DataSheet1_Association between angiotensin-converting enzyme inhibitor-induced cough and the risk of lung cancer: a Mendelian randomization study.DOCX

Background: Observational studies and meta-analyses have demonstrated a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer. However, the findings remain controversial; furthermore, the relationship between ACEI-induced cough and lung cancer development remains unknown. We used Mendelian randomization (MR) to verify the association between ACEI use, ACEI-induced cough, and the risk of lung cancer.Methods: We performed a two-sample MR analysis to determine the unconfounded relationships between ACE inhibition, which mimics the effects of ACEIs, and genetic proxies for ACEI-induced cough and lung cancer. Single nucleotide polymorphisms that imitate ACE receptors and ACEI-induced cough were collected and integrated into a meta-analysis of existing genome-wide association studies for various lung cancers. The relationship was quantified using inverse variance weighting, weighted median, and MR-Egger methods.Results: A statistically significant association was observed between ACE inhibition and the risk of small cell lung cancer for Europeans (excluding rs118121655/rs80311894). Associations were identified between ACEI-induced cough and the risk of lung cancer for Europeans, although not for Asians, and between ACEI-induced cough and lung adenocarcinoma (excluding rs360206).Conclusion: Our findings reveal a relationship between ACE inhibition and lung cancer development, as well as a significant association between ACEI-induced cough and a higher risk of lung cancer for Europeans. Patients with hypertension who experience dry cough as a side effect of ACEI use should consider switching to an alternative antihypertensive treatment.

背景：观察性研究和系统综述已证实，使用血管紧张素转换酶抑制剂（ACEIs）与肺癌之间存在正相关关系。然而，这些发现仍存在争议；此外，ACEI诱导的咳嗽与肺癌发生发展之间的关系尚不明确。本研究采用孟德尔随机化（MR）方法验证ACEI使用、ACEI诱导的咳嗽与肺癌风险之间的关联。方法：我们进行了双样本MR分析，以确定模拟ACEIs效果的ACE抑制与ACEI诱导的咳嗽和肺癌遗传标记之间的未混杂关系。收集并整合了模拟ACE受体的单核苷酸多态性和ACEI诱导的咳嗽相关基因座，并将这些基因座纳入对多种肺癌的全基因组关联研究进行荟萃分析。采用逆方差加权、加权中位数和MR-Egger方法对关联关系进行量化。结果：在欧洲人群中观察到ACE抑制与小细胞肺癌风险之间存在显著关联（排除rs118121655/rs80311894）。在欧洲人群中，ACEI诱导的咳嗽与肺癌风险之间存在关联，但在亚洲人群中则不存在，且ACEI诱导的咳嗽与肺腺癌之间存在关联（排除rs360206）。结论：我们的研究揭示了ACE抑制与肺癌发生发展之间的关联，以及ACEI诱导的咳嗽与欧洲人群肺癌高风险之间的显著关联。对于使用ACEIs出现干咳作为副作用的高血压患者，应考虑更换为其他抗高血压治疗。