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
观察性研究与荟萃分析均已证实，血管紧张素转换酶抑制剂（angiotensin-converting enzyme inhibitors, ACEIs）的使用与肺癌存在正相关关联。但该研究结论尚存争议；此外，血管紧张素转换酶抑制剂诱发的咳嗽与肺癌发生之间的关联机制仍不明晰。本研究采用孟德尔随机化（Mendelian randomization, MR）方法，验证血管紧张素转换酶抑制剂使用、其诱发咳嗽与肺癌发病风险之间的关联。

### 方法
本研究实施两样本孟德尔随机化分析，旨在明确模拟血管紧张素转换酶抑制剂作用的血管紧张素转换酶抑制效应，与血管紧张素转换酶抑制剂诱发咳嗽的遗传替代标志物以及肺癌之间的无混杂关联。研究收集了模拟血管紧张素转换酶受体及血管紧张素转换酶抑制剂诱发咳嗽的单核苷酸多态性（single nucleotide polymorphisms）位点，并将其整合至针对各类肺癌的现有全基因组关联研究荟萃分析中。关联效应采用逆方差加权、加权中位数以及MR-Egger三种方法进行量化分析。

### 结果
针对欧洲人群（排除rs118121655/rs80311894位点），研究发现血管紧张素转换酶抑制效应与小细胞肺癌发病风险存在统计学显著关联。欧洲人群中可见血管紧张素转换酶抑制剂诱发咳嗽与肺癌发病风险存在关联，而亚洲人群中未发现该关联；此外，血管紧张素转换酶抑制剂诱发咳嗽与肺腺癌（排除rs360206位点）亦存在关联。

### 结论
本研究结果证实血管紧张素转换酶抑制效应与肺癌发生存在关联，同时发现欧洲人群中血管紧张素转换酶抑制剂诱发咳嗽与肺癌发病风险升高存在显著关联。因使用血管紧张素转换酶抑制剂出现干咳不良反应的高血压患者，可考虑更换为其他降压治疗方案。