Ute Hoffmann

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.

Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study

BACKGROUND The long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. OBJECTIVE We sought to investigate the effect of hydrolysate infant formulas on allergic phenotypes in children with family history of allergies at school age. METHODS We analyzed data from participants of the prospective German Infant Nutritional Intervention study after 10 years of follow-up. At birth, children were randomly assigned to receive, for the first 4 months, one of 4 blinded formulas as breast milk substitute, if necessary: partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), extensively hydrolyzed casein formula (eHF-C), or standard cows milk formula. Outcomes were parent-reported, physician-diagnosed allergic diseases. Log-binomial regression models were used for statistical analysis. RESULTS The relative risk for the cumulative incidence of any allergic disease in the intention-to-treat analysis (n = 2252) was 0.87 (95% CI, 0.77-0.99) for pHF-W, 0.94 (95% CI, 0.83-1.07) for eHF-W, and 0.83 (95% CI, 0.72-0.95) for eHF-C compared with standard cows milk formula. The corresponding figures for atopic eczema/dermatits (AD) were 0.82 (95% CI, 0.68-1.00), 0.91 (95% CI, 0.76-1.10), and 0.72 (95% CI, 0.58-0.88), respectively. In the per-protocol analysis (n = 988) effects were stronger. The period prevalence of AD at 7 to 10 years was significantly reduced with eHF-C in this analysis, but there was no preventive effect on asthma or allergic rhinitis. CONCLUSION The significant preventive effect on the cumulative incidence of allergic diseases, particularly AD, with pHF-W and eHF-C persisted until 10 years without rebound, whereas eHF-W showed no significant risk reduction. There is insufficient evidence of ongoing preventive activity at 7 to 10 years of age.

Infant-onset eczema in relation to mental health problems at age 10 years: Results from a prospective birth cohort study (German Infant Nutrition Intervention plus)

BACKGROUND Cross-sectional studies suggest an association between eczema and mental health problems, but the temporal relationship is unclear. OBJECTIVE To assess the association between infant-onset eczema and mental health problems in a prospective study. METHODS Between 1995 and 1998, a birth cohort study was recruited and followed until age 10 years. Physician-diagnosed eczema, comorbidities, and a broad set of environmental exposures were assessed at age 1, 2, 3, 4, 6, and 10 years. First, we investigated the association between infant-onset eczema (age 1-2 years) and mental health problems at age 10 years according to the Strengths and Difficulties Questionnaire. Second, we analyzed the likelihood of mental health problems at age 10 years in relation to the course of eczema. RESULTS A total of 2916 infants were eligible for analysis. Compared with participants never diagnosed as having eczema, children with infant-onset eczema had a significantly increased risk for possible/probable mental health problems (Strengths and Difficulties Questionnaire total score) at age 10 years (odds ratio, 1.49; 95% CI, 1.13-1.96) and for emotional symptoms (odds ratio, 1.62; 95% CI, 1.25-2.09). Eczema limited to infancy predicted a significantly higher risk for conduct problems at age 10 years. The strength of the association between eczema and emotional problems at age 10 years increased with increasing eczema persistence. CONCLUSION Infants with eczema are at increased risk for mental health problems at age 10 years. Even if cleared afterward, eczema at age 1 to 2 years may cause persistent emotional and behavioral difficulties.

Prenatal and Postnatal Tobacco Exposure and Behavioral Problems in 10-Year-Old Children: Results from the GINI-plus Prospective Birth Cohort Study

Background Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. Objective We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. Methods We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as “normal,” “borderline,” or “abnormal” according to the subscales “emotional symptoms,” “conduct problems,” “hyperactivity/inattention,” “peer-relationship problems,” and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. Results Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4–3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9–4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9–1.9). These results could not be explained by confounding by parental education, father’s employment, child’s time spent in front of computer or television screen, being a single father or mother, or mother’s age. Conclusions Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

The natural history of allergic rhinitis in childhood.

Keil T, Bockelbrink A, Reich A, Hoffmann U, Kamin W, Forster J, Schuster A, Willich SN, Wahn U, Lau S. The natural history of allergic rhinitis in childhood.
Pediatr Allergy Immunol 2010: 21: 962–969.
© 2010 John Wiley & Sons A/S

Early-life determinants of asthma from birth to age 20 years: A German birth cohort study

