Children were stratified into farm children, rural children and Innsbruck-town children. Within the farming environment, regular exposure to the following key factors of interest was predefined: the animal shed, the hay loft and farm milk. Wheezing in the past 12 months (W12), doctor-diagnosed (dd)-asthma, dd-allergic rhinitis and dd-atopic dermatitis were evaluated by using standardized questions from the International Study of Asthma and Allergies in Childhood (ISAAC) RESULTS: Farm children with regular exposure showed a lower risk for W12 (odds ratios (OR) = 0.3; 95%; confidence interval (CI) 0.2-0.5), dd-asthma (OR = 0.4; 95% CI 0.2-0.9) and dd-hay fever (OR 0.2; 95% CI 0.1-0.4). The protective effect of regular exposure extended to rural children but included W12 and dd-hay fever only. Multivariate logistic regression analysis for children being regularly exposed revealed protective attributes for the animal shed, the hay loft and farm milk. CONCLUSION: These data show that regular exposure to a farming environment protects against wheezing, asthma and hay fever. Regarding wheezing and hay fever, this effect was not restricted to children living on a farm but also notable in rural children with regular farm contact.

Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.

Using a whole-exome sequencing strategy, we identified recessive CCNO (encoding cyclin O) mutations in 16 individuals suffering from chronic destructive lung disease due to insufficient airway clearance. Respiratory epithelial cells showed a marked reduction in the number of multiple motile cilia (MMC) covering the cell surface. The few residual cilia that correctly expressed axonemal motor proteins were motile and did not exhibit obvious beating defects. Careful subcellular analyses as well as in vitro ciliogenesis experiments in CCNO-mutant cells showed defective mother centriole generation and placement. Morpholino-based knockdown of the Xenopus ortholog of CCNO also resulted in reduced MMC and centriole numbers in embryonic epidermal cells. CCNO is expressed in the apical cytoplasm of multiciliated cells and acts downstream of multicilin, which governs the generation of multiciliated cells. To our knowledge, CCNO is the first reported gene linking an inherited human disease to reduced MMC generation due to a defect in centriole amplification and migration.

The combined effects of family size and farm exposure on childhood hay fever and atopy.

BACKGROUND: Exposure to farming environments and siblings is associated with reduced risks of childhood hay fever and atopy. We explored the independence and interaction of these protective effects in the GABRIELA study. METHODS: Questionnaire surveys on farming, asthma, and allergies were conducted in four central European areas among 79,888 6-12-yr-old children. Aeroallergen-specific serum IgE was measured in a stratified sample of 8,023 children. Multiple logistic regression was used to compare gradients in allergy prevalence by sibship size across three categories of exposure to farming environments. RESULTS: The prevalence of hay fever ranged from 2% (95% confidence interval 1.6%; 2.7%) among farmers' children with more than two siblings to 12% (11.2%; 13.0%) among children with no farm exposure and no siblings. Farming families were larger on average. More siblings and exposure to farming environments independently conferred protection from hay fever and atopy. There was no substantial effect modification between family size and exposure to farming environments. The odds ratios for hay fever per additional sibling were 0.79 among unexposed non-farm children, 0.77 among farm-exposed non-farm children, and 0.72 among children from farming families (2df interaction test: p = 0.41). CONCLUSION: The inverse association of exposure to farming environments with hay fever is found in all sizes of family, with no substantial tendency to saturation or synergism. This suggests that different biological mechanisms may underlie these two protective factors. Combinations of a large family and exposure to farming environments markedly reduce the prevalence of hay fever and indicate the strength of its environmental determinants.

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans.

Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease.

Health-related quality of life in rural children living in four European countries: the GABRIEL study.

