Andrea von Berg

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Atopic Diseases, Allergic Sensitization, and Exposure to Traffic-related Air Pollution in Children

RATIONALE In vitro studies, animal experiments, and human exposure studies have shown how ambient air pollution increases the risk of atopic diseases. However, results derived from observational studies are inconsistent. OBJECTIVES To assess the relationship between individual-based exposure to traffic-related air pollutants and allergic disease outcomes in a prospective birth cohort study during the first 6 years of life. METHODS We studied 2,860 children at the age of 4 years and 3,061 at the age of 6 years to investigate atopic diseases and allergic sensitization. Long-term exposure to particulate matter (PM(2.5)), PM(2.5) absorbance, and long-term exposure to nitrogen dioxide (NO(2)) was assessed at residential addresses using geographic information systems based regression models and air pollution measurements. The distance to the nearest main road was used as a surrogate for traffic-related air pollutants. MEASUREMENTS AND MAIN RESULTS Strong positive associations were found between the distance to the nearest main road and asthmatic bronchitis, hay fever, eczema, and sensitization. A distance-dependent relationship could be identified, with the highest odds ratios (ORs) for children living less than 50 m from busy streets. For PM(2.5) absorbance, statistically significant effects were found for asthmatic bronchitis (OR, 1.56; 95% confidence interval [CI], 1.03-2.37), hay fever (OR, 1.59; 95% CI, 1.11-2.27), and allergic sensitization to pollen (OR, 1.40; 95% CI, 1.20-1.64). NO(2) exposure was associated with eczema, whereas no association was found for allergic sensitization. CONCLUSIONS This study provides strong evidence for increased risk of atopic diseases and allergic sensitization when children are exposed to ambient particulate matter.

Dietary prevention of allergic diseases in infants and small children.

Because of scientific fraud four trials have been excluded from the original Cochrane meta‐analysis on formulas containing hydrolyzed protein for prevention of allergy and food intolerance in infants. Unlike the conclusions of the revised Cochrane review the export group set up by the Section on Paediatrics, European Academy of Allergology and Clinical Immunology (SP‐EAACI) do not find that the exclusion of the four trials demands a change of the previous recommendations regarding primary dietary prevention of allergic diseases. Ideally, recommendations on primary dietary prevention should be based only on the results of randomized and quasi‐randomized trials (selection criteria in the Cochrane review). However, regarding breastfeeding randomization is unethical, Therefore, in the development of recommendations on dietary primary prevention, high‐quality systematic reviews of high‐quality cohort studies should be included in the evidence base. The study type combined with assessment of the methodological quality determines the level of evidence. In view of some methodological concerns in the Cochrane meta‐analysis, particularly regarding definitions and diagnostic criteria for outcome measures and inclusion of non peer‐reviewed studies/reports, a revision of the Cochrane analysis may seem warranted. Based on analysis of published peer‐reviewed observational and interventional studies the results still indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is effective in the prevention of allergic diseases in high‐risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4–6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cows milk for the first 4 months.The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer-reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high-risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4-6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4-6 months should be used.

A major susceptibility locus for atopic dermatitis maps to chromosome 3q21

Atopic dermatitis (eczema) is a chronic inflammatory skin disease with onset mainly in early childhood. It is commonly the initial clinical manifestation of allergic disease, often preceding the onset of respiratory allergies. Along with asthma and allergic rhinitis, atopic dermatitis is an important manifestation of atopy that is characterized by the formation of allergy antibodies (IgE) to environmental allergens. In the developed countries, the prevalence of atopic dermatitis is approximately 15%, with a steady increase over the past decades. Genetic and environmental factors interact to determine disease susceptibility and expression, and twin studies indicate that the genetic contribution is substantial. To identify susceptibility loci for atopic dermatitis, we ascertained 199 families with at least two affected siblings based on established diagnostic criteria. A genome-wide linkage study revealed highly significant evidence for linkage on chromosome 3q21 (Zall=4.31, P= 8.42×10−6). Moreover, this locus provided significant evidence for linkage of allergic sensitization under the assumption of paternal imprinting (hlod=3.71, α=44%), further supporting the presence of an atopy gene in this region. Our findings indicate that distinct genetic factors contribute to susceptibility to atopic dermatitis and that the study of this disease opens new avenues to dissect the genetics of atopy.

