Volume 124, Issue 2 , Pages 222-229, August 2009
A thymic stromal lymphopoietin gene variant is associated with asthma and airway hyperresponsiveness
Background
The epithelial cell–derived protein thymic stromal lymphopoietin stimulates dendritic and mast cells to promote proallergic TH2 responses. Studies of transgenic expression of thymic stromal lymphopoietin and its receptor knockout mice have emphasized its critical role in the development of allergic inflammation. Association of genetic variation in thymic stromal lymphopoietin with IgE levels has been reported for human subjects.
Objective
The aim of this study was to evaluate the relationship between variants of thymic stromal lymphopoietin and asthma and related phenotypes.
Methods
We selected 6 single nucleotide polymorphisms in thymic stromal lymphopoietin and genotyped 5565 individuals from 4 independent asthma studies and tested for association with asthma, atopy, atopic asthma, and airway hyperresponsiveness by using a general allelic likelihood ratio test. P values were corrected for the effective number of independent single nucleotide polymorphisms and phenotypes.
Results
The A allele of rs1837253, which is 5.7 kb upstream of the transcription start site of the gene, was associated with protection from asthma, atopic asthma, and airway hyperresponsiveness, with the odds ratios and corrected P values for each being 0.79 and 0.0058; 0.75 and 0.0074; and 0.76 and 0.0094, respectively. Associations between thymic stromal lymphopoietin and asthma-related phenotypes were the most statistically significant observations in our study, which has to date examined 98 candidate genes. Full results are available online at http://genapha.icapture.ubc.ca/.
Conclusions
A genetic variant in the region of the thymic stromal lymphopoietin gene is associated with the phenotypes of asthma and airway hyperresponsiveness.
Key words: Airway hyperresponsiveness, association study, asthma genetics, atopy, polymorphisms, thymic stromal lymphopoietin
Abbreviations used: AHR, Airway hyperresponsiveness, CAPPS, Canadian Asthma Primary Prevention Study, LD, Linkage disequilibrium, OR, Odds ratio, SAGE, Study of Asthma Genes and the Environment, SLSJ, Saguenay-Lac-Saint-Jean and Québec City Familial Asthma Collection, SNP, Single nucleotide polymorphism, TSLP, Thymic stromal lymphopoietin, TSLPR, Thymic stromal lymphopoietin receptor
Supported by AllerGen, a National Centre of Excellence Network (Canada); the Canadian Institutes of Health Research; the Institutes of Gender and Health; British Columbia Lung Association; Génome Québec; and the Respiratory Health Network of the Fonds de la Recherche en Santé du Québec. The 1994 Busselton follow-up study was funded by Healthway, Australia. J.-Q.H. is the recipient of a Michael Smith Foundation for Health Research Doctoral Award and an Izaak Walton Killam Memorial Scholarship Award. D.K. is a Canada Research Chair, a recipient of a Michael Smith Foundation Scholarship and the William Thurlbeck Distinguished Research Award. A.J. is a recipient of a National Health and Medical Research Council of Australia Practitioner Fellowship. Y.B. and D.D. were recipients of fellowship awards (Canadian Institutes of Health Research), and A.L.K. is a recipient of a New Investigator Award (Canadian Institutes of Health Research). 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.
Disclosure of potential conflict of interest: D. Daley receives grant support from AllerGen and the Canadian Institutes of Health Research. T. S. Hallstrand is on the speakers' bureau for Merck and Schering-Plough, is a consultant for Merck, and receives grant support from the National Institutes of Health, the American Lung Foundation, the Firland Foundation, and Novartis. D. Knight receives grant support from Centocor and Sepracor. A. Sandford receives grant support from the British Columbia Lung Association and the Canadian Institutes of Health Research. Y. Bossé receives grant support from the Québec Institute of Cardiology, Fonds de la Recherche en Santé du Québec, the Heart and Stroke Foundation, and the Respiratory Health Network of the Fonds de la Recherche en Santé du Québec. The rest of the authors have declared that they have no conflict of interest.
PII: S0091-6749(09)00643-5
doi:10.1016/j.jaci.2009.04.018
© 2009 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 124, Issue 2 , Pages 222-229, August 2009
