Enhanced expression of the leukotriene C4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma

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) C-4 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 C-444 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 beta-galactosidase reporter for the C-444 variant. The C-444 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 C-444 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 C-444 allele due to binding with the histone H4 promoter element of the gene. Genetic predisposition to cys-LT pathway upregulation, a hallmark of AlA can be related to overactive expression of the LTC4S C-444 allele.