Effect of genetic polymorphism of ALOX15 on aspirin-exacerbated respiratory disease.
BACKGROUND
Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD.


METHODS
We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (-427G/A, -272C/A, -217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay.


RESULTS
No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the -427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of -427G/A, -272C/A and -217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001).


CONCLUSIONS
These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients.
Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
Young-Sin
YS
Song
Eun-Mi
EM
Yang
Seung-Hyun
SH
Kim
Hyun Jung
HJ
Jin
Hae-Sim
HS
Park
D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D055963:Asthma, Aspirin-Induced / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D004804:Eosinophils / Q000201:enzymology / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D056910:Republic of Korea; D012130:Respiratory Hypersensitivity / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D055815:Young Adult
D017931:DNA Primers; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D001241:Aspirin