Background It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects ...genetically predisposed to COPD show their first symptoms or reduced lung function in childhood. Objective We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke ETS) modifies these effects. Methods The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1 , forced vital capacity (FVC), and FEV1 /FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. Results AGER showed replicated association with FEV1 /FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2 , FAM13A , and MMP12 associated with higher FEV1 and FVC, and SERPINE2 , HHIP , and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD. Conclusion Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.
Background Perturbations in the intestinal microbiota may disrupt mechanisms involved in the development of immunologic tolerance. The present study aimed to examine the establishment of the infant ...microbiota and its association to the development of atopic dermatitis (AD). Methods Within a randomized, placebo-controlled trial on the prevention of AD by oral supplementation of a bacterial lysate between week 5 and the end of month 7, feces was collected at the ages of 5 weeks (n = 571), 13 weeks (n = 332), and 31 weeks (n = 499) and subjected to quantitative PCRs to detect bifidobacteria, bacteroides, lactobacilli, Escherichia coli , Clostridium difficile , and Clostridium cluster I. Results Birth mode, breast-feeding but also birth order had a strong effect on the microbiota composition. With increasing number of older siblings the colonization rates at age 5 weeks of lactobacilli ( P < .001) and bacteroides ( P = .02) increased, whereas rates of clostridia decreased ( P < .001). Colonization with clostridia, at the age of 5 and 13 weeks was also associated with an increased risk of developing AD in the subsequent 6 months of life (odds ratioadjusted = 2.35; 95% CI, 1.36-3.94 and 2.51; 1.30-4.86, respectively). Mediation analyses demonstrated that there was a statistically significant indirect effect via Clostridium cluster I colonization for both birth mode and birth order in association to AD. Conclusion The results of this study are supportive for a role of the microbiota in the development of AD. Moreover, the “beneficial” influence of older siblings on the microbiota composition suggests that this microbiota may be one of the biological mechanisms underlying the sibling effect.
Background Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of ...the microbiota in the association between birth mode and atopic manifestations has not been studied yet. Objectives We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. Methods The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. Results Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. Conclusion Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.
Objective To investigate whether birth weight and postnatal growth rates are independently related to the development of overweight and wheeze up to age 3 years. Study design Children from the LucKi ...Birth Cohort Study with complete follow-up for repeated questionnaires (at age 0, 7, and 14 months and 3 years) and informed consent to use height and weight data (measured by trained personnel at age 0, 7, and 14 months and 2 and 3 years) were included (n = 566). Wheeze (parental-reported) and overweight (body mass index BMI >85th percentile) were regressed with generalized estimating equations on birth weight and relative growth rates (difference SDS for weight, height, and BMI). Results Higher birth weight and higher weight and BMI growth rates were associated with increased risk of overweight, but not of wheeze, up to age 3 years. Higher height growth rate was associated with lower risk of wheeze up to 3 years, independent of overweight (aOR, 0.65; 95% CI, 0.53-0.79). In time-lag models, wheeze was associated with subsequently reduced height growth up to age 14 months, but not vice versa. Conclusion Only height growth rate, and not weight and BMI growth rate, is associated with preschool wheeze, independent of overweight. Children who wheeze demonstrate a subsequent reduction in height growth up to age 14 months, but not vice versa. Because height growth rate is not associated with overweight, preschool wheeze and overweight are not associated throughout early life growth.
Today quantitative information about the type of complications and their incidence during long-term pacemaker (PM) follow-up is scarce.
To assess the incidence and determinants of short- and ...long-term complications after first pacemaker implantation for bradycardia.
A prospective multicenter cohort study (the FOLLOWPACE study) was conducted among 1517 patients receiving a PM between January 2003 and November 2007. The independent association of patient and implantation-procedure characteristics with the incidence of PM complications was analyzed using multivariable Cox regression analysis.
A total of 1517 patients in 23 Dutch PM centers were followed for a mean of 5.8 years (SD 1.1), resulting in 8797 patient-years. Within 2 months, 188 (12.4%) patients developed PM complications. Male gender, age at implantation, body mass index, a history of cerebrovascular accident, congestive heart failure, use of anticoagulant drugs, and passive atrial lead fixation were independent predictors for complications within 2 months, yielding a C-index of 0.62 (95% confidence interval 0.57-0.66). Annual hospital implanting volume did not additionally contribute to the prediction of short-term complications. Thereafter, 140 (9.2%) patients experienced complications, mostly lead-related complications (n = 84). Independent predictors for long-term complications were age, body mass index, hypertension, and a dual-chamber device, yielding a C-index of 0.62 (95% confidence interval 0.57-0.67). The occurrence of a short-term PM complication was not predictive of future PM complications.
