Association of the CCR3 gene polymorphism with aspirin exacerbated respiratory disease.
BACKGROUND
Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway.


OBJECTIVE
The main objective of this study is to investigate the association between CCR3 gene polymorphisms and aspirin hypersensitivity, including AERD and AICU.


METHODS
CCR3 mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two CCR3 promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay.


RESULTS
CCR3 mRNA expression was significantly increased after aspirin provocation in AERD patients (P=0.002) but not in AICU patients. An in vitro functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (P<0.001). We found -520G and -174T specific bands on EMSA.


CONCLUSIONS
This result suggests that the CCR3 genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes.
Kim
Seung-Hyun
SH
Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea.
Yang
Eun-Mi
EM
Lee
Haet-Nim
HN
Choi
Gil-Soon
GS
Ye
Young-Min
YM
Park
Hae-Sim
HS
D000328:Adult; D001241:Aspirin / Q000009:adverse effects / Q000276:immunology*; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency / Q000235:genetics / Q000276:immunology; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D054397:Receptors, CCR3 / Q000235:genetics*; D012120:Respiration Disorders / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D014581:Urticaria / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology
C515350:CCR3 protein, human; D005819:Genetic Markers; D054397:Receptors, CCR3; D001241:Aspirin