Published ahead of print on March 15, 2007, doi:10.1164/rccm.200607-1012OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200607-1012OC
Association of Urokinase-type Plasminogen Activator with Asthma and Atopy1 University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec, Canada; 2 Department of Medicine, University of Montreal, Montreal, Quebec, Canada; 3 Department of Medicine, Université Laval, Laval, Quebec, Canada; 4 James Hogg iCAPTURE Centre, University of British Columbia, Vancouver, British Columbia, Canada; 5 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; 6 Department of Fundamental Sciences, Université du Québec à Chicoutimi, Saguenay, Quebec, 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 Centre for Health Policy, Winnipeg, Manitoba, Canada; and 9 Ontario Institute for Cancer Research, Toronto, Ontario, Canada Correspondence and requests for reprints should be addressed to Catherine Laprise, Ph.D., Université du Québec à Chicoutimi, 555 Boulevard de l'Université, Chicoutimi, PQ, Canada G7H 2B1. E-mail: catherine_laprise{at}uqac.ca Rationale: Urokinase plasminogen activator (uPA) interacts with its receptor on inflammatory and migrating cells to regulate extracellular matrix degradation, cell adhesion, and inflammatory cell activation. It is necessary for the development of an appropriate immune response and is involved in tissue remodeling. The PLAU gene codes for this enzyme, and is located on 10q24. This region has demonstrated evidence for linkage in a genome scan for asthma in a sample from northeastern Quebec. Here, we hypothesized that uPA may function as a regulator of asthma susceptibility. Objectives: To test for association between asthma and genetic variants of PLAU. Methods: We sequenced PLAU and tested for genetic association between identified variants and asthma-related traits in a French-Canadian familial collection (231 families, 1,139 subjects). Additional association studies were performed in two other family-based Canadian cohorts (Canadian Asthma Primary Prevention Study [CAPPS], 238 trios; and Study of Asthma Genes and the Environment [SAGE], 237 trios). Measurements and Main Results: In the original sample, under the dominant model, the common alleles, rs2227564C (P141) and rs2227566T, were associated with asthma (p = 0.011 and 0.045, respectively) and with airway hyperresponsiveness (AHR) (p = 0.026 and 0.038, respectively). Analysis of the linkage disequilibrium pattern also revealed association of the common haplotype for asthma, atopy, and AHR (p = 0.031, 0.043, and 0.006, respectively). Whereas no significant association was detected for PLAU single-nucleotide polymorphisms in the CAPPS cohort, association was observed in the SAGE cohort between the rs4065C allele and atopy under additive (p = 0.005) and dominant (p = 0.0001) genetic models. Conclusions: This suggests a role for the uPA pathway in the pathogenesis of the disease.
Key Words: airway hyperresponsiveness • association study • asthma • atopy • haplotypes • urokinase-type plasminogen activator gene
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