[show abstract][hide abstract] ABSTRACT: When evaluating the causal link between obesity and the development of asthma in children, prospective cohort studies are essential. The results of the most recently published birth cohort studies from Sweden, Germany, Brazil, Belarus, and California, USA, as well as from a joint analysis of eight European birth cohorts of the Global Allergy and Asthma European Network are evaluated. Moreover, the results of two meta-analyses are presented.
Most recent prospective cohort studies found a dose-response association between overweight or obesity and asthma. The evidence of effect modification by sex, ethnicity, and age was inconsistent. Both meta-analyses also showed that overweight children were at an increased risk of incident asthma compared with nonoverweight children and that the relationship was further elevated for obesity.
Prospective cohort studies and two recently published meta-analyses found an association between overweight (and especially obesity) and asthma in the appropriate temporal sequence and in a dose-response manner. Children with a pronounced weight gain slope in early life were particularly at risk for asthma within the first 6 years of life. The gain in BMI over time during infancy may be an even more important predictor for asthma in childhood than excess weight at any specific age.
Current Opinion in Allergy and Clinical Immunology 02/2014; · 3.40 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective
To investigate whether birth by cesarean delivery rather than vaginal delivery is a risk factor for later childhood obesity.
Healthy, full-term infants were recruited. Overweight and obesity were defined using measured weight and height according to World Health Organization reference data. Associations between cesarean delivery and being overweight or obese were investigated at age 2, 6, and 10 years (n = 1734, 1244, and 1170, respectively) by multivariate logistic regression models adjusted for socioeconomic status, child characteristics, and maternal prepregnancy characteristics.
Mothers who gave birth by cesarean delivery (∼17%) had a higher mean prepregnancy body mass index (23.7 kg/m2 vs 22.5 kg/m2), greater mean gestational weight gain (15.3 kg vs 14.5 kg), and shorter mean duration of exclusive breastfeeding (3.4 months vs 3.8 months) compared with those who delivered vaginally. The proportion of obese children was greater in the cesarean delivery group compared with the vaginal delivery group at age 2 years (13.6% vs 8.3%), but not at older ages. Regression analyses revealed a greater likelihood of obesity at age 2 years in the cesarean delivery group compared with the vaginal delivery group at age 2 years (aOR, 1.68; 95% CI, 1.10-2.58), but not at age 6 years (aOR, 1.49; 95% CI, 0.55-4.05) or age 10 years (aOR, 1.16; 95% CI, 0.59-2.29).
Cesarean delivery may increase the risk of obesity in early childhood. Our results do not support the hypothesis that an increasing rate of cesarean delivery contributes to obesity in childhood.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 x 10-10) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 x 10-9), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 x 10-8) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
Journal of Allergy and Clinical Immunology 12/2013; · 12.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background/objectives:Growth parameters during infancy and early childhood might predict adipokine levels later in life. This study investigates the association between peak growth velocities, body mass index (BMI) and age at adiposity rebound (AR), with leptin and adiponectin levels at age 10 years.subjects/Methods:Peak height (PHV) and weight (PWV) velocities were calculated from height and weight measurements obtained between birth and age 2 years from 2880 children participating in the GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics) birth cohorts. BMI and age at AR were calculated using BMI measurements between age 1.5 and 12 years. Blood samples were collected during a physical examination at age 10. Adiponectin and leptin levels were measured by radioimmunoassay. Linear regression models were fitted after adjustment for potential confounding factors and results are presented per interquartile range increase in the exposure.Results:Age at AR was negatively associated with leptin in males and females (percent difference β*: -41.71%; 95% confidence interval: (-44.34;-38.96) and β*: -43.22%; (-45.59; -40.75), respectively). For both males and females PWV (β*: 14.23%; (7.60; 21.26) and β*: 18.54%; (10.76; 26.87), respectively) and BMI at AR (β*: 63.08%; (55.04; 71.53) and β*: 67.02%; (59.30; 75.10), respectively) were positively associated with leptin levels. PHV showed a positive effect on leptin in females only (β*: 10.75%; (3.73; 18.25)). Growth parameters were not significantly associated with adiponectin except for age at AR among females (β: 0.75 ng/ml; (0.42; 1.09)) and PWV among males (β: 0.45 ng/ml; (0.11; 0.79)).Conclusion:Growth patterns in early life may be associated with leptin levels at age 10 years.European Journal of Clinical Nutrition (2013) 0, 000-000.advance online publication, 30 October 2013; doi:10.1038/ejcn.2013.213.
