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 performed a genome wide association study on these samples using the Illumina 550,000 single nucleotide polymorphism platform. We identified a novel locus on chromosome 9 associated with asthma in our population which replicated in independent study of childhood onset asthma in a Mexican population (Hancock et al., 2009). The region contains the TLE4 gene which is plausibly involved in asthma. Analysis of our results in relation to publically available gene expression data from various tissues suggests that there are signals for other genes at lower levels of significance and that these genes are disproportionate expressed in tissues of relevance to asthma. In addition, ancestry analysis suggests that this association might not extend to other ethnic groups. 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 (Tang et al. in press). To make optimal use of the genome wide association data, we undertook the most comprehensive analysis to date of candidate genes from the prior literature on asthma both human association studies and mouse knockout models. A limitation of the existing candidate gene literature is the lack of systematic replication and evidence of publication bias. Further, large genes implicated in positional cloning studies that requiring genotyping of many SNPs to provide good coverage, tend to be understudied. In this analysis of over 230 genes, our most statistically significant findings emerged for TGFB1, IL1RL1, IL18R1, and DPP10. Of note DPP10 is an example of a very large gene that had been minimally studied since its identification from positional cloning (Wu et al. 2010). 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 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 will be submitted soon. 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. 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) that children of mothers taking folate supplements had slightly higher risk of wheeze and lower respiratory illness in early childhood is of potential public health importance. This 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 have followed up this observation by analyzing asthma phenotypes at a later time point (3 years of age) in relation to actual folate measurements in maternal blood taken during pregnancy. This work is under review. We are also beginning work to address the question of whether folate levels in maternal blood are related to epigenetic changes in the offspring cord blood. 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. Therefore we pilot tested a questionnaire to be administered to mothers whose children turn seven years. We obtained good response rates. We performed linkage of the MoBa database to the new Norwegian Prescription Drug Registry and found that nonrespondents to the questionnaire do not differ from respondents with respect to asthma status. Further we found that mothers report of asthma medication use in the children correlates with with registry data. Follow-up at age seven would 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.
Showing the most recent 10 out of 86 publications
