质子抑制剂的使用和胃肠道疾病的风险:孟德尔对omics和药理途径的随机化研究
Weixiong Zhu1, Chuanlei Fan2, Hongyu Wang3
1The Second Clinical Medical College, Lanzhou University, Gansu, China.
概括
质子抑制剂 (PPI) 与胃肠道疾病有关,但机制尚不清楚. 这项研究揭示了像CYP2D6这样的基因具有双重作用,可能解释癌症风险和胰腺炎的保护作用.
科学领域:
- 药物基因组学 药物基因组学
- 胃肠病学 胃肠病学
- 癌症研究 癌症研究
背景情况:
- 流行病学研究表明,质子抑制剂 (PPI) 与各种胃肠道疾病之间存在关联,但基本的生物机制在很大程度上仍未知.
- 了解影响药物代谢和运输的遗传因素对于阐明直接蛋白质标之外的药物效应至关重要.
研究的目的:
- 通过检查参与PPI标,代谢和运输的基因,系统地调查PPI相关的胃肠道疾病的遗传基础.
- 确定特定的基因和途径,调解PPI的双重作用,可能有助于治疗效益和致癌性等不良影响.
主要方法:
- 使用大规模的多祖先队列 (英国生物银行/FinnGen) 进行双样本孟德尔随机化分析.
- 局部化,SMR分析,疾病/解剖学分层,基于人类蛋白质图谱 (HPA) 的组织表达概况和单细胞测序.
- 分析证实了PPI使用与胃肠道疾病之间的关联.
主要成果:
- 鉴定出CYP2D6是一种高度性基因,在肝癌和胰腺癌中表现出剂量依赖的致癌作用,但对急性和慢性胰腺炎有保护作用.
- ABCB1和SLC22A1在整个胃肠道疾病中表现出广泛的风险调节.
- 观察到组织特异性基因效应,CYP2D6 (肝脏) 和CYP2C19 (结肠直肠) 在致癌与癌前状态中的作用相反. 在瘤细胞中丰富了AHR,这表明它在PPI诱导的胃肠道致癌性中发挥了作用.
- 分析证实了PPI使用与胃肠道癌症风险增加之间存在显著联系.
结论:
- 该研究阐明了PPI的组织特异性药理学,确定了具有双重治疗和致癌潜力的遗传标,这有助于解释观察到的流行病学不一致性.
- 研究结果强调了药物基因组因素在PPI相关的胃肠道疾病中的复杂作用,需要对良性疾病进行进一步的研究.
- 已识别的基因和通路为PPI治疗和胃肠道疾病管理中的个性化医疗方法提供了基础.
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