European journal of clinical nutrition 10/2013; · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is evidence for adverse effects of outdoor air pollution on lung function of children. Quantitative summaries of the effects of air pollution on lung function, however, are lacking due to large differences among studies.
To study the association between residential exposure to air pollution and lung function in five European birth cohorts with a standardized exposure assessment following a common protocol.
As part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) we analyzed data from birth cohort studies situated in Germany, Sweden, The Netherlands, and the United Kingdom that measured lung function at 6-8 years of age (N=5,921). Annual average exposure to air pollution [nitrogen oxides (NO2, NOx), mass concentrations of particulate matter with diameters < 2.5, < 10, and 2.5-10 µm (PM2.5, PM10, and PMcoarse), and PM2.5 absorbance] at the birth address and current address was estimated by land-use regression models. Associations of lung function with estimated air pollution levels and traffic indicators were estimated for each cohort using linear regression analysis, and then combined by random effects meta-analysis.
Estimated levels of NO2, NOx, PM2.5 absorbance, and PM2.5 at the current address, but not at the birth address, were associated with small decreases in lung function. For example, changes in forced expiratory volume in 1 second (FEV1) ranged from -0.86% (95% CI: -1.48, -0.24%) for a 20-µg/m(3) increase in NOx, to -1.77% (95% CI: -3.34, -0.18%) for a 5-µg/m(3) increase in PM2.5.
Exposure to air pollution may result in reduced lung function in school children.
Environmental Health Perspectives 09/2013; · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
[show abstract][hide abstract] ABSTRACT: Objective:To develop a prediction model that quantifies the risk of being overweight at 10 years of age.Subjects/Methods:In total, 3121 participants from the GINIplus (German Infant Nutritional Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics) German birth cohorts were recruited. We predicted standardized body mass index (BMI) at 10 years of age using standardized BMIs from birth to 5 years. Parental education, family income and maternal smoking during pregnancy were considered as covariates. Linear and logistic regression models were used to evaluate the impact of risk factors on BMI and on being overweight at 10 years of age, respectively.Results:Birth weight, standardized BMI at 5 years (60-64 months) (β=0.77; 95% confidence interval (CI): 0.73-0.81) and maternal smoking during pregnancy were positively associated with standardized BMI at 10 years of age. Standardized BMI and overweight at 5 years were strongest predictors of being overweight at 10 years. Conversely, high parental education conferred a protective effect (β=-0.15; 95% CI: -0.29 to -0.01). Being overweight at 5 years (60-64 months) increased the risk of being overweight at 10 years of age with odds ratios above 10. Among children who were predicted to be overweight at 10 years, cross-validation results showed that 76.8% of female subjects and 68.1% of male subjects would be overweight at 10 years of age.Conclusion:BMI and being overweight at 5 years of age are strong predictors of being overweight at 10 years of age. The effectiveness of targeted interventions in children who are overweight at 5 years of age should be explored.European Journal of Clinical Nutrition advance online publication, 24 April 2013; doi:10.1038/ejcn.2013.80.
European journal of clinical nutrition 04/2013; · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics.
We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
[show abstract][hide abstract] ABSTRACT: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. While little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty, and cancer progression, pointing to shared underlying mechanisms.To discover genetic loci influencing pubertal height and growth and place them in context of overall growth and maturation, we performed genome-wide association (GWA) meta-analyses in up to 18,737 European samples utilizing longitudinally collected height measurements. We found significant associations (P<1.67 x 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased BMI, reduced pubertal growth, and earlier puberty.While epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty, and childhood obesity, and provides new information to pinpoint processes linking these traits.
