Variable expression of cysteinyl leukotriene type I receptor splice variants in asthmatic females with different promoter haplotypes

Abstract

BackgroundCysteinyl leukotrienes are potent inflammatory mediators implicated in the pathogenesis of asthma. Human cysteinyl leukotriene receptor 1 (CYSLTR1) gene contains five exons that are variably spliced. Within its promoter few polymorphisms were described. To date, there has been no evidence about the expression of different splice variants of CysLT1 in asthma and their association with CYSLTR1 promoter polymorphisms.The goal of our study was to investigate CysLT1 alternative transcripts expression in asthmatic patients with different CYSLTR1 promoter haplotypes.The study groups consisted of 44 patients with asthma, diagnosed according to GINA 2008 criteria and 18 healthy subjects. Genomic DNA and total RNA was extracted from peripheral blood mononuclear cells. Real-time PCR was performed with specific primers for transcript I [GenBank:DQ131799] and II [GenBank:DQ131800]. Fragments of the CYSLTR1 promoter were amplified by PCR and sequenced directly to identify four single nucleotide polymorphisms: C/T [SNP:rs321029], A/C [SNP:rs2637204], A/G [SNP:rs2806489] and C/T [SNP:rs7066737].ResultsThe expression of CysLT1 transcript I and II in asthma did not differ from its expression in healthy control group. However, in major alleles homozygotic CAAC/CAAC women with asthma we found significantly higher expression of transcript I as compared to heterozygous CAAC/TCGC women in that loci. CysLT1 transcript I expression tended to negative correlation with episodes of acute respiratory infection in our asthmatic population. Moreover, expression of CysLT1 transcript II in CAAC/CAAC homozygotic women with asthma was significantly lower than in CAAC/CAAC healthy control females.ConclusionsGenetic variants of CYSLTR1 promoter might be associated with gender specific expression of CysLT1 alternative transcripts in patients with asthma. CysLT1 splice variants expression might also correlate with the susceptibility to infection in asthmatic population.

EAACI position paper: Influence of dietary fatty acids on asthma, food allergy, and atopic dermatitis

“…PTGDR and LTC4S polymorphisms influence responsiveness to leukotriene receptor antagonists in Korean children with asthma . CYSLTR1 promoter polymorphisms were associated with atopy and N‐ERD in some populations and in a gender‐specific manner, while other variants of CYSLTR1 were associated with atopy, and/or asthma in some but not all studies . CYSLTR2 gene variants also showed associations with asthma, N‐ERD, and atopy, but were not associated with AD or asthma in different genetic backgrounds …”

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies

“…Taken together, many studies suggest that transcriptionally active CYSLTR1 variants influence the onset and severity of asthma associated endophenotypes such as atopy (Sokolowska et al, 2009). The significance of CYSLTR1 variants can be interpreted in the context of a large study of asthmatics born in Great Britain during 1958.…”

Evolutionary aspects of lipoxygenases and genetic diversity of human leukotriene signaling

“…The gene encoding for hCYSLTR1 is located on X chromosome and spans about 56 kbp [339,340]. Little is known about transcriptional regulation of the gene, but a 4-fold promoter polymorphism haplotype (rs321029, rs2806489, rs7066737, and rs2637204) causes a significant decrease in transcription of the CYSLTR1 gene when compared with wildtype individuals [341]. In vitro studies indicated that the polymorphism rs2806489 reduces promoter activity by factor 2 [342] but in vivo confirmation of the effect is lacking.…”