中国汉族人群中COX-2基因多态性与偏头痛发病风险的相关性研究

发布时间：2018-05-30 06:28

本文选题：偏头痛 + 环氧化酶　；参考：《南京医科大学》2017年博士论文

【摘要】：背景:偏头痛是临床常见的原发性头痛,其特点为反复发作性,多为中重度头痛,一般持续4-72小时,常伴有恶心、呕吐、畏光、畏声。在中国大陆地区发病率达9.3%。环氧化酶(cyclooxygenase,COX)又称前列腺素合成酶,是花生四烯酸在各种刺激作用下转变为前列腺素的关键酶。COX-2在炎症因子诱导下表达,促进前列腺素合成参与炎性疼痛。临床研究结果提示偏头痛组COX-2的表达量显著高于对照组,且选择性COX-2抑制剂与非选择性COX抑制剂治疗偏头痛急性发作无显著差异。所以说,COX-2在偏头痛病理生理过程中起着重要的作用。人类COX-2基因位于染色体1q25.2-q25.3上,由位于第10个外显子长度约8.3 KB的片段构成。COX-2基因的功能性单核苷酸多态性(single-nucleotide polymorphisms,SNPs)被广泛研究,其中包括启动子区的-765 GC(rs20417),编码区的-1759 GA(Gly587Arg,rs3218625)以及 3'UTR区的-8473 CT(rs5275)。这3个SNPs与COX-2的表达水平和转录活性相关。有研究报道COX-2单核苷酸多态性与多种COX-2参与发病机制的疾病相关,包括支气管哮喘、冠状动脉疾病、脑梗死,卒中亚型等等。但是目前涉及-765 GC/-1759 GA/-8473 CT突变和偏头痛发病风险,特别是在中国汉族人群中的研究,却鲜有报道。目的:研究中国汉族人群中COX-2-765 GC/-1759 GA/-8473 CT基因多态性和偏头痛发病风险的关系。方法:本课题设计了一项基于医院的病例对照研究,共包含110例偏头痛患者,以及108例年龄和性别相匹配的非偏头痛对照,采用连接酶检测反应(LDR-PCR)测序分型技术的方法来鉴别COX-2-765 GC、-1759 GA和-8473 CT单核苷酸多态性的基因型。结果:对照组人群中三种多态性的基因型和等位基因频率分布符合Hardy-Weinberg 平衡(P值分别为 0.884,0.215,0.689)。COX-2-1759GA 的基因型和等位基因的分布在病例组和对照组之间存在显著差异(P值分别为0.038和0.040)。相比于携带A/G基因型的个体,携带基因型G/G的个体显著地增加了偏头痛的发病风险(OR =8.720,95%CI= 1.072-70.960,P = 0.038);对照组携带COX-2 1759A等位基因的频率显著高于病例组,所以与1759G等位基因相比,COX-2 1759A等位基因降低了偏头痛的发病风险(OR=0.119,95%CI=0.015-0.957,P=0.040)。然而我们没有发现-765GC 和-8473TC 多态性与偏头痛发病风险之间的关系。结论:本研究结果提示在中国汉族人群中COX-2 1759A等位基因可能是偏头痛的一个独立的保护因素。
[Abstract]:Background: migraine is a common clinical primary headache, characterized by recurrent attacks, mostly moderate and severe headache, usually lasting 4-72 hours, often accompanied by nausea, vomiting, photophobia, fear of sound. The incidence rate in mainland China is 9.3%. Cyclooxygenase, also known as prostaglandin synthase, is the key enzyme of arachidonic acid to change to prostaglandin under various stimuli. COX-2 is induced by inflammatory factors and promotes prostaglandin synthesis to participate in inflammatory pain. The clinical results showed that the expression of COX-2 in migraine group was significantly higher than that in control group, and there was no significant difference between selective COX-2 inhibitor and non-selective COX inhibitor in the treatment of migraine acute attack. Therefore, COX-2 plays an important role in the pathophysiological process of migraine. Human COX-2 gene is located on chromosome 1q25.2-q25.3. The functional single nucleotide polymorphisms of COX-2 gene, composed of a fragment of about 8.3KB in exon 10, have been extensively studied. These include -765 GCU rs20417 in the promoter region, -1759 GAGly587Arg rs3218625 in the coding region, and -8473 CTS5275 in the 3'UTR region. These three SNPs were related to the expression level and transcription activity of COX-2. COX-2 single nucleotide polymorphisms have been reported to be associated with a variety of diseases involved in the pathogenesis of COX-2, including bronchial asthma, coronary artery disease, cerebral infarction, stroke subtype and so on. However, there are few reports of-765 GC/-1759 GA/-8473 CT mutation and migraine risk, especially in Chinese Han population. Objective: to study the association between COX-2-765 GC/-1759 GA/-8473 CT gene polymorphism and migraine risk in Chinese Han population. Methods: a hospital-based case-control study was designed, including 110 migraine patients and 108 age-matched non-migraine controls. The genotypes of single nucleotide polymorphisms (SNP) of COX-2-765 GCn-1759GA and -8473CT were identified by ligase detection of LDR-PCR sequencing technique. Results: the genotypic and allele frequencies of the three polymorphisms in the control group were in accordance with the Hardy-Weinberg equilibrium P value of 0.884A 0.2150.689% .COX-2-1759GA. There were significant differences in genotype and allele distribution between the case group and the control group (P = 0.038 and P = 0.040, respectively). Compared with the individuals carrying the A / G genotype, the individuals with the genotype G / G significantly increased the risk of migraine. The frequency of allele COX-2 1759A in the control group was significantly higher than that in the case group, and the risk of migraine was significantly higher than that in the control group (OR = 8.720 / 95 CI = 1.072-70.960A P = 0.038). So compared with 1759G allele, COX-2 1759A allele reduced the risk of migraine. However, we did not find any association between the-765GC and-8473TC polymorphisms and the risk of migraine. Conclusion: the results suggest that COX-2 1759A allele may be an independent protective factor for migraine in Chinese Han population.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R747.2

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