Human Molecular Genetics 02/2013; · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Most previous studies which have investigated the short-term effects of air pollution on airway inflammation, assessed by an increase of exhaled nitric oxide (eNO), have been conducted among asthmatic children. Few studies have considered this potential association among non-asthmatics. Furthermore, although both short- and long-term effects of air pollution on eNO had been reported separately, studies which include both are scarce. We explored associations between 24 h NO2 and PM10 (particles with aerodynamic diameters below 10 μm) mass with eNO in 1985 children (192 asthmatics and 1793 non-asthmatics) aged 10 years and accounted for the long-term effects of air pollution by adjusting for annual averages of NO2, PM10 mass, PM2.5 mass (particles with aerodynamic diameters below 2.5 μm) and PM2.5 absorbance, using data from two German birth cohorts in Munich and Wesel. In total, robust associations between 24 h NO2 and eNO were observed in both single-pollutant (percentage change: 18.30%, 95% confidence interval: 11.63–25.37) and two-pollutant models (14.62%, 6.71–23.11). The association between 24 h PM10 mass and eNO was only significant in the single-pollutant model (9.59%, 4.80–14.61). The same significant associations were also observed in non-asthmatic children, while they did not reach significant levels in asthmatic children. Associations between annual averages of ambient air pollution (NO2, PM10 mass, PM2.5 mass and PM2.5 absorbance) and eNO were consistently null. In conclusion, significantly positive associations were observed between short-term ambient air pollution and eNO. No long-term effects of air pollution on eNO were found in this study.
International Journal of Hygiene and Environmental Health. 01/2013;
[show abstract][hide abstract] ABSTRACT: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
[show abstract][hide abstract] ABSTRACT: Background: The diagnostic use of lung function using spirometry depends on the validity of reference equations. A multitude of spirometric prediction values have been published, but in most of these studies older age groups are underrepresented. Objectives: The aim of the present study was to establish new spirometric reference values for advanced age and to compare these to recent prediction equations from population-based studies. Methods: In the present study spirometry was performed in a population-based sample from the KORA-F4 and KORA-Age cohorts (2006-2009, Augsburg, Germany) comprising 592 never-smoking subjects aged 42-89 years and with no history of respiratory disease. Using quantile regression analysis, equations for the median and lower limit of normal were derived for indices characterizing the expiratory flow-volume curve: forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), FEV(1)/FVC, peak expiratory flow (PEF), and forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF(25), FEF(50) and FEF(75)). Results: FEV(1) and FVC were slightly higher, and PEF was lower compared to recently published equations. Importantly, forced expiratory flow rates at middle and low lung volume, as putative indicators of small airway disease, were in good agreement with recent data, especially for older age. Conclusion: Our study provides up-to-date reference equations for all major indices of flow-volume curves in middle and advanced age in a South German population. The small deviations from published equations indicate that there might be some regional differences of lung function within the Caucasian population of advanced age in Europe.
[show abstract][hide abstract] ABSTRACT: Numerous chronic diseases in childhood and adulthood have their origins in perinatal life and are potentially influenced by trans-generational epigenetic processes. Therefore, prospective birth cohorts can substantially contribute to our knowledge about the etiology of diseases including modifiable risk factors. The two population-based German birth cohorts GINIplus and LISAplus aim to describe the natural course of chronic diseases and intermediate phenotypes in childhood and its determinants, and to identify potential genetic effect modifications. In the mid-1990s, 5,991 (GINIplus) and 3,097 (LISAplus) healthy, term newborns were recruited for long-term follow-up in four regions of Germany. The follow-up rate for the first 10 years was about 55%. We analyzed the growth and development of overweight, infections and allergic diseases, mental and oral health, metabolic and inflammatory parameters and the role of potential risk factors including genetics. The results of these two birth cohorts substantially contribute to the current knowledge about the natural course of these health parameters. These data were included in many international projects and consortia for purposes of international comparisons of prevalence and consistency of findings, and to increase the power of the analyses.
[show abstract][hide abstract] ABSTRACT: Growth velocities during infancy might affect the risk of asthma in childhood. This study examines the association between peak height and weight velocities during the first 2 years of life and onset of asthma and wheeze up to 10 years of age.