Complication incidence in modern pacing therapy is still substantial. Most complications occur early after PM implantation. Although various patient- and procedure-related characteristics are independent predictors for early and late complications, their ability to identify the patient at high risk is rather poor. This relatively high incidence of PM complications and their poor prediction underscores the usefulness of current guidelines for regular follow-up of patients with PM.
Objective To examine the timing, frequency, and type of antibiotic exposure during the first 10 years of life in association with (over)weight across this period in a cohort of 979 children. Study ...design Within the Child, Parents and Health: Lifestyle and Genetic Constitution Birth Cohort Study, antibiotic exposure record was obtained from general practitioners. Anthropometric outcomes (age- and sex-standardized body mass index, weight and height z-scores, and overweight) were measured repeatedly at 7 time points during the first 10 years of life. Generalized estimating equations method was used for statistical analysis. Results After adjusting for confounding factors, children exposed to one course of antibiotics compared with none in the first 6 months of life had increased weight- (adjusted generalized estimating equations estimates adjβ 0.24; 95% CI 0.03-0.44) and height (adjβ 0.23; 95% CI 0.0002-0.46) z-scores; exposure to ≥2 courses during the second year of life was associated with both increased weight (adjβ 0.34; 95% CI 0.07-0.60), and height z-scores (adjβ 0.29; 95% CI −0.003 to 0.59). Exposure later in life was not associated with anthropometric outcomes. Associations with weight z-scores were mainly driven by exposure to broad- (≥2 courses: adjβ 0.11; 95% CI 0.003-0.22) and narrow-spectrum β-lactams (1 course: adjβ 0.18; 95% CI 0.005-0.35) during the follow-up period. Specific antibiotic used was not associated with body mass index z-scores and overweight. Conclusions Repeated exposure to antibiotics early in life, especially β-lactam agents, is associated with increased weight and height. If causality of obesity can be established in future studies, this further highlights the need for restrictive antibiotic use and avoidance of prescriptions when there is minimal clinical benefit.
Objective To investigate the potential effect of modification by maternal allergic status on the relationship between breast-feeding duration and infant atopic manifestations in the first 2 years of ...life. Study design Data from 2705 infants of the KOALA Birth Cohort Study (The Netherlands) were analyzed. The data were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Total and specific immunoglobulin E measurements were performed on venous blood samples collected during home visits at age 2 years. Relationships were analyzed using logistic regression analyses. Results Longer duration of breast-feeding was associated with a lower risk for eczema in infants of mothers without allergy or asthma ( Ptrend = .01) and slightly lower risk in those of mothers with allergy but no asthma ( Ptrend = .14). There was no such association for asthmatic mothers ( Ptrend = .87). Longer breast-feeding duration decreased the risk of recurrent wheeze independent of maternal allergy ( Ptrend = .02) or asthma status ( Ptrend = .06). Conclusions Our findings show that the relationship between breast-feeding and infant eczema in the first 2 years of life is modified by maternal allergic status. The protective effect of breast-feeding on recurrent wheeze may be associated with protection against respiratory infections.
Background Regulatory T–cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes ...involved in the development and function of regulatory T cells are associated with atopy and asthma development. Objective To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T–cell function— IL6 , IL6R , IL10 , heme-oxygenase 1 (HMOX1) , IL2 , Toll-like receptor 2 (TLR2) , TGFB1 , TGF-β receptor (TGFBR)–1 , TGFBR2 , IL2RA , and forkhead box protein 3 (FOXP3) —in relation to atopy and asthma. Methods Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by χ2 tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). Results Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. Conclusion Genes involved in the development and function of regulatory T cells, specifically IL2RA , TLR2 , TGFBR2 , and FOXP3 , associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.
Objective To examine clustering of energy balance-related behaviors (EBRBs) in young children. This is crucial because lifestyle habits are formed at an early age and track in later life. This study ...is the first to examine EBRB clustering in children as young as 2 years. Study design Cross-sectional data originated from the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study. Parents of 2578 2-year-old children completed a questionnaire. Correlation analyses, principal component analyses, and linear regression analyses were performed to examine clustering of EBRBs. Results We found modest but consistent correlations in EBRBs. Two clusters emerged: a “sedentary-snacking cluster” and a “fiber cluster.” Television viewing clustered with computer use and unhealthy dietary behaviors. Children who frequently consumed vegetables also consumed fruit and brown bread more often and white bread less often. Lower maternal education and maternal obesity were associated with high scores on the sedentary-snacking cluster, whereas higher educational level was associated with high fiber cluster scores. Conclusions Obesity-prone behavioral clusters are already visible in 2-year-old children and are related to maternal characteristics. The findings suggest that obesity prevention should apply an integrated approach to physical activity and dietary intake in early childhood.
Background Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) ...but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy. Objective We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations. Methods Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli . Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction. Results Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 ( P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing. Conclusion The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development.
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