| | Genetic variation in immune signaling genes differentially expressed in asthmatic lung tissuesReceived 10 December 2007; received in revised form 14 April 2008; accepted 23 May 2008. BackgroundEight genes in the immune signaling pathway shown to be differentially expressed in asthmatic lung biopsy specimens in a previous microarray experiment were selected as candidate genes for asthma susceptibility. ObjectiveWe sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and 1 Australian asthma case-control study. MethodsTagging single nucleotide polymorphisms were selected by using the HapMap public database (r2 > 0.8; minor allele frequency >0.10) and genotyped with the Illumina platform. Family-based association and trend tests for asthma, atopy, airway hyperresponsiveness, and allergic asthma phenotypes were done in each sample, correcting for multiple testing. ResultsUncorrected associations with polymorphisms within 7 genes were detected with 1 or more of the phenotypes in 1 or more of the 4 populations (.001 < P < .05). After correction, the 15-lipoxygenase (15-LO) associations with airway hyperresponsiveness and allergic asthma remained significant in 2 Canadian samples (corrected P = .022 and .049, respectively), and the association of the CD14 antigen with asthma remained significant in 1 Canadian sample (corrected P = .042). In both cases a protective effect of the minor alleles was observed. ConclusionExpression profiling studies are a useful way to identify candidate genes for asthma because this approach has led to the first report of an association with 15-LO in 2 independent populations. Because 15-LO is involved in anti-inflammatory processes, further functional and clinical investigation of the role of this biologic pathway in asthma is warranted. Abbreviations used: AHR, Airway hyperresponsiveness, ALOX15, Arachidonate 15-lipoxygenase gene, CAPPS, Canadian Asthma Primary Prevention Study, CXCL12, Chemokine (C-X-C motif) ligand 12 (stromal cell–derived factor 1) gene, FBAT, Family-based Association Test, IL2RB, IL-2 receptor β gene, IL7R, IL-7 receptor gene, LD, Linkage disequilibrium, 15-LO, 15-Lipoxygenase, NOS2A, Nitric oxide synthase 2A gene, SAGE, Study of Asthma Genetics and Environment Cohort, SFRP1, Secreted frizzled-related protein 1 gene, 15(S)-HETE, 15(S)-hydroxyeicosatetraenoic acid, SLSJ, Saguenay–Lac-Saint-Jean, SNP, Single nucleotide polymorphism a Hôpital Laval, Université Laval, Quebec, Canada b Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Quebec City, Canada c James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, British Columbia, Canada d Ontario Institute for Cancer Research, Toronto, Ontario, Canada e McGill University and the Genome Quebec Innovation Centre, Montreal, Quebec, Canada f Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia g Western Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia h Occupational and Environmental Lung Disease Unit, University of British Columbia, Vancouver, British Columbia, Canada i Department of Pediatrics and Child Health, Manitoba Centre for Health Policy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada j Faculty of Pharmacy and the Department of Community Health Sciences, Manitoba Centre for Health Policy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada k University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec City, Canada  Reprint requests: Catherine Laprise, PhD, Université du Québec à Chicoutimi, 555 boulevard de l'Université, Saguenay, Quebec, G7H 2B1, Canada.
Supported by a grant from AllerGen NCE, Inc (http://www.allergen-nce.ca/), the Canadian Institutes of Health Research, the Respiratory Health Network of the Fonds de la recherche en santé du Québec, and the Western Australia Healthway. K.T. is an AllerGen PhD trainee and is supported by the Fondation de l'Université Laval studentship. D.D. is supported by grants from the Canadian Institutes of Health Research (CIHR), the Institutes of Gender and Health, Genetics, Population and Public Health, a CIHR STIHR IMPACT fellowship, and the Lung Association of British Columbia. A.C. is supported by the Fondation de l'Université du Québec à Chicoutimi studentship. A.L.K. is the recipient of a CIHR New Investigator award. A.S. is the chairholder of the Canada Research Chair (www.chairs.gc.ca) on genetic susceptibility to inflammatory disease. P.D.P. is a Michael Smith Foundation and Jacob Churg Scholar. T.J.H. is recipient of an Investigator Award from the CIHR and a Clinician-scientist Award in Translational Research from the Burroughs Wellcome Fund. C.L. is the chairholder of the Canada Research Chair on genetic determinants in asthma and the director of the Genetics platform of the Respiratory Health Network (RHN) of the Fonds de la recherche en santé du Québec (FRSQ). Disclosure of potential conflict of interest: D. Daley has received grant support from Allergan, the Canadian Institutes of Health Research (CIHR), and the Michael Smith Foundation for Health Research. M. Laviolette has received grant support from the CIHR, Asthmatx, AstraZeneca, GlaxoSmithKline, and Merck-Frosst. A. L. James has received grant support from Merck, Sharpe, and Dohme. A. L. Kozyrskyj has received grant support from AllerGen NCE and the CIHR. A. J. Sandford has received grant support from the Canadian CF Foundation. T. J. Hudson has received grant support from the Allergen Network, the CIHR, and the Burroughs Wellcome Fund. P. D. Paré has received grant support from Merck. The rest of the authors have declared that they have no conflict of interest. PII: S0091-6749(08)01172-X doi:10.1016/j.jaci.2008.05.049 © 2008 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. | |
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