Data from 9086 children who participated in the GINIplus and LISAplus birth cohorts were analyzed. Information on asthma was requested annually from 1 to 10 years and information on wheeze at 1, 2, 4, 6, and 10 years. Peak height and weight velocities were calculated using height and weight measurements obtained between birth and 2 years of age. Cox proportional hazards models and generalized linear mixed models were calculated after adjustment for potential confounding factors including birth weight and body mass index at 10 years of age.
Per interquartile range increase in peak weight velocity (PWV), the risk of asthma increased significantly (adjHR: 1.22; CI: 1.02-1.47). The relationship between peak height velocity (PHV) and onset of asthma was nonsignificant (adjHR: 1.08; CI: 0.88-1.31). Wheeze was not significantly associated with PHV or with PWV (adjOR: 1.07; CI: 0.64-1.77 and adjOR: 1.11; CI: 0.68-1.79, respectively).
Weight gain during infancy is positively associated with physician-diagnosed asthma in school-aged children.
[show abstract][hide abstract] ABSTRACT: We wanted to identify the importance of the duration of invasive ventilation and of renal replacement therapy for short-term prognosis of surgical patients treated in an intensive care unit (ICU).
We analyzed adult patients (n = 1462) who had an ICU length of stay of more than 4 days and who were followed up until the end of the short-term phase after ICU admission. Duration of different invasive therapies was evaluated by constructing specific vectors that tested effects of time-dependent variables on outcome after a lag time of 7 days.
Eight hundred eight patients (56.6%) were still alive at the end of the short-term phase. During the short-term phase, 85.3% of the 1462 patients required invasive ventilation, and 16.1%, a continuous renal replacement therapy. Besides the underlying disease and disease severity at ICU admission, the need for invasive ventilation or renal replacement therapy was associated with poorer outcome. Duration of invasive ventilation shortened survival if treatment lasted for more than 11 days (nonlinear association). In contrast, duration of renal replacement therapy was unimportant for short-term prognosis.
Prolonged duration of invasive ventilation but not of renal replacement therapy is inversely related to short-term survival.
Journal of critical care 07/2011; 27(1):73-82. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Zahlreiche chronische Erkrankungen in der Kindheit und im Erwachsenenalter haben ihren Ursprung in der perinatalen Entwicklungsphase und sind zudem möglicherweise transgenerational, epigenetisch beeinflusst. Daher tragen gerade prospektive Geburtskohorten maßgeblich zum Verständnis der Ätiologie von Erkrankungen bei und können veränderbare Risikofaktoren identifizieren. Die beiden populationsbasierten deutschen Geburtskohorten GINIplus und LISAplus verfolgen als Hauptziele den natürlichen Verlauf chronischer Erkrankungen im Kindesalter sowie intermediäre Phänotypen und Funktionseinschränkungen zu beschreiben, deren Determinanten zu analysieren und mögliche Effektmodifikationen durch genetische Polymorphismen zu identifizieren. Mitte der 1990er-Jahre wurden in vier Regionen Deutschlands 5991 (GINIplus) beziehungsweise 3097 (LISAplus) gesunde reife Neugeborene für ein Langzeit-Follow-up-Programm rekrutiert und bislang mit einer Response von etwa 55% über zehn Jahre hinweg beobachtet. Es wurden Wachstums- und Gewichtsentwicklung, Infektionskrankheiten und Allergien, seelische Gesundheit, Mundgesundheit, metabolische und inflammatorische Parameter teils im Längsschnitt auf potenzielle Risikofaktoren hin untersucht und der Einfluss genetischer Varianten analysiert. Ergebnisse dieser beiden Geburtskohorten haben den Wissensstand zum Verlauf häufiger Erkrankungen und intermediärer Phänotypen im Längsschnitt maßgeblich bereichert. Ergebnisse dieser Studien sind in zahlreiche internationale Projekte und Konsortien mit dem Ziel eingeflossen, deutsche Daten in den europäischen Kontext zu stellen und gemeinsam auszuwerten. Auf diese Weise wurde die Konsistenz der Ergebnisse untersucht und die Power für gemeinsame Analysen erhöht.