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An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma.

ABSTRACT: BACKGROUND:Single omic analyses have provided some insight into the basis of lung function in children with asthma, but the underlying biologic pathways are still poorly understood. METHODS:Weighted gene coexpression network analysis (WGCNA) was used to identify modules of coregulated gene transcripts and metabolites in blood among 325 children with asthma from the Genetic Epidemiology of Asthma in Costa Rica study. The biology of modules associated with lung function as measured by FEV1, the FEV1/FVC ratio, bronchodilator response, and airway responsiveness to methacholine was explored. Significantly correlated gene-metabolite module pairs were then identified, and their constituent features were analyzed for biologic pathway enrichments. RESULTS:WGCNA clustered 25,060 gene probes and 8,185 metabolite features into eight gene modules and eight metabolite modules, where four and six, respectively, were associated with lung function (P ? .05). The gene modules were enriched for immune, mitotic, and metabolic processes and asthma-associated microRNA targets. The metabolite modules were enriched for lipid and amino acid metabolism. Integration of correlated gene-metabolite modules expanded the single omic findings, linking the FEV1/FVC ratio with ORMDL3 and dysregulated lipid metabolism. This finding was replicated in an independent population. CONCLUSIONS:The results of this hypothesis-generating study suggest a mechanistic basis for multiple asthma genes, including ORMDL3, and a role for lipid metabolism. They demonstrate that integrating multiple omic technologies may provide a more informative picture of asthmatic lung function biology than single omic analyses.

SUBMITTER: Kelly RS

PROVIDER: S-EPMC6689076 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma.

Kelly Rachel S RS Chawes Bo L BL Blighe Kevin K Virkud Yamini V YV Croteau-Chonka Damien C DC McGeachie Michael J MJ Clish Clary B CB Bullock Kevin K Celedón Juan C JC Weiss Scott T ST Lasky-Su Jessica A JA

Chest 20180613 2

<h4>Background</h4>Single omic analyses have provided some insight into the basis of lung function in children with asthma, but the underlying biologic pathways are still poorly understood.<h4>Methods</h4>Weighted gene coexpression network analysis (WGCNA) was used to identify modules of coregulated gene transcripts and metabolites in blood among 325 children with asthma from the Genetic Epidemiology of Asthma in Costa Rica study. The biology of modules associated with lung function as measured ...[more]

PMID: 29908154

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Project description:IntroductionDNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos.ResultsWe conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10-7 in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10-8) showed significant association with pre-bronchodilator Tiffeneau-Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10-7), cg16405908 (MRGPRE, p = 2.05 × 10-8), and cg07428101 (MUC2, p = 5.02 × 10-9) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau-Pinelli index (p = 1.13 × 10-8). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau-Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations.ConclusionsWe replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.

Project description:Changes in dietary patterns may partly explain the epidemic of asthma in industrialized countries. The objective of this study was to examine the relationship between dietary patterns and lung function and asthma exacerbations in Puerto Rican children. This is a case-control study of 678 Puerto Rican children (ages 6-14 years) in San Juan (Puerto Rico). All participants completed a respiratory health questionnaire and a 75-item food frequency questionnaire. Food items were aggregated into 7 groups: fruits, vegetables, grains, protein, dairy, fats, and sweets. Logistic regression was used to evaluate consumption frequency of each group and asthma. Based on the results, a dietary score was created [range from -2 (unhealthy diet: high consumption of dairy and sweets, low consumption of vegetables and grains) to 2 (healthy diet: high consumption of vegetables and grains and low consumption of dairy and sweet)]. Multivariable linear or logistic regression was used to assess the relationship between dietary score and lung function or asthma exacerbations. After adjustment for covariates, a healthier diet (each 1-point increment in dietary score) was associated with significantly higher %predicted forced expiratory volume in the first second (FEV1) and %predicted forced vital capacity (FVC) in control subjects. Dietary pattern alone was not associated with asthma exacerbations, but children with an unhealthy diet and vitamin D insufficiency (plasma 25(OH)D <30?ng/mL) had higher odds of ?1 severe asthma exacerbation [odds ratio (OR)?=?3.4, 95% confidence interval (CI)?=?1.5-7.5] or ?1 hospitalization due to asthma (OR?=?3.9, 95% CI?=?1.6-9.8, OR?=?3.4, 95% CI?=?1.5-7.5) than children who ate a healthy diet and were vitamin D sufficient. A healthy diet, with frequent consumption of vegetables and grains and low consumption of dairy products and sweets, was associated with higher lung function (as measured by FEV1 and FVC). Vitamin D insufficiency, together with an unhealthy diet, may have detrimental effects on asthma exacerbations in children.

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An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma.

Publications

An Integrative Transcriptomic and Metabolomic Study of Lung Function in Children With Asthma.

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