5' flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States.
BACKGROUND
Approximately 10% of patients with asthma have a distinct clinical entity in which their symptoms are exacerbated by aspirin and most other nonsteroidal anti-inflammatory agents. These individuals typically have significant basal overproduction of cysteinyl leukotrienes, and within their biosynthetic pathway, the terminal enzyme, leukotriene C(4) synthase (LTC(4)S), is significantly overexpressed. A single nucleotide polymorphism consisting of an adenine (A) to cytosine (C) transversion -444 nucleotides upstream of the ATG translation start site in the LTC(4)S gene has been associated with a relative risk of 3.89 for the aspirin-intolerant phenotype in Polish patients.


OBJECTIVE
These studies were undertaken to further investigate the functional effect of this allele in LTC(4)S gene expression and subsequently to determine whether an association between the presence of this polymorphism and aspirin-intolerant asthma existed within patients of the United States.


METHODS
Functionality of the C-444 allele was assessed by using promoter-reporter constructs and transient transfection assays in the THP-1 monocytic cell line. Genotyping was performed on 137 unaffected control subjects, 33 patients with aspirin-tolerant asthma, and 61 patients with aspirin-intolerant asthma from the United States.


RESULTS
Promoter-reporter constructs containing the C-444 allele revealed no significant upregulatory or downregulatory effects in the transcription of the LTC(4)S gene. The LTC(4)S genotype distribution was consistent with the Hardy-Weinberg equilibrium in patients with aspirin-tolerant asthma and unaffected control subjects but not in patients with aspirin-intolerant asthma; however, the distributions were not significantly different among the phenotype groups.


CONCLUSIONS
Our data demonstrate that the C-444 allele in the LTC4S gene is not statistically different among patients with the aspirin-intolerant asthmatic phenotype, patients with the aspirin-tolerant asthmatic phenotype, and unaffected control subjects in the United States. This finding, along with the lack of functionality of this polymorphism, suggest that it is not related to a specific asthma phenotype and may represent a population-stratified polymorphism within patients of eastern European descent.
Van Sambeek
R
R
Department of Medicine, Harvard Medical School, Division of Rheumatology, Brigham and Women's Hospital, Boston, Mass, USA.
Stevenson
D D
DD
Baldasaro
M
M
Lam
B K
BK
Zhao
J
J
Yoshida
S
S
Yandora
C
C
Drazen
J M
JM
Penrose
J F
JF
D000483:Alleles; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D014481:United States
D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D001241:Aspirin