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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: Kim BS, etal., Pharmacogenet Genomics. 2010 Dec;20(12):748-58. doi: 10.1097/FPC.0b013e3283402155.
Pubmed: (View Article at PubMed) PMID:20921925
DOI: Full-text: DOI:10.1097/FPC.0b013e3283402155

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 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.

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CRRD Object Information
CRRD ID: 11528633
Created: 2016-08-17
Species: All species
Last Modified: 2016-08-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.