OBJECTIVE: Measuring children's health-related quality of life (HRQOL) is of growing importance given increasing chronic diseases. By integrating HRQOL questions into the European GABRIEL study, we assessed differences in HRQOL between rural farm and non-farm children from Germany, Austria, Switzerland and Poland to relate it to common childhood health problems and to compare it to a representative, mostly urban German population sample (KIGGS). METHODS: The parents of 10,400 school-aged children answered comprehensive questionnaires including health-related questions and the KINDL-R questions assessing HRQOL. RESULTS: Austrian children reported highest KINDL-R scores (mean: 80.9; 95 % CI [80.4, 81.4]) and Polish children the lowest (74.5; [73.9, 75.0]). Farm children reported higher KINDL-R scores than non-farm children (p = 0.002). Significantly lower scores were observed in children with allergic diseases (p < 0.001), with sleeping difficulties (p < 0.001) and in overweight children (p = 0.04). The German GABRIEL sample reported higher mean scores (age 7-10 years: 80.1, [79.9, 80.4]; age 11-13 years: 77.1, [74.9, 79.2]) compared to the urban KIGGS study (age 7-10 years: 79.0, [78.7-79.3]; age 11-13 years: 75.1 [74.6-75.6]). Socio-demographic or health-related factors could not explain differences in HRQOL between countries. CONCLUSIONS: Future increases in chronic diseases may negatively impact children's HRQOL.

Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide.

BACKGROUND: Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes. OBJECTIVE: We sought to study the farm effect on wheeze phenotypes and objective markers, such as lung function and exhaled nitric oxide, and their interrelation with atopy in children. METHODS: The GABRIEL Advanced Studies are cross-sectional, multiphase, population-based surveys of the farm effect on asthma and allergic disease in children aged 6 to 12 years. Detailed data on wheeze, farming exposure, and IgE levels were collected from a random sample of 8023 children stratified for farm exposure. Of those, another random subsample of 858 children was invited for spirometry, including bronchodilator tests and exhaled nitric oxide measurements. RESULTS: We found effects of exposure to farming environments on the prevalence and degree of atopy, on the prevalence of transient wheeze (adjusted odds ratio, 0.78; 95% CI, 0.64-0.96), and on the prevalence of current wheeze among nonatopic subjects (adjusted odds ratio, 0.45; 95% CI, 0.32-0.63). There was no farm effect on lung function and exhaled nitric oxide levels in the general study population. CONCLUSIONS: Children living on farms are protected against wheeze independently of atopy. This farm effect is not attributable to improved airway size and lung mechanics. These findings imply as yet unknown protective mechanisms. They might include alterations of immune response and susceptibility to triggers of wheeze, such as viral infections.

Health-related quality of life does not explain the protective effect of farming on allergies.

BACKGROUND: Numerous studies report a protective effect of farming against allergic diseases. Some specific underlying exposures contributing to this effect have recently been described in the GABRIEL survey. So far, psycho-social factors have not been included in these analyses. METHODS: In order to assess the potential influence of health-related quality of life (HRQOL) on the protective effect of farming, 8259 school aged children from the European GABRIEL study answered questions concerning farming and allergic diseases, as well as validated questions about HRQOL. RESULTS: Farm children reported higher HRQOL than non farm children. However, HRQOL did not modify the protective effect of farming against allergies. Children with allergic diseases reported significantly lower HRQOL scores suggesting that the higher HRQOL of farm children was in part explained by the lower prevalence of these diseases among farm children. CONCLUSION: Although farm children reported higher HRQOL scores than did non-farm children, HRQOL did not explain the protective effect of farming against allergic diseases. The relationship between allergic diseases and HRQOL is likely bidirectional and needs to be assessed prospectively.

Protection from childhood asthma and allergy in Alpine farm environments-the GABRIEL Advanced Studies.

BACKGROUND: Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining this protective farm effect has consistently been identified. OBJECTIVE: We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy. METHODS: In rural regions of Austria, Germany, and Switzerland, 79,888 school-aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever. RESULTS: Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio [aOR], 0.68; 95% CI, 0.59-0.78; P< .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P< .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P= .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P< .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity. CONCLUSION: A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy.

Assessing asthma control: symptom scores, GINA levels of asthma control, lung function, and exhaled nitric oxide.

