Association of urokinase-type plasminogen activator with asthma and atopy.
BACKGROUND
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.


OBJECTIVE
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).


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.
Bégin
Philippe
P
University of Montreal Community Genomic Medicine Centre, Chicoutimi University Hospital, Saguenay, Quebec, Canada.
Tremblay
Karine
K
Daley
Denise
D
Lemire
Mathieu
M
Claveau
Sébastien
S
Salesse
Charleen
C
Kacel
Sabine
S
Montpetit
Alexandre
A
Becker
Allan
A
Chan-Yeung
Moira
M
Kozyrskyj
Anita L
AL
Hudson
Thomas J
TJ
Laprise
Catherine
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001249:Asthma / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011379:Prognosis; D011792:Quebec / Q000453:epidemiology; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000235:genetics*
D004247:DNA; D014568:Urokinase-Type Plasminogen Activator