A major project is a family study of genetic susceptibility to asthma in a highly ozone exposed population, Mexico City. This study uses the case-parent triad design. We identified a novel locus for asthma in Mexicans in a genome wide association study and also comprehensively evaluated candidates genes. We have also used these data to quantify the contribution of allele-based and ancestry-based association testing under a family-design, and demonstrate that the two tests can provide non-redundant information However, we realize that our GWAS is modest in size and both analysis of main effects, and especially interactions, require much larger samples sizes. To this end, we are participating actively in an NHLBI-led consortium called EVE which brings together GWAS of asthma funded by NIH. We have completed a meta-analysis of asthma which has been recently published. We are undertaking meta-analysis of additional respiratory and allergic outcomes in the EVE consortium and evaluating genome wide interactions with environmental exposures including parental smoking, ozone and traffic related air pollution. We have also participating in the establishment of an international asthma GWAS consortium (TAGC) which will perform a larger meta-analysis of asthma as its first project. We are also participating in an extramural consortium called ABRIDGE to go integrative genome analyses across asthma GWAS studies. Increasing evidence suggest the importance of pregnancy and early life factors in the etiology of asthma and allergy in childhood. Various investigators 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 have established a collaboration with the asthma group in Norway around gene-environment interaction and epigenetics. NIEHS/DIR partially supports the MoBa study with the goal of enabling such add-on studies. I have been working on analyses of early childhood outcomes with the MoBa investigators. Our finding (Haberg et al., 2009 and Haberg et al. 2010) 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. Our was the first human study to address a recent finding in mouse models that supplementation with folate and other methyl donors in pregnancy lead to an allergic asthma phenotype in offspring due to epigenetic mechanisms. Norway is an ideal place to examine this association because food is not fortified with folate. We are following the children to age seven to see whether this association is present with the more relevant phenotype of asthma at school age. We are also genome wide methylation techniques (Illumina Methyl450K) to examine whether levels of folate and other methyl donors in maternal blood are related to epigenetic changes in the offspring cord blood. To examine possible epigenetic mechanisms for adverse effects of in utero environmental exposures on the offspring, we have examined genome wide methylation using the Illumina Methyl450K platform on approximately 1,068 cord blood DNA samples from the Norwegian Mother and Child Cohort Study (MoBa). We were the first study to use this platform to study maternal smoking in pregnancy and identified a number of novel findings that replicated in a second population (Joubert et al. 2012). We are currently analyzing asthma outcomes, birth outcomes as well as folate other environmental exposures. We realize that many children have wheezing illness in the first few years of life and that much of this resolves by school age and does not become asthma. Therefore it is important to follow-up our findings by following the children to age seven year when asthma is more reliably diagnosed and inhalant allergies have become common. Follow-up at age seven will enable high quality, well powered studies of genetics and epigenetics of childhood asthma and allergies, including consideration of interactions with environmental factors, including diet, parental smoking, wood burning and ambient air pollution.
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