Shared DNA methylation signatures in childhood allergy: The MeDALL study.

BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Prenatal Vitamin D Levels Influence Growth and Body Composition until 11 Years in Boys.

BACKGROUND: Gestational vitamin D levels may influence offspring growth and modulate adipogenesis. Findings from prospective studies are inconsistent, and few have evaluated the persistence of these associations into late childhood. OBJECTIVE: To examine the association between prenatal vitamin D levels and growth and adiposity in late childhood. METHODS: We included 2027 mother-child pairs from the INMA birth cohort. 25-hydroxyvitamin D3 (vitamin D3) levels were measured in serum at 13 weeks of pregnancy. Sex- and age-specific body mass index z-scores were calculated at 7 and 11 years, overweight was defined as z-score ≥ 85th percentile, and body fat mass was measured at 11 years. Z-score body mass index (zBMI) trajectories from birth to 11 years were identified using latent class growth analysis. RESULTS: The prevalence of vitamin D3 deficiency (<20 ng/mL) was 17.5%, and around 40% of the children had overweight at both ages. Associations between vitamin D levels and outcomes differed by sex. In boys, maternal vitamin D3 deficient status was associated with higher zBMI, higher fat mass percentage, higher odds of being overweight, and with an increased risk of belonging to lower birth size followed by accelerated BMI gain trajectory. In girls no associations were observed. CONCLUSION: Our results support a sex-specific programming effect of early pregnancy vitamin D3 levels on offspring body composition into late childhood observed in boys.

[Social determinants of dietary patterns during pregnancy]. / Determinantes sociales de los patrones dietéticos durante el embarazo.

OBJECTIVES: To identify dietary patterns in pregnancy and describe their relationship with sociodemographic factors, smoking, and body mass index. As a secondary objective, intakes were evaluated relative to current dietary recommendations for pregnant women. METHODS: Cross-sectional assessment of dietary intakes in 473 pregnant women from the Island of Menorca (Spain) was performed. Dietary patterns were identified using a principal components analysis, and dietary quality was assessed by comparing food group intakes with recommended intakes in pregnancy. RESULTS: Two dietary patterns were identified, one characterized by high intakes of energy-dense foods and low intakes of fruits and vegetables (<>), and the other by high intakes of vegetables, legumes, fish, meat, rice and pasta (<>). Scores for the caloric pattern were higher in immigrants, smokers, parous women and women with only primary school education (p<0,05). Scores for the healthy pattern were higher in women originally from other parts of Spain and immigrants (p<0,05). No associations were found with the remaining variables. Adherence to dietary recommendations was high for fruit, meat and especially dairy products, while intakes of vegetables, cereals and legumes were only one-third of recommended levels. CONCLUSIONS: Dietary patterns during pregnancy were similar to previously reported patterns in the general population, showing consistent associations with sociodemographic factors and smoking. There were substantial deficiencies in intakes of cereals, legumes and vegetables in all women, suggesting the need for educational interventions and monitoring during prenatal care to improve the quality of dietary habits during pregnancy.

Prenatal and postnatal exposure to persistent organic pollutants and attention-deficit and hyperactivity disorder: a pooled analysis of seven European birth cohort studies.

