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

Cited 42 time in Web of Science Cited 44 time in Scopus
Authors
Kim, Byung Soo; Park, Se-Min; Uhm, Tae Gi; Kang, Jin Hyun; Jang, An-Soo; Kim, Mi-Kyeong; Cho, Sang Heon; Lee, Yong Won; Choi, Byoung Whui; Park, Choon-Sik; Chung, Il Yup; Shin, Hyoung Doo; Park, Byung Lae; Park, Hae-Sim; Lee, Jae-Young; Hong, Cheon-Soo; Choi, Inseon S.; Uh, Soo-Taek; Park, Jong-Sook
Issue Date
2010-12
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
PHARMACOGENETICS AND GENOMICS; Vol.20 12; 748-758
Keywords
aspirin-intolerant asthmaticsinterleukin-4promoterpolymorphism
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 aspirintolerant 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 50-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(corr) = 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 beta 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. Pharmacogenetics and Genomics 20:748-758 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
ISSN
1744-6872
Language
English
URI
http://hdl.handle.net/10371/77727
DOI
https://doi.org/10.1097/FPC.0b013e3283402155
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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