Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma.
BACKGROUND
Aspirin-intolerant asthma (AIA) is a subtype of asthma induced by non-steroidal anti-inflammatory drugs and characterized by an aggressive mucosal inflammation of the lower airway (asthma) and the upper airways (rhinitis and nasal polyp). The lower airway lesion and the nasal polyp in AIA are postulated to have common pathogenic features involving aspirin sensitivity that would be reflected in the gene expression profile of AIA polyps.


OBJECTIVE
This study was conducted to clarify the pathogenesis of AIA using gene expression analysis in nasal polyps, and identify genetic susceptibilities underlying AIA in a case-control association study.


METHODS
Global gene expression of nasal polyps from nine AIA patients was examined using microarray technology in comparison with nasal polyps from five eosinophilic sinusitis (ES) patients, a related disease lacking aspirin sensitivity. Based on the AIA-specific gene expression profile of nasal polyp, candidate genes for AIA susceptibility were selected and screened by a case-control design of 219 AIA patients, 374 non-asthmatic control (CTR), and 282 aspirin-tolerant asthmatic (ATA) subjects.


RESULTS
One hundred and forty-three elevated and three decreased genes were identified as AIA-specific genes that were enriched in immune response according to Gene Ontology analysis. In addition, a k-means-based algorithm was applied to cluster the genes, and a subclass characteristic of AIA comprising 18 genes that were also enriched in immune response was identified. By examining the allelic associations of single nucleotide polymorphisms (SNPs) of AIA candidate genes relevant to an immune response with AIA, two SNPs, one each of INDO and IL1R2, showed significant associations with AIA (P=0.011 and 0.026 after Bonferroni's correction, respectively, in AIA vs. CTR). In AIA-ATA association analysis, modest associations of the two SNPs with AIA were observed.


CONCLUSIONS
These results indicate that INDO and IL1R2, which were identified from gene expression analyses of nasal polyps in AIA, represent susceptibility genes for AIA.
Sekigawa
T
T
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan.
Tajima
A
A
Hasegawa
T
T
Hasegawa
Y
Y
Inoue
H
H
Sano
Y
Y
Matsune
S
S
Kurono
Y
Y
Inoue
I
I
D000328:Adult; D000368:Aged; D000465:Algorithms; D001185:Artificial Intelligence; D001241:Aspirin / Q000009:adverse effects* / Q000276:immunology; D001249:Asthma / Q000139:chemically induced* / Q000235:genetics*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism; D009298:Nasal Polyps / Q000235:genetics* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
C508592:IL1R2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053574:Receptors, Interleukin-1 Type II; D001241:Aspirin