Herman T. den Dekker

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illuminas HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO2 Air Pollution Exposure

Background: Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation. Objectives: We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation. Methods: We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239). Results: We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression. Conclusions: NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways. Citation: Gruzieva O, Xu CJ, Breton CV, Annesi-Maesano I, Antó JM, Auffray C, Ballereau S, Bellander T, Bousquet J, Bustamante M, Charles MA, de Kluizenaar Y, den Dekker HT, Duijts L, Felix JF, Gehring U, Guxens M, Jaddoe VV, Jankipersadsing SA, Merid SK, Kere J, Kumar A, Lemonnier N, Lepeule J, Nystad W, Page CM, Panasevich S, Postma D, Slama R, Sunyer J, Söderhäll C, Yao J, London SJ, Pershagen G, Koppelman GH, Melén E. 2017. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ Health Perspect 125:104–110; http://dx.doi.org/10.1289/EHP36

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.

Tobacco Smoke Exposure, Airway Resistance, and Asthma in School-age Children: The Generation R Study

BACKGROUND Tobacco smoke exposure has been associated with early childhood asthma symptoms. We assessed the associations of tobacco smoke exposure during pregnancy and childhood with wheezing patterns, asthma, airway interrupter resistance (Rint), and fractional exhaled nitric oxide (Feno) in school-age children and whether birth characteristics explained the associations. METHODS This study was embedded in a population-based prospective cohort study among 6,007 children. Paternal and maternal smoking during pregnancy (never, first trimester only, continued), secondhand tobacco smoke exposure during childhood, wheezing patterns, and asthma were prospectively assessed by questionnaires. Wheezing patterns were defined as never, early (≤ 3 years only), late (> 3 years only), and persistent (≤ 3 and > 3 years) wheezing. Rint and Feno were measured at age 6 years. Birth characteristics were available from registries. RESULTS Continued maternal smoking during pregnancy was associated with increased risks of early and persistent wheezing (OR: 1.24 [1.01, 1.52]; 1.48 [1.13, 1.95]) and asthma (1.65 [1.07, 2.55], for at least five cigarettes per day), but not with Rint or Feno. Birth characteristics did not explain these associations. Childhood tobacco smoke exposure was associated with higher Rint (difference z score: 0.45 [0.00, 0.90]), but this effect attenuated after adjustment for birth characteristics. Maternal smoking during first trimester only or paternal smoking during pregnancy was not associated with Rint, Feno, wheezing, or asthma. CONCLUSIONS Continued maternal smoking during pregnancy was associated with increased risks of asthma outcomes in school-age children, whereas childhood tobacco smoke exposure was associated with higher Rint. Birth characteristics may explain part of these associations.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study

Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma.

Breastfeeding and asthma outcomes at the age of 6 years: The Generation R Study.

Breastfeeding is associated with a lower risk of asthma symptoms in early childhood, but its effect at older ages remains unclear. We examined the associations of duration and exclusiveness of breastfeeding with asthma outcomes in children aged 6 years, and whether these associations were explained by atopic or infectious mechanisms.

A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis

Background Maternal smoking during pregnancy is linked to reduced birth weight but the gestation at onset of this relationship is not certain. We present a systematic review of the literature describing associations between maternal smoking during pregnancy and ultrasound measurements of fetal size, together with an accompanying meta-analysis. Methods Studies were selected from electronic databases (OVID, EMBASE and Google Scholar) that examined associations between maternal smoking or smoke exposure and antenatal fetal ultrasound measurements. Outcome measures were first, second or third trimester fetal measurements. Results There were 284 abstracts identified, 16 papers were included in the review and the meta-analysis included data from eight populations. Maternal smoking was associated with reduced second trimester head size (mean reduction 0.09 standard deviation (SD) [95% CI 0.01, 0.16]) and femur length (0.06 [0.01, 0.10]) and reduced third trimester head size (0.18 SD [0.13, 0.23]), femur length (0.27 SD [0.21, 0.32]) and estimated fetal weight (0.18 SD [0.11, 0.24]). Higher maternal cigarette consumption was associated with a lower z score for head size in the second (mean difference 0.09 SD [0, 0.19]) and third (0.15 SD [0.03, 0.26]) trimesters compared to lower consumption. Fetal measurements were not reduced for those whose mothers quit before or after becoming pregnant compared to mothers who had never smoked. Conclusions Maternal smoking during pregnancy is associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects may be attenuated if mothers quit or reduce cigarette consumption during pregnancy.

Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age

Background: Obesity and asthma often coexist. We hypothesized that detailed body fat distribution measures might be more strongly associated than body mass index (BMI) with childhood asthma. Objective: We examined the associations of total body and abdominal fat measures with respiratory resistance (Rint), fractional exhaled nitric oxide (Feno), and risks of wheezing and asthma in school‐aged children. Methods: In a population‐based prospective cohort study among 6178 children aged 6 years, we measured BMI, fat mass index, android/gynoid ratio, and preperitoneal and subcutaneous fat mass by physical examinations, dual‐energy x‐ray absorptiometry, and ultrasound, respectively. We performed Rint and Feno measurements, and assessed physician‐diagnosed wheezing and asthma by questionnaires. Results: A higher BMI was associated with a higher Rint (Z score [95% CI], 0.06 [0.01‐0.12]) and increased risk of wheezing (odds ratio [95% CI], 1.07 [1.00‐1.14], per Z score BMI increase), but not with Feno or asthma. A high fat mass index was associated with a higher Rint (Z score [95% CI], 0.40 [0.13‐0.68]). A high android/gynoid fat mass ratio was associated with a lower Feno (Sym% [95% CI], −9.8 [−16.3 to −3.4]), whereas a high preperitoneal fat mass was associated with a higher Feno (Sym% [95% CI], 6.5 [0.1‐12.9]). Subcutaneous fat mass was not associated with any respiratory outcome. Conclusions: Studying detailed body fat distribution measures might provide better insight into the obesity‐asthma paradigm. GRAPHICAL ABSTRACT Figure. No caption available.

Early childhood growth patterns and school-age respiratory resistance, fractional exhaled nitric oxide and asthma

Greater infant weight gain is associated with lower lung function and increased risk of childhood asthma. The role of early childhood peak growth patterns is unclear. We assessed the associations of individually derived early childhood peak growth patterns with respiratory resistance, fractional exhaled nitric oxide, wheezing patterns, and asthma until school‐age.