Salome Scholtens

Cohort Profile: LifeLines, a three-generation cohort study and biobank

The LifeLines Cohort Study is a large population-based cohort study and biobank that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy ageing. Between 2006 and 2013, inhabitants of the northern part of The Netherlands and their families were invited to participate, thereby contributing to a three-generation design. Participants visited one of the LifeLines research sites for a physical examination, including lung function, ECG and cognition tests, and completed extensive questionnaires. Baseline data were collected for 167 729 participants, aged from 6 months to 93 years. Follow-up visits are scheduled every 5 years, and in between participants receive follow-up questionnaires. Linkage is being established with medical registries and environmental data. LifeLines contains information on biochemistry, medical history, psychosocial characteristics, lifestyle and more. Genomic data are available including genome-wide genetic data of 15 638 participants. Fasting blood and 24-h urine samples are processed on the day of collection and stored at -80 °C in a fully automated storage facility. The aim of LifeLines is to be a resource for the national and international scientific community. Requests for data and biomaterials can be submitted to the LifeLines Research Office [LLscience@umcg.nl].

Asthma at 8 years of age in children born by caesarean section

Background: Caesarean section might be a risk factor for asthma because of delayed microbial colonisation, but the association remains controversial. A study was undertaken to investigate prospectively whether children born by caesarean section are more at risk of having asthma in childhood and sensitisation at the age of 8 years, taking into account the allergic status of the parents. Methods: 2917 children who participated in a birth cohort study were followed for 8 years. The definition of asthma included wheeze, dyspnoea and prescription of inhaled steroids. In a subgroup (n = 1454), serum IgE antibodies for inhalant and food allergens were measured at 8 years. Results: In the total study population, 12.4% (n = 362) of the children had asthma at the age of 8 years. Caesarean section, with a total prevalence of 8.5%, was associated with an increased risk of asthma (OR 1.79; 95% CI 1.27 to 2.51). This association was stronger among predisposed children (with two allergic parents: OR 2.91; 95% CI 1.20 to 7.05; with only one: OR 1.86; 95% CI 1.12 to 3.09) than in children with non-allergic parents (OR 1.36; 95% CI 0.77 to 2.42). The association between caesarean section and sensitisation at the age of 8 years was significant only in children of non-allergic parents (OR 2.14; 95% CI 1.16 to 3.98). Conclusions: Children born by caesarean section have a higher risk of asthma than those born by vaginal delivery, particularly children of allergic parents. Caesarean section increases the risk for sensitisation to common allergens in children with non-allergic parents only.

Overweight and changes in weight status during childhood in relation to asthma symptoms at 8 years of age.

BACKGROUND Asthma may be more prevalent in overweight children. However, how early overweight and changes in weight status during childhood affect the asthma risk is unclear. OBJECTIVES To investigate overweight and changes in overweight status in children age 1 to 8 years in relation to asthma symptoms in childhood. METHODS We studied 3756 children who participated in a large birth cohort study. The parents reported their childrens weight and height, and wheeze, dyspnea, and prescription of inhaled corticosteroids in yearly questionnaires. Sensitization to inhalant allergens and bronchial hyperresponsiveness (BHR) were determined at 8 years. RESULTS At 8 years, 275 children (7.3%) wheezed, 361 (9.6%) had dyspnea, and 268 (7.1%) had a prescription of inhaled corticosteroids in the preceding year. Children who had a persistent high body mass index (BMI, weight/height2) during childhood or a high BMI at 6 to 7 years had a significantly increased risk of dyspnea (adjusted odds ratio, 1.68; 95% CI, 1.18-2.39, for a high BMI at 6-7 years) and measured BHR (adjusted odds ratio, 1.66; 95% CI, 1.10-2.52) at 8 years. Children with a high BMI at a young age, but who developed a normal BMI at 6 to 7 years, did not have an increased risk of dyspnea or BHR at 8 years. BMI was not associated with sensitization. CONCLUSION Children with a current high BMI are at increased risk to have dyspnea and BHR at 8 years. A high BMI at an earlier age is not related to an increased risk if the child has become normal weight at 6 to 7 years.

Breast feeding, parental allergy and asthma in children followed for 8 years. The PIAMA birth cohort study.