BACKGROUND: The childhood asthma control test (C-ACT) is a validated symptom score for assessing asthma control in children. We used a slightly modified version (C-ACT(M) ) of the German C-ACT and compared our results with the literature, correlated the children's part of C-ACT (C-ACT(children) ) with a visual analogue scale (VAS(children) ), explored the agreement between C-ACT(M) and GINA levels of asthma control, as well as the relationship between C-ACT(M) and lung function and exhaled nitric oxide (FeNO). METHODS: We investigated 107 children with a diagnosis of asthma. The study protocol consisted of a clinical examination, assessment of asthma control according to GINA guidelines, administration of C-ACT(M) , VAS(children) , lung function, and FeNO. RESULTS: Of our patients 66% had, according to GINA, partly controlled-/uncontrolled asthma, 18% were uncontrolled according to C-ACT(M) . Children with partly controlled-/uncontrolled asthma according to GINA had lower C-ACT(M) scores than did children with controlled asthma (16.1 ± 3.6 SD vs. 25.4 ± 1.8 SD; P < 0.000), and children with a C-ACT(M) score ≤ 19 had poorer lung function (mean FEV1% predicted 81.5 ± 13.5 SD vs. 94.2 ± 12.1 SD; P = 0.002). Spearman's rank correlation coefficients revealed significant correlations between all symptom scores. Multiple linear regression adjusted for age, gender, FEV1 and FeNO demonstrated a significant relationship between C-ACT(M) , VAS(children) , and FEV1 (P = 0.003, resp. <0.000), but no significant correlation between C-ACT(M) , VAS(children) , and FeNO. CONCLUSIONS: The German version of C-ACT(M) is valid and useful for monitoring children with asthma along with tests aimed to follow up lung function and airway inflammation. Concordance between C-ACT(M) and GINA is moderate, because asthma control assessed by C-ACT(M) allows more symptoms and lung function is not included in the scoring.

The GABRIEL Advanced Surveys: study design, participation and evaluation of bias.

Exposure to farming environments has been shown to protect substantially against asthma and atopic disease across Europe and in other parts of the world. The GABRIEL Advanced Surveys (GABRIELA) were conducted to determine factors in farming environments which are fundamental to protecting against asthma and atopic disease. The GABRIEL Advanced Surveys have a multi-phase stratified design. In a first-screening phase, a comprehensive population-based survey was conducted to assess the prevalence of exposure to farming environments and of asthma and atopic diseases (n = 103,219). The second phase was designed to ascertain detailed exposure to farming environments and to collect biomaterial and environmental samples in a stratified random sample of phase 1 participants (n = 15,255). A third phase was carried out in a further stratified sample only in Bavaria, southern Germany, aiming at in-depth respiratory disease and exposure assessment including extensive environmental sampling (n = 895). Participation rates in phase 1 were around 60% but only about half of the participating study population consented to further study modules in phase 2. We found that consenting behaviour was related to familial allergies, high parental education, wheeze, doctor diagnosed asthma and rhinoconjunctivitis, and to a lesser extent to exposure to farming environments. The association of exposure to farm environments with asthma or rhinoconjunctivitis was not biased by participation or consenting behaviour. The GABRIEL Advanced Surveys are one of the largest studies to shed light on the protective 'farm effect' on asthma and atopic disease. Bias with regard to the main study question was able to be ruled out by representativeness and high participation rates in phases 2 and 3. The GABRIEL Advanced Surveys have created extensive collections of questionnaire data, biomaterial and environmental samples promising new insights into this area of research.

The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study.

BACKGROUND: Farm milk consumption has been identified as an exposure that might contribute to the protective effect of farm life on childhood asthma and allergies. The mechanism of action and the role of particular constituents of farm milk, however, are not yet clear. OBJECTIVE: We sought to investigate the farm milk effect and determine responsible milk constituents. METHODS: In rural regions of Germany, Austria, and Switzerland, a comprehensive questionnaire about farm milk consumption and other farm-related exposures was completed by parents of 8334 school-aged children, and 7606 of them provided serum samples to assess specific IgE levels. In 800 cow's milk samples collected at the participants' homes, viable bacterial counts, whey protein levels, and total fat content were analyzed. Asthma, atopy, and hay fever were associated to reported milk consumption and for the first time to objectively measured milk constituents by using multiple regression analyses. RESULTS: Reported raw milk consumption was inversely associated to asthma (adjusted odds ratio [aOR], 0.59; 95% CI, 0.46-0.74), atopy (aOR, 0.74; 95% CI, 0.61-0.90), and hay fever (aOR, 0.51; 95% CI, 0.37-0.69) independent of other farm exposures. Boiled farm milk did not show a protective effect. Total viable bacterial counts and total fat content of milk were not significantly related to asthma or atopy. Increased levels of the whey proteins BSA (aOR for highest vs lowest levels and asthma, 0.53; 95% CI, 0.30-0.97), α-lactalbumin (aOR for interquartile range and asthma, 0.71; 95% CI, 0.52-0.97), and ß-lactoglobulin (aOR for interquartile range and asthma, 0.62; 95% CI, 0.39-0.97), however, were inversely associated with asthma but not with atopy. CONCLUSIONS: The findings suggest that the protective effect of raw milk consumption on asthma might be associated with the whey protein fraction of milk.

