Department of Clinical Biochemistry, University Hospital of Salamanca, Spain.
Allergy. 2011 Dec;66(12):1553-62. doi: 10.1111/j.1398-9995.2011.02685.x. Epub 2011 Aug 24.
Asthma affects more than 300 million individuals in the world. Several studies have demonstrated the importance of the genetic component. The aim of this study is to develop a holistic approach, including genetic, epigenetic, and expression analysis to study the Prostaglandin D2 receptor gene (PTGDR) in asthmatic patients.
In this study, 637 Caucasian individuals were included. Genetic variants were characterized by sequencing, and haplotype and diplotype combinations were established. Electrophoretic mobility shift assays (EMSAs) were performed with different promoter variants. An epigenetic analysis of PTGDR was for the first time developed by MassArray assays, and gene expression was determined by real-time polymerase chain reaction.
The -197T > C (Fisher's P = 0.028) and -613C > T (Fisher's P < 0.001) polymorphisms were found to be significantly associated with allergic asthma and allergy to pollen and mites, respectively. In addition, several haplotype and diplotype combinations were associated with different allergy and asthma phenotypes. The presence of the -613C > T SNP determined variations in the EMSAs. Moreover, consistent differences in the methylation and expression patterns were observed between asthmatic patients and controls determining a 2.34-fold increase of PTGDR gene expression in asthmatic patients.
Genetic combinations described have functional implications in the PTGDR promoter activity by changing the transcription factors affinity that will help characterize different risk groups. The differences observed in the transcription factors affinity and in the methylation pattern bring insight into different transcription regulation in these patients. To the best of our knowledge, this is the first work in which the implication of genetic and epigenetic factors of PTGDR has been characterized pointing to putative therapeutic targets.
哮喘影响着全球超过 3 亿人。多项研究已经证实了遗传因素的重要性。本研究旨在采用综合方法，包括遗传、表观遗传和表达分析，来研究哮喘患者的前列腺素 D2 受体基因（PTGDR）。
本研究纳入了 637 名白种人个体。通过测序对遗传变异进行了特征描述，并建立了单倍型和二倍型组合。采用不同启动子变异进行电泳迁移率变动分析（EMSA）。首次通过 MassArray 分析对 PTGDR 的表观遗传进行了分析，并通过实时聚合酶链反应测定了基因表达。
-197T>C（Fisher's P = 0.028）和-613C>T（Fisher's P < 0.001）多态性与过敏性哮喘和对花粉和螨的过敏分别显著相关。此外，几种单倍型和二倍型组合与不同的过敏和哮喘表型相关。-613C>T SNP 的存在决定了 EMSA 的变化。此外，哮喘患者和对照组之间观察到的甲基化和表达模式存在一致差异，导致哮喘患者的 PTGDR 基因表达增加 2.34 倍。
所描述的遗传组合通过改变转录因子亲和力对 PTGDR 启动子活性具有功能意义，这将有助于确定不同的风险群体。在转录因子亲和力和甲基化模式方面观察到的差异为这些患者的不同转录调控提供了深入了解。据我们所知，这是首次对 PTGDR 的遗传和表观遗传因素的意义进行了特征描述，指出了潜在的治疗靶点。