Background: It is unclear how the association between breast feeding and asthma develops with age of the child and how this association over time is influenced by maternal or paternal allergy. These factors—the age of the child and maternal or paternal allergy—might partly explain the conflicting results observed in cross-sectional studies. Methods: The study population consisted of 3115 Dutch children born in 1996/1997 who participated in the PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort study. Data on breast feeding and asthma (based on wheeze, dyspnoea and prescription of inhaled steroids) were collected by yearly questionnaires. At 8 years, specific immunoglobulin E (IgE) to airborne allergens and bronchial responsiveness were measured. Data were analysed by logistic regression and generalised estimating equations (GEEs), and stratified by maternal and paternal allergic status. Results: 35% (n = 1081) of the children were breast fed for >16 weeks. At 8 years of age, 12.6% (n = 392) had asthma. Breast feeding (>16 weeks vs no breast feeding) was significantly associated with a lower asthma prevalence from 3 to 8 years of age, in children of both non-allergic and allergic mothers. The inverse association between breast feeding and sensitisation to airborne allergens at 8 years was non-significant. Breast feeding was not associated with bronchial hyper-responsiveness. No interaction between breast feeding and gender, maternal allergy or paternal allergy was observed in any of the associations. Conclusions: Breast feeding is associated with a lower asthma risk in children until 8 years of age without evidence of attenuation and regardless of the family history of allergy.

DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring

Background: We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood. Methods: First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR) < 0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring’s sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis. Results: We found 35 differentially methylated CpGs (FDR < 0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P < 1 × 10-7). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P < 0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12–19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity. Conclusions: Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system.

Early Daycare Is Associated with an Increase in Airway Symptoms in Early Childhood but Is No Protection against Asthma or Atopy at 8 Years

RATIONALE Daycare exposes young children to more infections early in life and may thereby prevent the development of asthma and allergy. OBJECTIVES To prospectively study the effect of daycare on the development of asthma and allergic sensitization during the first 8 years of life. METHODS In the Prevention and Incidence of Asthma and Mite Allergy birth cohort 3,963 newborn children were followed prospectively for 8 years. Daycare use and respiratory health were assessed yearly by questionnaires. At 8 years, sensitization to airborne allergens and airway responsiveness were measured. Daycare was defined as early (aged 0-2 yr), late (aged 2-4 yr), or none (no daycare before age 4 yr). Associations of daycare and/or older siblings with asthma symptoms (wheezing, shortness of breath, and inhaled steroids taken in the last year), airway responsiveness, and allergic sensitization were assessed in a longitudinal repeated-event analysis. MEASUREMENTS AND MAIN RESULTS Children with early daycare had more wheezing in the first years of life, but less wheezing and steroid use between 4 and 8 years of age. At the age of 8 years, early daycare was not protective for asthma symptoms (adjusted odds ratio [aOR], 0.99; 95% confidence interval [CI], 0.74-1.32), allergic sensitization (aOR 0.86; 95% CI, 0.63-1.18), or airway hyperresponsiveness (aOR, 0.80; 95% CI, 0.57-1.14). The transient reduction in airway symptoms between age 4 and 8 years was only observed in children without older siblings. CONCLUSION Early daycare is associated with an increase in airway symptoms until the age of 4 years, and fewer symptoms between the ages of 4 and 8 years. We found no protection against asthma symptoms, hyperresponsiveness, or allergic sensitization at the age of 8 years.

Maternal overweight before pregnancy and asthma in offspring followed for 8 years.

Objective:The aim of this study was to investigate the association between maternal overweight before pregnancy and offspring asthma in an ongoing birth cohort study. Maternal overweight may affect the pulmonary and immunological development of the fetus in utero because of the increased levels of inflammatory factors associated with being overweight and thereby increase the asthma risk in childhood.Design:Birth cohort study with follow-up until 8 years of age.Subjects:The study population included 3963 children and their mothers who participated in the Prevention and Incidence of Asthma and Mite Allergy study.Measurements:Maternal overweight before pregnancy was defined as a body mass index (BMI) above 25 kg m−2. Data on wheeze, dyspnea and prescription of inhaled corticosteroids of the child were reported yearly by the parents in a questionnaire. Sensitization to inhalant allergens and bronchial hyperresponsiveness (BHR) were determined at 8 years. Effect modification by predisposition for asthma in the child was tested. Data were analyzed by logistic regression and generalized estimating equations analyses.Results:At 8 years, 14.4% (n=571) of the children had asthma. In total, 20.9% (n=830) of the mothers were overweight before pregnancy. In children predisposed for asthma (n=1058), maternal overweight before pregnancy was associated with an increased risk of asthma in the child at 8 years (OR=1.52, 95% CI: 1.05–2.18) after adjustment for confounding factors, birth weight and the childs BMI. No association was observed in children without a predisposition (OR=0.86, 95% CI: 0.60–1.23). There was no association with sensitization or BHR.Conclusion:Children with a predisposition for asthma may have a higher risk to develop asthma during childhood when their mothers are overweight before pregnancy, irrespective of the childs BMI.

Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy

Previous studies have suggested possible adverse side-effects of maternal use of folic acid-containing supplements (FACSs) during pregnancy on wheeze and asthma in early childhood. We investigated the association between maternal use of FACSs and childhood respiratory health and atopy in the first 8 yrs of life. Data on maternal use of FACSs, collected during pregnancy, were available for 3,786 children participating in the Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Questionnaire data on children’s respiratory and allergic symptoms were collected annually and allergic sensitisation and bronchial hyperresponsiveness (BHR) were measured at 8 yrs of age. No overall (from 1 to 8 yrs of age) associations were observed between maternal use of FACSs and (frequent) asthma symptoms, wheeze, lower respiratory tract infection, frequent respiratory tract infection and eczema. Maternal folic acid use was associated with wheeze at 1 yr of age (prevalence ratio 1.20, 95% CI 1.04–1.39), but not with wheeze at later ages. Pre-natal exposure to FACSs was not associated with sensitisation and BHR. Apart from a small increased risk of early wheeze, we observed no adverse respiratory or allergic outcomes associated with pre-natal FACSs exposure in our study population.

Comorbidities of obesity in school children: a cross-sectional study in the PIAMA birth cohort

BackgroundThere is ample evidence that childhood overweight is associated with increased risk of chronic disease in adulthood. The aim of this study was to investigate associations between childhood overweight and common childhood health problems.MethodsData were used from a general population sample of 3960 8-year-old children, participating in the Dutch PIAMA birth cohort study. Weight and height, measured by the investigators, were used to define BMI status (thinness, normal weight, moderate overweight, obesity). BMI status was studied cross-sectionally in relation to the following parental reported outcomes: a general health index, GP visits, school absenteeism due to illness, health-related functional limitations, doctor diagnosed respiratory infections and use of antibiotics.ResultsObesity was significantly associated with a lower general health score, more GP visits, more school absenteeism and more health-related limitations, (adjusted odds ratios around 2.0 for most outcomes). Obesity was also significantly associated with bronchitis (adjusted odds ratio (aOR) and 95% confidence intervals (95%CI): 5.29 (2.58;10.85) and with the use of antibiotics (aOR (95%CI): 1.79 (1.09;2.93)). Associations with flu/serious cold, ear infection and throat infection were positive, but not statistically significant. Moderate overweight was not significantly associated with the health outcomes studied.ConclusionChildhood obesity is not merely a risk factor for disease in adulthood, but obese children may experience more illness and health related problems already in childhood. The high prevalence of the outcomes studied implies a high burden of disease in terms of absolute numbers of sick children.

Cohort profile: LifeLines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics

Purpose There is a critical need for population-based prospective cohort studies because they follow individuals before the onset of disease, allowing for studies that can identify biomarkers and disease-modifying effects, and thereby contributing to systems epidemiology. Participants This paper describes the design and baseline characteristics of an intensively examined subpopulation of the LifeLines cohort in the Netherlands. In this unique subcohort, LifeLines DEEP, we included 1539 participants aged 18 years and older. Findings to date We collected additional blood (n=1387), exhaled air (n=1425) and faecal samples (n=1248), and elicited responses to gastrointestinal health questionnaires (n=1176) for analysis of the genome, epigenome, transcriptome, microbiome, metabolome and other biological levels. Here, we provide an overview of the different data layers in LifeLines DEEP and present baseline characteristics of the study population including food intake and quality of life. We also describe how the LifeLines DEEP cohort allows for the detailed investigation of genetic, genomic and metabolic variation for a wide range of phenotypic outcomes. Finally, we examine the determinants of gastrointestinal health, an area of particular interest to us that can be addressed by LifeLines DEEP. Future plans We have established a cohort of which multiple data levels allow for the integrative analysis of populations for translation of this information into biomarkers for disease, and which will offer new insights into disease mechanisms and prevention.