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1 James Hogg iCAPTURE Center, 4 Occupational and Environmental Lung Disease Unit, University of British Columbia, Vancouver, British Columbia, Canada; 2 McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada; 3 Ontario Institute for Cancer Research, Toronto, Ontario, Canada; 5 Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Québec, Canada; 6 Laval University Hospital Research Center, Québec, Canada; 7 Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 8 Faculty of Pharmacy and Department of Community Health Sciences, Manitoba Center for Health Policy, Winnipeg, Manitoba Canada; 9 Sir Charles Gairdner Hospital, Perth, Western Australia; 10 Laboratory for Genetic Epidemiology, Western Australian Insititute for Medical Research, UWA Centre for Medical Research and School of Population Health, University of Western Australia, Perth, Australia; 11 Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Québec, Canada; and 12 Université de Montréal Community Genomic Medicine Center, Chicoutimi Hospital, Saguenay, Québec, Canada
Correspondence and requests for reprints should be addressed to Denise Daley, UBC James Hogg iCAPTURE Centre, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: ddaley{at}mrl.ubc.ca
Extensive research has been conducted and over a hundred genes have been associated with asthma phenotypes; many of these findings are of a tenuous nature, and fail to replicate in subsequent studies. The aim of this study was to identify by rigorous replication the most likely candidate genes for asthma and related phenotypes, based on a common-disease, common-variant hypothesis. To separate true associations from false positives, candidate genes must be examined in large, well-characterized samples by using standardized methods (genotyping, phenotyping, and analysis). We amalgamated the power and resources of four studies to conduct a genetic association study by using the same set of single-nucleotide polymorphisms (SNPs), a common genotyping platform, and harmonized phenotypes. The study design involved testing genetic variants in 92 genes, previously reported (in one or more studies) to be associated with asthma and/or related traits, in four panels that include three family-based studies and a population-based, case-control sample. We have used physician diagnosis (asthma), skin prick tests (atopy), and results of methacholine challenge (AHR) to define both affected and unaffected individuals. After correction for multiple testing at each locus, we found the following genes to be associated with asthma (IL13, IFNGR2, EDN1, and IL4R), atopy (FLG, CHIA, IL18, TBXA2R, TLR10, IL4R, IFNGR2, LTA, and VDR), airway hyperresponsiveness (TLR9, TBXA2R, VDR, and NOD2), and atopic asthma (TLR10, IFNGR2, STAT6, VDR, and C3).
FOOTNOTES
This work was supported by AllerGen, a National Centre of Excellence Network (Canada); the Canadian Institutes of Health Research (CIHR); the Institutes of Gender and Health; BC Lung Association; Génome Québec; and the Respiratory Health Network of the Fonds de la Recherche en Santé du Québec (FRSQ). The 1994 Busselton follow-up study was funded by Healthway, Western Australia. A.L.J. is a recipient of a National Health and Medical Research Council of Australia Practitioner Fellowship. Y.B. is a research scholar from the Fonds de la recherche en santé du Québec. Y.B. and D.D. were recipients of fellowship awards (CIHR) and A.K. is a recipient of a New Investigator Award (CIHR). D.D. is the recipient of a Michael Smith Foundation Career Scholar Award. D.D., C.L., and A.S. hold Canadian Research Chair appointments. This work was also supported by the National Health and Medical Research Council of Australia (303145, 458513), the Child Health Research Foundation of Western Australia, and the Asthma Foundation of Western Australia.
Conflict of Interest Statement: D.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.C.-Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.Q.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Y.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.-C.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.L.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.D.P. is the principal investigator of a project funded by GlaxoSmithKline to develop CT-based algorithms to quantitate emphysema and airway disease in COPD. With collaborators he has received 
$300,000 to develop and validate these techniques. The funds he has applied solely to the research to support programs and technicians. He is also PI of a Merck Frosst–supported research program to investigate gene expression in the lungs of patients who have COPD. He and collaborators have received $200,000 for this project. These funds have supported the technical personnel and expendables involved in the project. T.J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form July 7, 2008; accepted in final form November 17, 2008)
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