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Integrative analysis of the intestinal metabolome of childhood asthma.

ABSTRACT: 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.

SUBMITTER: Lee-Sarwar KA

PROVIDER: S-EPMC6688902 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Integrative analysis of the intestinal metabolome of childhood asthma.

Lee-Sarwar Kathleen A KA Kelly Rachel S RS Lasky-Su Jessica J Zeiger Robert S RS O'Connor George T GT Sandel Megan T MT Bacharier Leonard B LB Beigelman Avraham A Laranjo Nancy N Gold Diane R DR Weiss Scott T ST Litonjua Augusto A AA

The Journal of allergy and clinical immunology 20190323 2

<h4>Background</h4>The intestinal metabolome reflects the biological consequences of diverse exposures and might provide insight into asthma pathophysiology.<h4>Objective</h4>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.<h4>Methods</h4>Metabolomic profiling was performed by using mass spectrometry on fecal samples collected from 361 three-year-old subjects. Adjust ...[more]

PMID: 30914378

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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.

Project description:BackgroundChildhood-onset asthma is highly affected by genetic components. In recent years, many genome-wide association studies (GWAS) have reported a large group of genetic variants and susceptible genes associated with asthma-related phenotypes including childhood-onset asthma. However, the regulatory mechanisms of these genetic variants for childhood-onset asthma susceptibility remain largely unknown.MethodsIn the current investigation, we conducted a two-stage designed Sherlock-based integrative genomics analysis to explore the cis- and/or trans-regulatory effects of genome-wide SNPs on gene expression as well as childhood-onset asthma risk through incorporating a large-scale GWAS data (N = 314,633) and two independent expression quantitative trait loci (eQTL) datasets (N = 1890). Furthermore, we applied various bioinformatics analyses, including MAGMA gene-based analysis, pathway enrichment analysis, drug/disease-based enrichment analysis, computer-based permutation analysis, PPI network analysis, gene co-expression analysis and differential gene expression analysis, to prioritize susceptible genes associated with childhood-onset asthma.ResultsBased on comprehensive genomics analyses, we found 31 genes with multiple eSNPs to be convincing candidates for childhood-onset asthma risk; such as, PSMB9 (cis-rs4148882 and cis-rs2071534) and TAP2 (cis-rs9267798, cis-rs4148882, cis-rs241456, and trans-10,447,456). These 31 genes were functionally interacted with each other in our PPI network analysis. Our pathway enrichment analysis showed that numerous KEGG pathways including antigen processing and presentation, type I diabetes mellitus, and asthma were significantly enriched to involve in childhood-onset asthma risk. The co-expression patterns among 31 genes were remarkably altered according to asthma status, and 25 of 31 genes (25/31 = 80.65%) showed significantly or suggestively differential expression between asthma group and control group.ConclusionsWe provide strong evidence to highlight 31 candidate genes for childhood-onset asthma risk, and offer a new insight into the genetic pathogenesis of childhood-onset asthma.

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Integrative analysis of the intestinal metabolome of childhood asthma.

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Integrative analysis of the intestinal metabolome of childhood asthma.

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