title: Gene-metabolite expression in blood can discriminate allergen-induced isolated early from dual asthmatic responses.
abstract: Some asthmatic individuals undergoing allergen inhalation challenge develop an isolated early response whereas others develop a dual response (early plus late response). In the present study we have used transcriptomics (microarrays) and metabolomics (mass spectrometry) of peripheral blood to identify molecular patterns that can discriminate allergen-induced isolated early from dual asthmatic responses. Peripheral blood was obtained prior to (pre-) and 2 hours post allergen inhalation challenge from 33 study participants. In an initial cohort of 14 participants, complete blood counts indicated significant differences in neutrophil and lymphocyte counts at pre-challenge between early and dual responders. At post-challenge, significant genes (ALOX15, FADS2 and LPCAT2) and metabolites (lysolipids) were enriched in lipid metabolism pathways. Enzymes encoding for these genes are involved in membrane biogenesis and metabolism of fatty acids into pro-inflammatory and anti-inflammatory mediators. Correlation analysis indicated a strong negative correlation between ALOX15, FADS2, and IL5RA expression with 2-arachidonoylglycerophosphocholine levels in dual responders. However, measuring arachidonic acid and docosahexaenoic acid levels in a validation cohort of 19 participants indicated that the free form of DHA (nmoles/µg of protein) was significantly (p = 0.03) different between early and dual responders after allergen challenge. Collectively these results may suggest an imbalance in lipid metabolism which dictates pro- (anti-) inflammatory and pro-resolving mechanisms. Future studies with larger sample sizes may reveal novel mechanisms and therapeutic targets of the late phase asthmatic response.
authors.affiliation: James Hogg Research Centre, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amrit
authors.initials: A
authors.lastname: Singh
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Sarah H Y
authors.initials: SH
authors.lastname: Kam
authors.forename: Jian
authors.initials: J
authors.lastname: Ruan
authors.forename: Gail M
authors.initials: GM
authors.lastname: Gauvreau
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Byrne
authors.forename: J Mark
authors.initials: JM
authors.lastname: FitzGerald
authors.forename: Robert
authors.initials: R
authors.lastname: Schellenberg
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: Gabriella
authors.initials: G
authors.lastname: Wojewodka
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kanagaratham
authors.forename: Juan B
authors.initials: JB
authors.lastname: De Sanctis
authors.forename: Danuta
authors.initials: D
authors.lastname: Radzioch
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics; D000328:Adult; D000485:Allergens; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D016718:Arachidonic Acid / Q000097:blood / Q000378:metabolism; D001249:Asthma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D001772:Blood Cell Count; D001985:Bronchial Provocation Tests / Q000379:methods; D015331:Cohort Studies; D003937:Diagnosis, Differential; D004281:Docosahexaenoic Acids / Q000097:blood / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008244:Lysophosphatidylcholines / Q000097:blood / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D012680:Sensitivity and Specificity; D013997:Time Factors; D055815:Young Adult
chemical_list: C503491:2-arachidonoyllysophosphatidylcholine; D000485:Allergens; D008244:Lysophosphatidylcholines; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C586147:LPCAT2 protein, human