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Mechanistic indicators of childhood asthma (MICA) study: piloting an integrative design for evaluating environmental health.

ABSTRACT: BACKGROUND: Asthma is a common complex disease responsible for considerable morbidity and mortality, particularly in urban minority populations. The Mechanistic Indicators of Childhood Asthma study was designed to pilot an integrative approach in children's health research. The study incorporates exposure metrics, internal dose measures, and clinical indicators to decipher the biological complexity inherent in diseases such as asthma and cardiovascular disease with etiology related to gene-environment interactions. METHODS/DESIGN: 205 non-asthmatic and asthmatic children, (9-12 years of age) from Detroit, Michigan were recruited. The study includes environmental measures (indoor and outdoor air, vacuum dust), biomarkers of exposure (cotinine, metals, total and allergen specific Immunoglobulin E, polycyclic aromatic hydrocarbons, volatile organic carbon metabolites) and clinical indicators of health outcome (immunological, cardiovascular and respiratory). In addition, blood gene expression and candidate SNP analyses were conducted. DISCUSSION: Based on an integrative design, the MICA study provides an opportunity to evaluate complex relationships between environmental factors, physiological biomarkers, genetic susceptibility and health outcomes. PROJECT APPROVAL: IRB Number 05-EPA-2637: The human subjects' research protocol was reviewed by the Institutional Review Board (IRB) of the University of North Carolina; the IRB of Westat, Inc., the IRB of the Henry Ford Health System; and EPA's Human Subjects' Research Review Official.

SUBMITTER: Gallagher J

PROVIDER: S-EPMC3112137 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Mechanistic indicators of childhood asthma (MICA) study: piloting an integrative design for evaluating environmental health.

Gallagher Jane J Hudgens Edward E Williams Ann A Inmon Jefferson J Rhoney Scott S Andrews Gina G Reif David D Heidenfelder Brooke B Neas Lucas L Williams Ronald R Johnson Markey M Ozkaynak Haluk H Edwards Stephen S Hubal Elaine Cohen EC

BMC public health 20110519

<h4>Background</h4>Asthma is a common complex disease responsible for considerable morbidity and mortality, particularly in urban minority populations. The Mechanistic Indicators of Childhood Asthma study was designed to pilot an integrative approach in children's health research. The study incorporates exposure metrics, internal dose measures, and clinical indicators to decipher the biological complexity inherent in diseases such as asthma and cardiovascular disease with etiology related to gen ...[more]

PMID: 21595901

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Project description:BACKGROUND:The intestinal metabolome reflects the biological consequences of diverse exposures and might provide insight into asthma pathophysiology. OBJECTIVE:We sought to perform an untargeted integrative analysis of the intestinal metabolome of childhood asthma in this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial. METHODS:Metabolomic profiling was performed by using mass spectrometry on fecal samples collected from 361 three-year-old subjects. Adjusted logistic regression analyses identified metabolites and modules of highly correlated metabolites associated with asthma diagnosis by age 3 years. Sparse canonical correlation analysis identified associations relevant to asthma between the intestinal metabolome and other "omics": the intestinal microbiome as measured by using 16S rRNA sequencing, the plasma metabolome as measured by using mass spectrometry, and diet as measured by using food frequency questionnaires. RESULTS:Several intestinal metabolites were associated with asthma at age 3 years, including inverse associations between asthma and polyunsaturated fatty acids (adjusted logistic regression ? = -6.3; 95% CI, -11.3 to -1.4; P = .01) and other lipids. Asthma-associated intestinal metabolites were significant mediators of the inverse relationship between exclusive breast-feeding for the first 4 months of life and asthma (P for indirect association = .04) and the positive association between a diet rich in meats and asthma (P = .03). Specific intestinal bacterial taxa, including the family Christensenellaceae, and plasma metabolites, including ?-tocopherol/?-tocopherol, were positively associated with asthma and asthma-associated intestinal metabolites. CONCLUSION:Integrative analyses revealed significant interrelationships between the intestinal metabolome and the intestinal microbiome, plasma metabolome, and diet in association with childhood asthma. These findings require replication in future studies.

Project description:BackgroundInfants with bronchiolitis are at high risk for developing childhood asthma. While genome-wide association studies suggest common genetic susceptibilities between these conditions, the mechanisms underlying the link remain unclear.ObjectiveThrough integrated genetics-metabolomics analysis in this high-risk population, we sought to identify genetically driven metabolites associated with asthma development and genetic loci associated with both these metabolites and asthma susceptibility.MethodsIn a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we profiled the nasopharyngeal metabolome and genotyped the whole genome at hospitalization. We identified asthma-related metabolites from 283 measured compounds and conducted metabolite quantitative trait loci (mtQTL) analyses. We further examined the mtQTL associations by testing shared genetic loci for metabolites and asthma using colocalization analysis and the concordance between the loci and known asthma-susceptibility genes.ResultsIn 744 infants hospitalized with bronchiolitis, 28 metabolites (e.g., docosapentaenoate [DPA], 1,2-dioleoyl-sn-glycero-3-phosphoglycerol, sphingomyelin) were associated with asthma risk. A total of 349 loci were associated with these metabolites-161 for non-Hispanic white, 120 for non-Hispanic black, and 68 for Hispanics. Of these, there was evidence for 30 shared loci between 16 metabolites and asthma risk (colocalization posterior probability ≥0.5). The significant SNPs within loci were aligned with known asthma-susceptibility genes (e.g., ADORA1, MUC16).ConclusionThe integrated genetics-metabolomics analysis identified genetically driven metabolites during infancy that are associated with asthma development and genetic loci associated with both these metabolites and asthma susceptibility. Identifying these metabolites and genetic loci should advance research into the functional mechanisms of the infant bronchiolitis-childhood asthma link.

Dataset Information

Mechanistic indicators of childhood asthma (MICA) study: piloting an integrative design for evaluating environmental health.

Publications

Mechanistic indicators of childhood asthma (MICA) study: piloting an integrative design for evaluating environmental health.

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