Background: Attention-deficit/hyperactivity disorder (ADHD) is increasing worldwide for reasons largely unknown and environmental chemicals with neurotoxic properties, such as persistent organic pollutants (POPs), have been proposed to play a role. We investigated the association between prenatal and postnatal exposure to polychlorinated biphenyl-153 (PCB-153), p-p´-dichlorodiphenyldichloroethylene (p-p'-DDE) and hexachlorobenzene (HCB) and ADHD in childhood. Methods: We pooled seven European birth cohort studies encompassing 4437 mother-child pairs from the general population with concentrations of PCB-153, p-p´-DDE and HCB measured in cord blood, maternal blood or milk. We then calculated prenatal (birth) and postnatal (3, 6, 12 and 24 months) POP concentrations using a pharmacokinetic model. The operational definition of ADHD varied across cohorts and ranged from doctor diagnosis obtained from patient registries to maternal or teachers reports. We used multilevel (mixed) logistic regression models to estimate the associations between exposure to POPs at birth, 3, 6, 12 and 24 months and ADHD. Results: The global prevalence of ADHD in our study was 6%. The mean age at assessment of ADHD was 5.8 years (range: 3.8-9.5 years). We found no association between exposure to PCB-153, p-p´-DDE and HCB at any age point between birth and 24 months and ADHD, in the pooled analyses (pooled odds ratios ranging from 1.00 to 1.01). A number of sensitivity analyses gave basically the same results. Conclusions: In the largest study to date of 4437 children in seven European birth cohorts, we did not observe any association between either pre- or postnatal exposure (up to 24 months) to PCB-153, p-p´-DDE and HCB and the risk of ADHD before the age of 10 years.

[Adaptation and validation of a questionnaire on susceptibility, benefits and barriers in breast cancer screening with mammography]. / Adaptación y validación del cuestionario de susceptibilidad, beneficios y barreras ante el cribado con mamografía.

OBJECTIVES: To adapt the <> on breast cancer screening to Spanish, and to asses its validity and reliability. METHODS: We assessed validation of a scale with 3 dimensions (susceptibility, benefits and barriers) with Likert responses in a case-control study. Cases were women not participating in a breast cancer screening program and controls consisted of participating women. A process of translation and back-translation was carried out and a technical committee analyzed discrepancies. Comprehension was tested in 17 women. Two hundred seventy-four women participated in the study. In 32 of these women, the questionnaire was administered twice after a 1-month interval to estimate its reliability. RESULTS: The intraclass correlation coefficients were 0.89, 0.70 and 0.90, and Cronbach's alpha coefficient was 0.71, 0.48 and 0.57 for susceptibility, benefits and barriers, respectively. Construct validity: from the factorial analysis, 3 factors were obtained explaining 34% of the variance. The confirmatory factorial analysis indicated acceptable goodness-of-fit of the data to the theoretical model. Older women perceived less susceptibility to breast cancer as well as greater barriers to attending screening. Women with a lower educational level perceived greater barriers. The scale did not seem to predict adherence to the program. CONCLUSIONS: The adapted scale presents problems of validity and internal consistency. The dimensions of benefits and barriers require thorough adaptation and validation before the scale is used in Spanish women.

Smoking cessation and associated factors during pregnancy.

OBJECTIVE: To examine smoking habits before and during pregnancy, as well as factors associated with smoking cessation, in three European settings. METHODS: Women seeking antenatal care in Ashford (UK), Minorca and Barcelona (Spain) were recruited to the Asthma Multicenter Infant Cohort Study (AMICS). Questionnaires inquiring into the smoking habits of each woman and her partner, demographic data, occupation, educational level, number of previous children, breast feeding, alcohol intake, and history of asthma and of other allergic diseases were completed during pregnancy and in the first year after delivery. RESULTS: A total of 1,572 pregnant women were included in the three cohorts. Smoking prior to pregnancy was more common in Barcelona (46.2%) than in Minorca (39.8%) or Ashford (31.6%). Cessation rates during pregnancy also differed: 18% of women in Ashford, 20.4% in Minorca and 31.9% in Barcelona were still smoking during the first trimester. In a multivariate regression model, the factors showing a significant (negative) association with smoking cessation during pregnancy were having older children, having a partner who smoked and starting smoking at a young age. CONCLUSIONS: Baseline smoking habits and changes in smoking habits during pregnancy significantly differed between the three communities studied. Women pregnant with their first child, those who had started smoking at a later age and those whose partners were non-smokers were more likely to stop smoking when pregnant.

Diet, wheeze, and atopy in school children in Menorca, Spain.

