A recent population-based cohort study found an association between proton pump inhibitor (PPI) prescription and risk of inflammatory bowel disease which they attributed to protopathic bias (ie, the drug was prescribed in response to initial disease symptoms) rather than a causal effect of PPI usage.1 In a following Mendelian randomisation (MR) study, An et al selected genetic variants associated with PPI usage to proxy the effect of exposure to PPI treatment.2 However, interpretation of these results remains unclear due to concerns about the strategy for instrumental variable selection identifies genetic variants that mimic the treatment under investigation. The fundamental concern is the difference between genetic predictors of the drug target effect versus genetic predictors of taking the drug. The major concern is that the association between genetic variants and drug use likely stems from their potential to exacerbate the underlying condition targeted by the drug or to intensify associated symptoms. For example, the variant rs11591147 in the PCSK9 gene region is associated with an increased use of cholesterol-lowering medication but also higher levels of cholesterol.3 We also found contradictory results between genetically predicted medication usage behaviour and genetically predicted drug target effect …

中文翻译：

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孟德尔随机分析中对生物效应与质子泵抑制剂摄取的工具变量选择的担忧

最近的一项基于人群的队列研究发现，质子泵抑制剂（PPI）处方与炎症性肠病风险之间存在关联，他们将其归因于原病偏倚（即，该药物是针对初始疾病症状而开出的），而不是以下因素的因果影响： PPI 使用。1 在随后的孟德尔随机化 (MR) 研究中，An 等人选择了与 PPI 使用相关的遗传变异来代表暴露于 PPI 治疗的影响。2 然而，由于对治疗策略的担忧，这些结果的解释仍不清楚。工具变量选择识别模仿正在研究的治疗的遗传变异。最根本的问题是药物靶效应的遗传预测因子与服用药物的遗传预测因子之间的差异。主要的担忧是，基因变异与药物使用之间的关联可能源于它们可能加剧药物所针对的潜在病症或加剧相关症状。例如，PCSK9 基因区域中的变异 rs11591147 与降胆固醇药物的使用增加有关，但也与胆固醇水平升高有关。3我们还发现基因预测的药物使用行为和基因预测的药物靶点效应之间存在矛盾的结果……