The metabolomics of asthma control: a promising link between genetics and disease

被引：73

作者：

McGeachie, Michael J. ^{[1
,2
]}

Dahlin, Amber ^{[1
,2
]}

Qiu, Weiliang ^{[1
,2
]}

Croteau-Chonka, Damien C. ^{[1
,2
]}

Savage, Jessica ^{[1
,2
]}

Wu, Ann Chen ^{[1
,2
,3
,4
,5
]}

Wan, Emily S. ^{[1
,2
]}

Sordillo, Joanne E. ^{[1
,2
]}

Al-Garawi, Amal ^{[1
,2
]}

Martinez, Fernando D. ^{[6
,7
]}

Strunk, Robert C. ^{[8
]}

Lemanske, Robert F., Jr. ^{[9
]}

Liu, Andrew H. ^{[10
,11
]}

Raby, Benjamin A. ^{[1
,2
]}

Weiss, Scott ^{[1
,2
]}

Clish, Clary B. ^{[12
]}

Lasky-Su, Jessica A. ^{[1
,2
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA USA

[3] Childrens Hosp, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Populat Med, Boston, MA USA

[5] Harvard Pilgrim Hlth Care Inst, Boston, MA USA

[6] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA

[7] Univ Arizona, Inst BIO5, Tucson, AZ USA

[8] Washington Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Pulm Med, St Louis, MO USA

[9] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA

[10] Natl Jewish Hlth, Dept Pediat, Div Allergy & Clin Immunol, Denver, CO USA

[11] Univ Colorado, Sch Med, Denver, CO 80202 USA

[12] Broad Int, Cambridge, MA USA

来源：

IMMUNITY INFLAMMATION AND DISEASE | 2015年 / 3卷 / 03期

关键词：

Albuterol; asthma; epigenetics; genetics; metabolomics;

D O I：

10.1002/iid3.61

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Short-acting beta 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 b 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), using plasma samples from 20 individuals with 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.

引用

页码：224 / 238

页数：15

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