Am. J. Respir. Cell Mol. Biol., Volume 23, Number 3, September, 2000 290-296

Enhanced Expression of the Leukotriene C₄ Synthase Due to Overactive Transcription of an Allelic Variant Associated with Aspirin-Intolerant Asthma

Marek Sanak, Magorzata Pierzchalska, Stanisawa Bazan-Socha, and Andrzej Szczeklik

Department of Medicine, Jagiellonian University Medical School, Cracow, Poland

Aspirin-intolerant asthma (AIA), a distinct clinical syndrome affecting about 10% of adult asthmatics, appears to be unusually dependent on cysteine leukotriene (cys-LT) overproduction by pulmonary eosinophils. The gene coding for leukotriene (LT) C₄ synthase (LTC₄S), the enzyme controlling cys-LT biosynthesis, exists as two common alleles distinguished by an A to C transversion at a site 444 nucleotides upstream of the translation start. We tested the hypothesis that this single nucleotide polymorphism (SNP) affects binding of transcription factors and influences the transcription rate, predisposing to AIA. Gel shift assay studies revealed that the ₄₄₄C allele, conferring an activator protein-2 binding sequence, is an additional target for a transcription factor of histone H4 consensus. Introduction of the H4TF-2 decoy oligonucleotide into LTC₄S-positive, differentiated HL-60 cells decreased accumulation of LTC₄ to 68%. Transfection of COS-7 with promoter construct increased expression of -galactosidase reporter for the ₄₄₄C variant. The ₄₄₄C allelic frequency was significantly higher in AIA patients (n = 76) as compared with matched aspirin-tolerant asthmatics (n = 110) and healthy controls (n = 75). Patients with AIA had also upregulated LTC₄S messenger RNA expression in peripheral blood eosinophils. An inhaled provocation test with lysine-aspirin led to an increase in urinary output of LTE₄, which reached statistical significance only in carriers of the ₄₄₄C allele. Our results suggest that a transcription factor, present in dividing and bone marrow resident progenitors of eosinophils, triggers LTC₄S transcription in carriers of a common ₄₄₄C allele due to binding with the histone H4 promoter element of the gene. Genetic predisposition to cys-LT pathway upregulation, a hallmark of AIA, can be related to overactive expression of the LTC₄S ₄₄₄C allele.

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