Project description:The prevalence of respiratory allergy in children is increasing. Epigenetic changes (e.g. DNA methylation) are plausible underlying molecular mechanisms. Longitudinal birth cohorts are instrumental to study the relation between early-life environmental factors and the development of complex diseases. Our AXA Research Fund and Cefic-LRI supported project explores the hypothesis that chemical exposures during pregnancy can influence the immune system and development of allergy in children. Questionnaire data, as well as cord blood, plus blood and saliva samples at age 11 years, were collected in substudies of two longitudinal birth cohorts in Belgium (FLEHS1 & FLEHS2) and analyzed with Illumina Methylation 450K BeadChips as well as gene targeted iPLEX MassArrays analysis. The project aims to answer the following questions: 1) can we identify specific changes in epigenetic modifications on DNA from allergic compared to not-allergic children; 2) are these allergy-related epigenetic changes a result of chemical exposure during pregnancy; and 3) did the early life exposures leave an epigenetic “mark” that is maintained through childhood. If chemicals exposures and resulting predictive markers of allergic diseases can be detected early, prevention strategies, particularly in children or before pregnancy, could be developed.
Project description:Background: Genetic heterogeneity in the innate immune system may account for variable susceptibility to respiratory tract infections (RTIs) in children. Objective: We aimed to assess the impact of polymorphisms rs273259 and rs1333969 in type I interferon related gene IFI44L on susceptibility to RTIs and acute otitis media in children. Methods: In two prospective, population-based birth cohorts, the FinnBrain Birth Cohort Study and the STEPS Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until one and two years of age, respectively, and adjusted incidence rate ratios (aIRR) or odds ratios (OR) were calculated. At age 3 months, whole blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. Results: In respiratory virus-positive children at 3 months of age, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other interferon related genes. Conclusions: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media in two independent birth cohorts, and they attenuated interferon pathway activation by respiratory viruses.
Project description:Epigenetic perturbations in the early embryo could have later effects during development. For a disease such as autism, where a diagnosis is hard before two years of age but earlier intervention is correlated with better outcomes, finding a molecular signature of the disease at birth could have a significant impact of the quality of life. Since placenta also derives from the early embryo, is a readily-available tissue at birth, and has a unique DNA methylation pattern, we tested whether disruptions in placental DNA methylation was predictive of autism. As part of the MARBLES study, parents that already had an autistic child and were therefore at much greater risk to have another autistic child were followed as they planned another pregnancy. Biological samples were collected at birth and the children followed for several years to determine the diagnosis. “Typical” children in this study were those that did not later develop autism.
Project description:Background: Farm exposures in early life reduce the risks for childhood allergic diseases and asthma. There is less information about how farm exposures relate to respiratory illnesses and mucosal immune development. Objective: We hypothesized that children raised in farm environments have a lower incidence of viral illnesses over the first two years of life than non-farm children. We also analyzed between farm exposures or respiratory illnesses were related to patterns of nasal cell gene expression. Methods: The Wisconsin Infant Study Cohort (WISC) birth cohort enrolled farm and non-farm pregnant women from central Wisconsin. Parents reported prenatal farm and other environmental exposures. Illness frequency and severity were assessed using illness diaries and periodic surveys. Nasopharyngeal cell gene expression at age two years was compared to farm exposure and respiratory illness history. Results: There was a higher rate of respiratory illnesses in the non-farm vs. farm group (rate ratio 0.82 [0.69,0.97], p=0.020), but no significant differences in wheezing illnesses. There was a stepwise reduction in rates of respiratory illnesses in children exposed at least weekly to 0, 1, or ≥2 animals (p=0.006). In analyzing nasal cell gene expression, farm exposures and preceding respiratory illnesses were positively related to gene signatures for mononuclear cells and innate and antimicrobial responses. Conclusions: Children exposed to farms and farm animals had lower rates of respiratory illnesses over the first two years of life. Both farm exposures and preceding respiratory illnesses were associated with increased innate immune responses, suggesting that these exposures stimulate mucosal immune responses to reduce subsequent illness frequency.
Project description:Children born small for gestational age (SGA) face elevated risks of metabolic, cardiovascular, respiratory, and neurodevelopmental disorders, as well as premature mortality, yet the underlying mechanisms remain only partly understood. We analyze blood proteomic data from multiple birth cohorts to identify molecular pathways linked to SGA and to later-life lung function. We find that approximately one-third of SGA children exhibit a distinct molecular endotype marked by dysregulation of axon-guidance proteins in cord blood. In peripheral blood collected later in life, these proteins are inversely associated with contemporaneous spirometric restriction. These findings offer new insight into the developmental origins of chronic disease and highlight axon-guidance pathways as promising targets for investigating multiorgan morbidity. This repository accompanies the publication entitled “Multicohort analysis unveils axon guidance pathways linking small for gestational age to spirometric restriction.”
Project description:We measured the DNA methylation levels at ~800,000 CpG sites from ethnically admixed children in CBMCs at birth and PBMCs age 7 to study the longitudinal dynamics of methylation marks. We found that self-reported race-dependent methylation levels were conserved over time, which helped to suggest that blood methylation levels are robust to environmental exposures during the first 7 years of life.
Project description:Evidence is accumulating that nutritional exposures in utero can influence health outcomes in later life. Animal studies and human epidemiological studies have implicated epigenetic modifications as playing a key role in this process, but there are limited data from large well-controlled human intervention trials. This study utilised a large double-blind randomized placebo-controlled trial to test whether a defined nutritional exposure in utero, in this case docosahexaenoic acid (DHA), could alter the infant epigenome. Pregnant mothers consumed DHA-rich fish oil (800 mg DHA/d) or placebo supplements from 20 weeks’ gestation to delivery. Blood spots were collected from the children at birth (n=991) and blood leukocytes at 5 years (n=667). Global DNA methylation was measured in all samples and Illumina HumanMethylation450K BeadChip arrays were used for genome-wide methylation profiling in a subset of 369 children at birth and 65 children at 5 years. There were no differences in global DNA methylation levels between the DHA and control group either at birth or at 5 years, but we identified 21 differentially methylated regions (DMRs) at birth, showing small DNA methylation differences (<5%) between the treatment groups, some of which seemed to persist until 5 years. The number of DMRs at birth was greater in males (127 DMRs) and in females (72 DMRs) separately, indicating a gender-specific effect. In conclusion, maternal DHA supplementation during the second half of pregnancy had small effects on DNA methylation of infants. While the potential functional significance of these changes remains to be determined, these findings further support the role of epigenetic modifications in developmental programming in humans, and points the way for future studies.