Published ahead of print on March 15, 2007, doi:10.1164/rccm.200607-1012OC Am. J. Respir. Crit. Care Med., Volume 175, Number 11, June 2007, 1109-1116 A more recent version of this article appeared on June 1, 2007
Submitted on July 24, 2006 Association of Urokinase-type Plasminogen Activator with Asthma and AtopyPhilippe Begin1,1 University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec, Canada; Department of Medicine, University of Montreal, Montreal, Quebec, Canada, 2 University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec, Canada; Department of Medicine, Universite Laval, Quebec, Quebec, Canada, 3 University of British Columbia, James Hogg iCapture Centre, Vancouver, British Columbia, Canada, 4 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada, 5 University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec, Canada; Department of Fundamental Sciences, Universite du Quebec a Chicoutimi, Saguenay, Quebec, Canada, 6 Faculty of Medicine, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada, 7 Faculty of Medicine, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada; Faculty of Pharmacy and Department of Community Health Sciences, Manitoba Centre for Health Policy, Winnipeg, Manitoba, Canada, 8 Ontario Institute for Cancer Research, Toronto, Ontario, Canada * To whom correspondence should be addressed. E-mail: claprise{at}saglac.qc.ca.
RATIONALE: Urokinase plasminogen activator 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 PLAU may function as a regulator of asthma susceptibility. METHOD: We sequenced PLAU and tested for genetic association between identified variants and asthma related traits in a French-Canadian cohort (231 families, 1139 subjects). Additional association studies were carried out in two other family-based Canadian cohorts (CAPPS, 238 trios, and SAGE, 237 trios). RESULTS: In the original cohort, under dominant model, the common alleles rs2227564C (P141) and rs2227566T were associated with asthma (p = 0.011; p = 0.045) and with airway hyperresponsiveness (AHR) (p = 0.026; p = 0.038). Analysis of the linkage disequilibrium pattern also revealed association of the common haplotype for asthma, atopy and AHR (p = 0.031; p = 0.043; p = 0.006). Whereas no significant association was detected for single PLAU SNPs in the CAPPS cohort, association was observed in the SAGE cohort between the rs4065C allele and protection from atopy in additive (p = 0.005) and dominant (p = 0.0001) genetic models. CONCLUSION: This suggests a role for the urokinase plasminogen activation pathway in the pathogenesis of the disease. Key words: asthma, airway hyperresponsiveness, atopy, haplotype, Urokinase-type plasminogen activator (PLAU gene)
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