Genetic And Environmental Factors In Childhood Respiratory and Allergic Illness

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

Increasing evidence suggests the importance of pregnancy and early life factors in the etiology of asthma and allergy in childhood. We and others in the Epidemiology Branch have established a collaboration with the Norwegian Mother and Child Cohort (called MoBa), a population-based cohort of approximately 100,000 pregnant women in Norway who are being followed until their children reach adulthood. I established a collaboration with the asthma group in Norway around early life factors and epigenetics. I worked on early childhood outcomes with the MoBa investigators and pre and postdoctoral trainees from NIEHS and Norway. Our finding that children of mothers with higher levels of folate had slightly higher risk of asthma phenotypes in early childhood is of potential public health importance. Norway is an ideal place to examine this association because food is not fortified with folate. Using the seven-year follow-up of MoBa funded by NIEHS, we recently published our findings through age seven years and find that the association with maternal folate status persists for school age asthma (PMID: 27518161). We also published an analysis of maternal folate levels and epigenome wide methylation in newborns and identified many novel signals not previously implicated in biologic response to folate (PMID: 26861414). A current project in the Pregnancy and Childhood Epigenetics Consortium that I founded is looking at other nutrients involved in the one carbon metabolism pathway. A major focus of this project is to examine effects of in utero exposures on the epigenome of newborns. For this purposes we measured DNA methylation in cord blood on approximately 1800 newborns from the Norwegian Mother and Child pregnancy cohort using the Illumina450K methylation bead chip. In the first paper to examine the effects of any in utero exposure using this platform we identified and replicated associations of maternal smoking with DNA methylation in a number of genes (PMID: 22851337). We have followed up this finding in several ways. This appears to be an in utero effect that requires sustained exposure during pregnancy (PMID: 24740201). These methylation signals enabled development biomarker in the newborn of sustained exposure to maternal smoking during pregnancy (PMID: 27323799). We also followed up this association with much larger sample size in an international consortium that we created called Pregnancy and Childhood Epigenetics (PACE). We identified over 6000 signals in newborns related to maternal smoking, about half in novel loci and found strong persistence into later childhood (PMID: 27040690). We are leading a project to examine prenatal exposure to smoking in a more complete way than we were able to do when PACE first began. We will also benefit from the larger sample size now in PACE plus the availability of data from the more extensive Illumina EPIC chip. PACE continues to grow with over 45 birth and child cohorts participating. Previous PACE publications have examined exposure to air pollution during pregnancy (PMID: 27448387, PMID: 31148503), development of childhood asthma (PMID: 30579849), maternal hypertension during pregnancy (PMID: 31230546), birthweight (PMID: 31015461). We published a large meta-analysis of gestational age (PMID: 32114984) which identified numerous signals. We also compared findings our comprehensive meta-analyses of methylation at birth in relation to smoking during pregnancy and methylation in adult in relation to their own smoking. This identified many genes that were overlapped but also genes that were uniquely differentially methylation in relation to the prenatal exposure (PMID 31536415). In a large sample size, we found no differential methylation in relation to maternal anxiety (PMID 33414500 ). Larger studies will most likely be needed to identify signals from this and related conditions. There are many ongoing PACE projects at various stages of completion including various analyses of maternal diet, vitamin D and stress. In 2019, I welcomed Dr. Musa Kana, a postdoctoral fellow participating in the inaugural year of the NIH African Postdoctoral Training Initiative. He returned to Nigeria in November 2021. Dr. Kana is interested in the causes of stunting, an important health problem in his home country of Nigeria. Dr Kana used his time at NIH to analyze data that he has collected on risk factors for reduced birthweight in Nigeria (PMID 32083347, 32083347). This year he published a paper on impacts of biomass burning on birthweight in term infants. Upon return to Nigeria he has been conducting scoping and pilot studies to support development of a birth cohort in Nigeria to study causes of stunting. With guest researcher Minjian Chen, I examined the impact of the exposome during pregnancy on metabolic phenotypes, which we termed metabotypes. Both the exposome and metabolites were measured in urine collected at two time points in pregnancy. This work identified numerous exogenous chemicals related to metabotypes (PMID: 35254863).