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Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity.

Authors
Kim, BS | Park, SM | Uhm, TG | Kang, JH | Park, JS | Jang, AS | Uh, ST | Kim, MK | Choi, IS | Cho, SH | Hong, CS | Lee, YW | Lee, JY | Choi, BW | Park, HS  | Park, BL | Shin, HD | Chung, IY | Park, CS
Citation
Pharmacogenetics and genomics, 20(12). : 748-758, 2010
Journal Title
Pharmacogenetics and genomics
ISSN
1744-68721744-6880
Abstract
OBJECTIVE: Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels.



METHODS: Aspirin-intolerant (AIA, n=103) and aspirin-tolerant asthmatics (n=270) were genotyped and functional promoter assays were performed.



RESULTS: Of 15 SNPs tested, seven (-589T>C (rs2243250) in promoter, -33T>C (rs2070874) in the 5'-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P=0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T>C T and -33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and -589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins β and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors.



CONCLUSION: Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity.
DOI
10.1097/FPC.0b013e3283402155
PMID
20921925
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
Ajou Authors
박, 해심
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