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Functional genetic variations of CYP2C19 promoter from patients with gastroesophageal reflux disease

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Author:: No author available

Journal Title:: World Chinese Journal of Digestology

Issue:: 24

DOI:: 10.11569/wcjd.v28.i24.1229

Key Word:: 胃食管反流病;CYP2C19启动子;基因变异;质子泵抑制剂

Abstract：背景胃食管反流病(gastroesophageal reflux disease,GERD)是一种慢性疾病,其发病率在世界范围内呈上升趋势.质子泵抑制剂(proton pump inhibitors,PPIs)作为抑酸药物,在临床上常用于治疗GERD,经肝脏中CYP2C19代谢后,血药浓度逐渐降低.先前的研究已证明CYP2C19基因多态性导致PPIs在代谢速率、半衰期和药效等方面个体差异大,影响疗效.目的筛选正常代谢型(*1/*1)的GERD患者CYP2C19基因启动子区的变异,并在细胞水平验证基因变异对启动子功能的影响,进而分析CYP2C19启动子区功能改变与GERD经PPIs治疗效果的相关性.方法收集入院治疗的散发性GERD患者全血163例,实验组患者经PPIs诊断性治疗后,症状积分降低＞50％,症状未完全消失(n = 82);对照组患者治疗后症状完全消失(n= 81);全部患者CYP2C19基因型经检测为*1/*1.利用PCR扩增并结合Sanger测序筛选入组患者CYP2C19启动子区的基因变异;将CYP2C19启动子片段(野生型/变异型)克隆至pGL3 basic载体,并转染HEK 293T细胞,通过双荧光素酶报告基因系统,检测基因变异对启动子功能的影响.结果我们在3个正常代谢型GERD患者的CYP2C19基因启动子中分别发现了3个新的杂合变异:g.94761364 T＞A,g.94762112 T＞A,g.94762514 G＞T;与野生型相比,携带g.94761364 T＞A变异的CYP2C19启动子的转录活性显著升高(P= 0.034).结论变异位点g.94761364 T＞A使得CYP2C19启动子转录活性在细胞水平升高,可能会进一步影响PPIs的代谢和血药浓度,这一发现为中国人群中GERD患者的临床用药和治疗提供了新的思路.

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