Gene-environment interaction for childhood asthma and exposure to farming in Central Europe.

BACKGROUND: Asthma is a disease in which both genetic and environmental factors play important roles. The farming environment has consistently been associated with protection from childhood asthma and atopy, and interactions have been reported with polymorphisms in innate immunity genes. OBJECTIVE: To detect gene-environment interactions for asthma and atopy in the farming environment. METHODS: We performed a genome-wide interaction analysis for asthma and atopy by using 500,000 genotyped single nucleotide polymorphisms (SNPs) and farm-related exposures in 1708 children from 4 rural regions of Central Europe. We also tested selectively for interactions between farm exposures and 7 SNPs that emerged as genome-wide significant in a large meta-analysis of childhood asthma and 5 SNPs that had been reported previously as interacting with farm exposures for asthma or atopy. RESULTS: Neither the asthma-associated SNPs nor the SNPs previously published for interactions with asthma showed significant interactions. The genome-wide interaction study did not reveal any significant interactions with SNPs within genes in the range of interacting allele frequencies from 30% to 70%, for which our study was well powered. Among rarer SNPs, we identified 15 genes with strong interactions for asthma or atopy in relation to farming, contact with cows and straw, or consumption of raw farm milk. CONCLUSION: Common genetic polymorphisms are unlikely to moderate the protective influence of the farming environment on childhood asthma and atopy, but rarer variants, particularly of the glutamate receptor, metabotropic 1 gene, may do so. Given the limited statistical power of our study, these findings should be interpreted with caution before being replicated in independent farm populations.

Lower prevalence of common filaggrin mutations in a community sample of atopic eczema: is disease severity important?

BACKGROUND: Recent studies have shown an association of loss-of-function mutations in the filaggrin gene (FLG) with ichthyosis vulgaris and atopic eczema (AE). Case selection may have distorted the hitherto reported prevalence of FLG mutations and their relation to atopic disease. The aim of the study was to determine the true population prevalence of FLG mutations in unselected children with and without reported physician diagnoses of asthma, allergic rhinitis and AE and their relationship with family history of atopic disease. METHODS: We used a nested case-control design by sampling children with reported doctor's diagnoses of AE, asthma and allergic rhinitis and randomly selected controls from a larger cross-sectional study (n = 1263). Most common FLG mutations R501X, 2282del4, and R2447X were screened in DNA extracted from defrosted urine samples. The relationship of the combined FLG variants with atopic diseases and with reported family history of AE, asthma, and rhinitis was assessed. RESULTS: In the patient group one homozygote (R501X/R501X), 4 compound heterozygotes (3 R501X/2282del4, one 2282del4/R2447X), and 17 heterozygotes (10 R501X/wt, 5 2282del4/wt, and 2 R2447X/wt), in the control group 9 heterozygotes (5 R501X/wt, 4 2282del4/wt) were detected. The combined prevalence of FLG loss-of-function alleles was 5% in the control group and 9% in the atopic sample. In a subgroup analysis, the combination of allergic rhinitis and AE showed a significant relationship with FLG mutations, OR = 3.7 (1.01-12.67, p = 0.024). Likewise, significant relations with reported family history of asthma, OR = 4.35 (1.78-10.62, p = 0.0012), allergic rhinitis, OR = 2.33 (1.49-3.63, p = 0.0002), and AE, OR = 5.08 (2.78-9.30, p ≤ 0.0001) were observed. In contrast to clinical studies with higher percentages of severely affected persons, FLG mutations here showed a moderate association with atopic disease. CONCLUSIONS: Case selection may be responsible for overestimating the prevalence of FLG mutations in atopic disease.