TY - JOUR
T1 - The metabolomics of asthma control
T2 - A promising link between genetics and disease
AU - McGeachie, Michael J.
AU - Dahlin, Amber
AU - Qiu, Weiliang
AU - Croteau-Chonka, Damien C.
AU - Savage, Jessica
AU - Wu, Ann Chen
AU - Wan, Emily S.
AU - Sordillo, Joanne E.
AU - Al-Garawi, Amal
AU - Martinez, Fernando D.
AU - Strunk, Robert C.
AU - Lemanske, Robert F.
AU - Liu, Andrew H.
AU - Raby, Benjamin A.
AU - Weiss, Scott
AU - Clish, Clary B.
AU - Lasky-Su, Jessica A.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/9
Y1 - 2015/9
N2 - Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative ‘‘omics’’ approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), usingplasma samples from 20individualswith asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites—monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.
AB - Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative ‘‘omics’’ approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), usingplasma samples from 20individualswith asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites—monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.
KW - Albuterol
KW - Asthma
KW - Epigenetics
KW - Genetics
KW - Metabolomics
UR - http://www.scopus.com/inward/record.url?scp=85011570000&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011570000&partnerID=8YFLogxK
U2 - 10.1002/iid3.61
DO - 10.1002/iid3.61
M3 - Article
AN - SCOPUS:85011570000
SN - 2050-4527
VL - 3
SP - 224
EP - 238
JO - Immunity, inflammation and disease
JF - Immunity, inflammation and disease
IS - 3
ER -