M. Sanak et al., Enhanced expression of the leukotriene C-4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma, AM J RESP C, 23(3), 2000, pp. 290-296
Citations number
37
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Aspirin-intolerant asthma (AIA), a distinct clinical syndrome affecting abo
ut 10% of adult asthmatics, appears to be unusually dependent on cysteine l
eukotriene (cys-LT) overproduction by pulmonary eosinophils, The gene codin
g for leukotriene (LT) C-4 synthase (LTC4S), the enzyme controlling cys-LT
biosynthesis, exists as two common alleles distinguished by an A to C trans
version at a site 444 nucleotides upstream of the translation start. We tes
ted the hypothesis that this single nucleotide polymorphism (SNP) affects b
inding of transcription factors and influences the transcription rate, pred
isposing to AIA, Gel shift assay studies revealed that the C-444 allele, co
nferring an activator protein-2 binding sequence, is an additional target f
or a transcription factor of histone H4 consensus. Introduction of the H4TF
-2 decoy oligonucleotide into LTC4S-positive, differentiated HL-60 cells de
creased accumulation of LTC4 to 68%. Transfection of COS-7 with promoter co
nstruct increased expression of beta-galactosidase reporter for the C-444 v
ariant. The C-444 allelic frequency was significantly higher in AIA patient
s (n = 76) as compared with matched aspirin-tolerant asthmatics (n = 110) a
nd healthy controls (n = 75), Patients with AIA had also upregulated LTC4S
messenger RNA expression in peripheral blood eosinophils, An inhaled provoc
ation test with lysine-aspirin led to an increase in urinary output of LTE4
, which reached statistical significance only in carriers of the C-444 alle
le, Our results suggest that a transcription factor, present in dividing an
d bone marrow resident progenitors of eosinophils, triggers LTC4S transcrip
tion in carriers of a common C-444 allele due to binding with the histone H
4 promoter element of the gene. Genetic predisposition to cys-LT pathway up
regulation, a hallmark of AlA can be related to overactive expression of th
e LTC4S C-444 allele.