Genetic variation in immune signaling genes differentially expressed in asthmatic lung tissues.
BACKGROUND
Eight genes in the immune signaling pathway shown to be differentially expressed in asthmatic lung biopsy specimens in a previous microarray experiment were selected as candidate genes for asthma susceptibility.


OBJECTIVE
We sought to perform an association study with these genes and asthma-related phenotypes in 3 independent Canadian familial asthma collections and 1 Australian asthma case-control study.


METHODS
Tagging single nucleotide polymorphisms were selected by using the HapMap public database (r(2) > 0.8; minor allele frequency >0.10) and genotyped with the Illumina platform. Family-based association and trend tests for asthma, atopy, airway hyperresponsiveness, and allergic asthma phenotypes were done in each sample, correcting for multiple testing.


RESULTS
Uncorrected associations with polymorphisms within 7 genes were detected with 1 or more of the phenotypes in 1 or more of the 4 populations (.001 <P < .05). After correction, the 15-lipoxygenase (15-LO) associations with airway hyperresponsiveness and allergic asthma remained significant in 2 Canadian samples (corrected P = .022 and .049, respectively), and the association of the CD14 antigen with asthma remained significant in 1 Canadian sample (corrected P = .042). In both cases a protective effect of the minor alleles was observed.


CONCLUSIONS
Expression profiling studies are a useful way to identify candidate genes for asthma because this approach has led to the first report of an association with 15-LO in 2 independent populations. Because 15-LO is involved in anti-inflammatory processes, further functional and clinical investigation of the role of this biologic pathway in asthma is warranted.
Tremblay
Karine
K
Hôpital Laval, Université Laval, Quebec, Canada.
Daley
Denise
D
Chamberland
Annie
A
Lemire
Mathieu
M
Montpetit
Alexandre
A
Laviolette
Michel
M
Musk
Arthur W
AW
James
Alan L
AL
Chan-Yeung
Moira
M
Becker
Allan
A
Kozyrskyj
Anita L
AL
Sandford
Andrew J
AJ
Hudson
Thomas J
TJ
Paré
Peter D
PD
Laprise
Catherine
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D002648:Child; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D018950:Lipopolysaccharide Receptors; D001093:Arachidonate 15-Lipoxygenase