PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline.
BACKGROUND
Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes.


OBJECTIVE
Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region.


METHODS
A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1, plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma.


RESULTS
The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5' region, intron 3, and 3' region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5' region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5' region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5' region and 3' region SNPs were found to be determinants of FEV1 decline in subjects with asthma.


CONCLUSIONS
This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma.
Barton
Sheila J
SJ
Division of Infection, Inflammation and Immunity, School of Medicine, University of Southampton, Southampton, United Kingdom.
Koppelman
Gerard H
GH
Vonk
Judith M
JM
Browning
Claudia A
CA
Nolte
Ilja M
IM
Stewart
Ceri E
CE
Bainbridge
Sue
S
Mutch
Stacey
S
Rose-Zerilli
Matthew J
MJ
Postma
Dirkje S
DS
Maniatis
Nikolas
N
Henry
Amanda P
AP
Hall
Ian P
IP
Holgate
Stephen T
ST
Tighe
Patrick
P
Holloway
John W
JW
Sayers
Ian
I
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008168:Lung / Q000503:physiopathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood* / Q000235:genetics*; D055815:Young Adult
C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator