Enhanced Expression of the Leukotriene C4 Synthase Due to Overactive Transcription of an Allelic Variant Associated with Aspirin-Intolerant Asthma
Year: 2000
Type: article
Study design: Observational Study
Abstract: 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 (LTC(4)S), 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 (-444)C 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 LTC(4)S-positive, differentiated HL-60 cells decreased accumulation of LTC(4) to 68%. Transfection of COS-7 with promoter construct increased expression of beta-galactosidase reporter for the (-444)C variant. The (-444)C 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 LTC(4)S messenger RNA expression in peripheral blood eosinophils. An inhaled provocation test with lysine-aspirin led to an increase in urinary output of LTE(4), which reached statistical significance only in carriers of the (-444)C allele. Our results suggest that a transcription factor, present in dividing and bone marrow resident progenitors of eosinophils, triggers LTC(4)S transcription in carriers of a common (-444)C 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 LTC(4)S (-444)C allele.
Institution: Jagiellonian University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2027490189