Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

Abstract

A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, -1708G→A, 21C→T, 270G→A, 1728G→A), ALOX5-activating protein (ALOX5AP, 218A→G), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, -162C→G, 10T→G, R228H, V511A), LTC4S (-444A→C), and CYSLTR1 (927T→C). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups (P>0.05). However, the frequency of the ALOX5-ht1 [G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability (P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54-17.9, and in the normal controls (P=0.03, OR=4.5, 95%CI=1.1-18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1 [G-C-G-A] in AIA development is suggested.

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

“…However, we could not find any significant associations of this new polymorphism or their haplotypes with AIA patients. Although we did not conduct a functional study of this polymorphism, our findings combined with previous observations (Choi et al 2004) suggest that the two promoter polymorphisms in the LTC4S gene, as well as their haplotypes, do not contribute to the pathogenesis of AIA development in a Korean population.…”

“…In contrast, no significant associations were detected in American (Van Sambeek et al 2000), Japanese (Kawagishi et al 2002), Australian (Kedda et al 2004), or Spanish (Isidoro-García et al 2005 populations. We also did not find an association between LTC4S -444A>C and AIA in a Korean population (Choi et al 2004). In this regard, the genetic pathogenesis of AIA might not be explained with a single nucleotide polymorphism (SNP) of LTC4S -444A>C despite the confirmed association in a Polish population.…”

“…This was the first association analysis of LTC4S -1702G>A in AIA patients to date. Our previous analysis of the association of leukot- riene-related gene polymorphisms (ALOX5, ALOX5AP, COX2, LTC4S, and CYSLTR1) with AIA in a Korean population found no significant associations between each SNP of those genes, including LTC4S -444A>C, and the phenotype of AIA, but the findings did suggest a significant association with a haplotype of ALOX5 (Choi et al 2004). Therefore, haplotype analysis rather than a single SNP can provide important information concerning the contribution of a gene to a specific disease.…”

Genetic association analysis of TAP1 and TAP2 polymorphisms with aspirin exacerbated respiratory disease and its FEV1 decline

“…2,4 Overproduction of CysLTs and deficiency of prostaglandin E 2 in bronchial fibroblasts by COX inhibition have been proposed to have crucial roles in AERD development. 4,15 However, along with conflicting results for the associations between polymorphisms of genes in leukotriene and COX pathways [16][17][18] genes on other pathways including bronchial hyperresponsiveness by MHC or structural genes have provided new insights for AERD pathogenesis. 5,19 Therefore, although further replications and functional evaluations are required, our findings on the associations of TAP2 with AERD-related symptoms, particularly with FEV1 decline by aspirin provocation, might provide evidences for the role of the gene in respiratory deficiencies.…”

“…Recent studies have reported associations of the genetic variations in many genes on the arachidonate, immune response and inflammation pathways, such as leukotriene C4 synthase (LTC4S), 26,27 arachidonate 5-lipoxygenase (ALOX5) 16 and MHC class II, DP beta 1 (HLA-DPB1), 25 with aspirin hypersensitivity in asthmatics. However, conflicting results of the associations between polymorphisms of the genes and AERD have been reported, suggesting that underlying mechanisms of AERD pathogenesis may be more complicated than previously thought.…”