Michael Borte

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

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.

Clinical picture and treatment of 2212 patients with common variable immunodeficiency

BACKGROUND Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. OBJECTIVE This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. METHODS Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. RESULTS Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. CONCLUSION Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

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.

Mode of delivery and development of atopic disease during the first 2 years of life.

It has been hypothesized that cesarean delivery might have an impact on the development of atopic diseases because of its gut flora modulating properties. In the present study, we analysed the association between cesarean delivery and atopic diseases using data of 2500 infants enrolled in the LISA‐Study, a German prospective multicenter birth cohort study. Data on symptoms and physician‐diagnosed atopic diseases were gathered by questionnaires shortly after birth and at infants age 6, 12, 18, and 24 months. In addition, sensitization to common food and inhalant allergens was assessed by measuring specific immunoglobulin E (IgE) using the CAP‐RAST FEIA method at the age of 2 yr. Confounder‐adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated by multiple logistic regression. We found a positive association between cesarean delivery and occurrence of at least one episode of wheezing [aOR 1.31 (95% CI 1.02–1.68)] and of recurrent wheezing [1.41 (1.02–1.96)] during the first 2 yr of life. Furthermore, effect estimates for allergic sensitization defined as at least one specific IgE ≥0.70 kU/l against any allergen [1.48 (0.98–2.24)], against food allergens [1.64 (1.03–2.63)], and against inhalant allergens [1.75 (0.98–3.12)] were increased. Symptoms of atopic dermatitis [1.21 (0.92–1.59)], physician‐diagnosed atopic dermatitis [1.04 (0.79–1.39)], and symptoms of allergic rhinoconjunctivitis [1.40 (0.80–2.44)] were only marginally increased in children delivered by cesarean section. In conclusion, our results suggest that cesarean delivery may be an additional risk factor for wheezing and allergic sensitization at least to food allergens up to the age of 2 yr. This should be considered when cesarean section is done for other than medical reasons.

Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study

Vitamin D levels are known to be associated with atopic disease development; however, existing data are controversial. The aim of this study was to investigate whether corresponding maternal and cord blood vitamin D levels are associated with atopic outcomes in early infancy.

Effects of indoor painting and smoking on airway symptoms in atopy risk children in the first year of life results of the LARS-study

INTRODUCTION The Leipzig Allergy High-Risk Children Study (LARS) is a prospective nested cohort control study about the influence of chemical indoor exposure in dwellings on the health outcome of atopy-risk children during the first years of life. DESIGN AND METHODS 475 premature children and children with allergic risk factors have been selected out of the 1995/1996 birth cohort in the city of Leipzig. Twenty-five volatile organic compounds (VOC) were measured in the infants bedrooms using passive sampling systems for 4 weeks after birth. The babies underwent a medical examination at the age of six weeks and 1 year. The parents answered a questionnaire. RESULTS Correlations between VOC exposures and infections were calculated by multiple logistic regression. Selected VOC show a direct association to actually painted dwellings (OR = 2.4; 95% Cl 1.1-5.3). An increase of risk of pulmonary infections was observed in infants aged 6 weeks if restoration (painting OR 5.6; 95% Cl 1.3-24.0) or flooring connected with painting had occurred during the pregnancy period. Higher concentration of styrene (> 2.0 micrograms/m3, indicator for flooring) elevated the risk of pulmonary infections in six-week-old infants (OR = 2.1; 95% Cl 1.1-4.2). Environmental benzene > 5.6 micrograms/m3 increased the risk of airway infections in six-week-old babies (OR = 2.4; 95% Cl 1.28-4.48). Smoking in the dwelling (OR = 2.0; 95% Cl 1.1-3.5) as well as restoration (OR = 1.9; 95% Cl 1.1-3.5) are also risk factors of the development of wheezing in the one-year-old child. CONCLUSIONS The data give indications in order to prevent allergies and chronic lung diseases in atopy risk children exposure to chemicals from indoor air should be minimised from birth on.

Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year

Regulatory T cells (Tregs) with stable FOXP3 expression are characterized by a specific demethylated region in the FOXP3 gene (Treg‐specific demethylated region, TSDR). The aim of this study was to analyse the influence of prenatal factors on cord blood Treg numbers, as detected by changes in the TSDR demethylation, and the subsequent risk for allergic diseases.

Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR

Severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) are inborn errors of immune function that require prompt diagnosis and treatment to prevent life-threatening infections. The lack of functional T or B lymphocytes in these diseases serves as a diagnostic criterion and can be applied to neonatal screening. A robust triplex PCR method for quantitation of T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs), using a single Guthrie card punch, was developed and validated in a cohort of 2560 anonymized newborn screening cards and in 49 original stored Guthrie cards from patients diagnosed with SCID, XLA, ataxia-telangiectasia, Nijmegen-breakage-syndrome, common variable immunodeficiency, immunoglobulin A deficiency, or X-linked hyper-IgM syndrome. Simultaneous measurement of TREC and KREC copy numbers in Guthrie card samples readily identified patients with SCID, XLA, ataxia-telangiectasia and Nijmegen-breakage-syndrome and thus facilitates effective newborn screening for severe immunodeficiency syndromes characterized by the absence of T or B cells.

Early endotoxin exposure and atopy development in infants: results of a birth cohort study

Background Exposure to endotoxin in childhood is currently discussed to protect from the development of allergic diseases.