Epidemiological studies have shown inverse associations of asthma symptoms with fish, vegetable, and fruit intake. We evaluated the association between several dietary factors with wheeze and atopy among children in Menorca, a Spanish Mediterranean island. A cross-sectional analysis was performed on 460 children at age 6.5 yr. Parents completed a questionnaire on the child's respiratory and allergic symptoms, and a 96-item food frequency questionnaire. Children underwent skin prick tests with six common aeroallergens. The average daily intake was relatively high for fruits (177 g) and fish (54 g), and moderate for vegetables (59 g). A high consumption (>40 g/day) of fruity vegetables (tomatoes, eggplants, cucumber, green beans, zucchini) was found to have beneficial effect on current wheeze [odds ratio (OR), 0.38; 95% confidence interval (CI), 0.15-0.95, p < 0.05], and atopic wheeze with a significant decreasing trend when intake was increased (OR, 0.19; 95% CI, 0.04-0.95, p for trend = 0.04). No other fruits or vegetables were significantly associated with wheeze or atopy prevalence. An inverse association was found between a fish intake > or =60 g/day and atopy (OR, 0.43; 95% CI, 0.21-0.90, p < 0.05). The associations remained significant after adjustment for energy intake and maternal diet during pregnancy. Our results support a potential protective effect of fruity vegetables and fish intake during childhood on wheeze and atopy respectively.

Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age.

RATIONALE: Although it is widely assumed that the incidence of childhood respiratory allergies to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated this issue, and available data are scarce and mainly limited to high-risk groups. OBJECTIVES: To assess, in a prospective manner and in a general population, the role of early life exposures to Der p1 and Fel d1 on the inception of sensitization and asthma. METHODS: Pregnant women and their children were recruited for the Asthma Multicentre Infant Cohort Study. Overall, 1,611 newborns were initially enrolled in three cohorts in the United Kingdom and Spain. Der p1 and Fel d1 allergens were measured in household dust samples at 3 months of age for 1,474 (91.5%) participants, and skin prick tests were performed at 6 years of age on 1,182 (80.2%) participants. Wheeze and diagnosed asthma were reported in yearly questionnaires. MEASUREMENTS AND MAIN RESULTS: Exposure to Der p1 early in life was not related to a positive specific prick test or to asthma or persistent wheeze at 6 years of age. Fel d1 showed an association with all these outcomes (third vs. first tertile; odds ratio, 4.43 for positive specific prick test and 2.6 for diagnosed asthma). CONCLUSIONS: Dose-response relationships between allergen exposure and sensitization or asthma may be allergen specific and nonlinear; a minimum threshold level is needed to induce sensitization, but no dose-response relationship exists above this level. The effect of a particular allergen seems to be similar on atopy and asthma inception.

Early-life domestic aeroallergen exposure and IgE sensitization at age 4 years.

BACKGROUND: Although it is widely assumed that childhood sensitization to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated this issue, and available data are scarce and mainly limited to high-risk groups. OBJECTIVE: We sought to assess the role of early exposure to 2 major household aeroallergens (Der p 1 and Fel d 1) in sensitization at the age of 4 years. METHODS: Pregnant women and their children were recruited for the Asthma Multicenter Infant Cohort Study. Three cohorts (Ashford in the United Kingdom and Menorca and Barcelona in Spain) followed the same research protocol. A total of 1611 newborn children were initially included in the cohort, from whose homes we collected dust samples at 3 months of age for 1474; Der p 1 and Fel d 1 levels were measured. Of these children, we obtained blood for specific IgE determination in 1019. RESULTS: The risk of Fel d 1 sensitization increased with exposure in a nonlinear manner. No association was found between specific IgE to Der p 1 and aeroallergen levels of exposure at early life in 2 centers, but a positive association was observed in the third. CONCLUSIONS: The dose-response relationships between allergen exposure and sensitization differ between allergens and might vary between different locales. The hypothesis that sensitization to house dust mite is directly related to levels of allergen exposure might not apply to the general population or to different ranges of exposure. CLINICAL IMPLICATIONS: Aeroallergen avoidance might not have any important effect on the incidence of sensitization.