Timing of solid food introduction in relation to atopic dermatitis and atopic sensitization : Results from a prospective birth cohort study

OBJECTIVE. Prophylactic feeding guidelines recommend a delayed introduction of solid foods for the prevention of atopic diseases. Scientific evidence for this is scarce. This study investigates whether a delayed introduction of solids (past 4 months or 6 months) is protective against the development of atopic dermatitis (AD) and atopic sensitization when considering reverse causality. METHODS. Data from 2612 infants in an ongoing birth cohort study were analyzed at 2 years of age. Information on diet and on symptoms and diagnoses of AD was collected semiannually, and information on specific immunoglobulin E levels was collected at 2 years of age. RESULTS. Solid food introduction past the first 4 months of life decreased the odds of symptomatic AD but not for doctor-diagnosed AD, combined doctor-diagnosed and symptomatic AD, or atopic sensitization. Postponing the introduction beyond the sixth month of life was not protective in relation to either definition of AD or atopic sensitization. There was also no evidence for a protective effect of a delayed introduction of solids on AD and atopic sensitization in children of atopic parents. There was clear evidence for reverse causality between early skin or allergic symptoms and the introduction of solids. CONCLUSIONS. This study does not find evidence supporting a delayed introduction of solids beyond the sixth month of life for the prevention of AD and atopic sensitization. We cannot rule out that delaying the introduction of solids for the first 4 months of life might offer some protection. Measures to avoid reverse causality have to be considered in the conduction, analysis, and interpretation of cohort studies on the topic.

Genome-Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer‐reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high‐risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4–6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4–6 months should be used.

Preventive effect of hydrolyzed infant formulas persists until age 6 years: Long-term results from the German Infant Nutritional Intervention Study (GINI)

BACKGROUND The long-term effect of nutritional intervention with hydrolyzed infant formulas on allergy development has not been sufficiently evaluated. OBJECTIVE We performed a follow-up of the German Infant Nutritional Intervention study until 6 years of life to investigate the long-term allergy-preventive effect of 3 hydrolyzed infant formulas compared with cows milk formula (CMF) in a randomized, double-blind trial. METHODS Between 1995 and 1998, 2252 newborns with atopic heredity were randomly assigned at birth to receive one of 4 blinded formulas: partially or extensively hydrolyzed whey formula, extensively hydrolyzed casein formula, or CMF as milk substitute for the first 4 months when breast-feeding was insufficient. The cohort was followed from birth until 6 years of age with yearly questionnaires. Outcomes were physician-diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma, and hay fever/allergic rhinitis). Log-binomial regression modeled with generalized estimation equations was used for the statistical analysis. RESULTS In the intent-to-treat analysis the relative risk of a physicians diagnosis of allergic manifestation (AM) compared with CMF was 0.82 (95% CI, 0.70-0.96) for partially hydrolyzed whey formula, 0.90 (95% CI, 0.78-1.04) for extensively hydrolyzed whey formula, and 0.80 (95% CI, 0.69-0.93) for extensively hydrolyzed casein formula. The corresponding figures for atopic eczema were 0.79 (95% CI, 0.64-0.97), 0.92 (95% CI, 0.76-1.11), and 0.71 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis all effects were stronger and significant. No significant effect on other AMs was found. CONCLUSION The data confirm a long-term allergy-preventive effect of hydrolyzed infant formulas on AM and atopic eczema until 6 years of age.

Does Pet Ownership in Infancy Lead to Asthma or Allergy at School Age? Pooled Analysis of Individual Participant Data from 11 European Birth Cohorts

Objective To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6–10 years. Design Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s. Exposure definition Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life. Outcome definition Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 6–10 years of age. Data synthesis Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models. Results We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with “no pets” (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with “no pets” (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to “no pets” resulted in an odds ratio of 1.04 (0.59 to 1.84) (I2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens. Conclusions Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given.

Timing of Solid Food Introduction in Relation to Eczema, Asthma, Allergic Rhinitis, and Food and Inhalant Sensitization at the Age of 6 Years: Results From the Prospective Birth Cohort Study LISA

OBJECTIVE. Current prophylactic feeding guidelines recommend a delayed introduction of solids for the prevention of atopic diseases. This study investigates whether a delayed introduction of solids (past 4 or 6 months) is protective against the development of eczema, asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years. METHODS. Data from 2073 children in the ongoing LISA birth cohort study were analyzed at 6 years of age. Multivariate logistic regression analyses were performed for all children and for children without skin or allergic symptoms within the first 6 months of life to take into account reverse causality. RESULTS. A delayed introduction of solids (past 4 or 6 months) was not associated with decreased odds for asthma, allergic rhinitis, or sensitization against food or inhalant allergens at 6 years of age. On the contrary, food sensitization was more frequent in children who were introduced to solids later. The relationship between the timing of solid food introduction and eczema was not clear. There was no protective effect of a late introduction of solids or a less diverse diet within the first 4 months of life. However, in children without early skin or allergic symptoms were considered, eczema was significantly more frequent in children who received a more diverse diet within the first 4 months. CONCLUSIONS. This study found no evidence supporting a delayed introduction of solids beyond 4 or 6 months for the prevention of asthma, allergic rhinitis, and food or inhalant sensitization at the age of 6 years. For eczema, the results were conflicting, and a protective effect of a delayed introduction of solids cannot be excluded. Positive associations between late introduction of solids and food sensitization have to be interpreted with caution. A true protective effect of a delayed introduction of solids on food sensitization seems unlikely.