BACKGROUND The lack of longitudinal data analyses from birth to adulthood is hampering long-term asthma prevention strategies. OBJECTIVE We aimed to determine early-life predictors of asthma incidence up to age 20 years in a birth cohort study by applying time-to-event analysis. METHODS In 1990, the Multicenter Allergy Study included 1314 newborns in 5 German cities. Children were evaluated from birth to age 20 years at 19 time points. Using a Cox regression model, we examined the associations between 36 early-life factors and onset of asthma based on a doctors diagnosis or asthma medication (primary outcome), typical asthma symptoms, or allergic asthma (including positive IgE measurements). RESULTS Response at 20 years was 71.6%. Two hundred eighteen subjects met the primary outcome criteria within 16,257 person years observed. Asthma incidence was lower in participants who were vaccinated (measles, mumps, and rubella vaccine/tick-borne encephalitis vaccine/BCG vaccine: adjusted hazard ratio [HR], 0.66 [95% CI, 0.47-0.93]). Up to age 20 years, asthma incidence was higher in subjects who had parents with allergic rhinitis (adjusted HR, 2.24 [95% CI, 1.67-3.02]), started day care early or late (before 18 months: adjusted HR, 1.79 [95% CI, 1.03-3.10]; after 3 years: adjusted HR, 1.64 [95% CI, 0.96-2.79]), had mothers who smoked during pregnancy (adjusted HR, 1.79 [95% CI, 1.20-2.67]), had poor parents (adjusted HR, 1.55 [95% CI, 1.09-2.22]), and had parents with asthma (adjusted HR, 1.65 [95% CI, 1.17-2.31]). Not associated with asthma were aspects of diet and breast-feeding, pet ownership, presence of older siblings, and passive smoking. CONCLUSION Parental asthma and nasal allergy increase asthma incidence in offspring up to adulthood. Avoiding tobacco smoke exposure during pregnancy, receiving vaccinations in early childhood, and starting day care between 1.5 and 3 years of age might prevent or delay the development of asthma.

Allergic multimorbidity of asthma, rhinitis and eczema over 20 years in the German birth cohort MAS.

The occurrence of allergic multimorbidity (coexistence of asthma, allergic rhinitis and eczema) has not been evaluated longitudinally from early childhood up to adulthood in a population‐based study sample. We aimed to determine the prevalence of allergic multimorbidity up to age 20 stratified by parental allergies and sex/gender using extensive prospective follow‐up data from two decades of a birth cohort study.

Allergic manifestation 15 years after early intervention with hydrolyzed formulas – the GINI Study

Data on the long‐term impact of hydrolyzed formulas on allergies are scarce.

Is there a positive relationship between molar incisor hypomineralisations and the presence of dental caries

OBJECTIVE This epidemiological study aimed to compare the caries experience in 10-year-olds with and without molar incisor hypomineralisation (MIH). METHODS About 693 children from an ongoing birth cohort study (GINIplus10) were examined for caries lesions to determine the DMF index. Furthermore, enamel hypomineralisation (EH) was scored on all permanent teeth/surfaces, according to the criteria of the European Academy of Paediatric Dentistry. Children with EH were categorised into those with a minimum of one EH in the permanent dentition (MIH/1), with EH on at least one-first permanent molar (MIH/1A), on at least one-first permanent molar and permanent incisor (MIH/1B), and on other permanent teeth (MIH/1C). RESULTS The mean caries experience was 0.4 (SD 0.9) DMFT. Existence of MIH/1, MIH/1A, MIH/1B, and MIH/1C was determined in 36.5%, 14.7%, 9.4%, and 21.8% of all children. The corresponding DMFT values were the following: no MIH: 0.3 (SD 0.8); MIH/1: 0.5 (SD 0.9); MIH/1A: 0.5 (SD 0.9); MIH/1B: 0.4 (SD 0.9); and MIH/1C: 0.4 (SD 0.9) DMFT. No significant differences were found between all groups. CONCLUSIONS There was no relationship between the presence of EH/MIH and caries in 10-year-olds. A ratio of one EH-associated defect to two caries lesions indicates that both conditions are prevalent and influence the oral health status of 10-year-old children from Munich, Germany.

Prediction and prevention of allergic rhinitis: A birth cohort study of 20 years.

BACKGROUND Allergic rhinitis (AR) is one of the most common chronic diseases, usually starting in the first 2 decades of life. Information on predictors, risk, and protective factors is missing because of a lack of long-term prospective studies. OBJECTIVE Our aim was to examine early-life environmental and lifestyle determinants for AR up to age 20 years. METHODS In 1990, the Multicenter Allergy Study included 1314 newborns in 5 German cities. Children were evaluated at 19 time points. A Cox regression model examined the associations between 41 independent early-life factors and onset of AR (as the primary outcome), including sensitization against aeroallergens and the secondary outcomes of nonallergic rhinitis and AR plus asthma. RESULTS Two hundred ninety subjects had AR within 13,179 person years observed. The risk of AR was higher with a parental history of AR (adjusted hazard ratio [aHR], 2.49; 95% CI, 1.93-3.21), urticaria (aHR, 1.32; 95% CI, 1.00-1.74), or asthma (aHR, 1.29; 95% CI, 0.95-1.75). Early allergic sensitization (aHR, 4.53; 95% CI, 3.25-6.32), eczema within the first 3 years of life (aHR, 1.83; 95% CI, 1.38-2.42), male sex (aHR, 1.28; 95% CI, 1.02-1.61), and birthday in summer or autumn (aHR, 1.26; 95% CI, 1.00-1.58) were independent predictors of AR up to age 20 years. None of the other socioeconomic, environmental, lifestyle, pregnancy, and birth-related factors were associated with AR. CONCLUSION Only nonmodifiable factors, particularly early allergic sensitization or eczema and parental AR, predicted AR up to age 20 years. No modifiable aspects of early-life environment or lifestyle were identified as targets for primary prevention.