DataSheet2_Assessing the role of lipid-lowering therapy on multi-cancer prevention: A mendelian randomization study.PDF

Background: Statin use for cancer prevention has raised wide attention but the conclusions are still controversial. Whether statins use have exact causal effects on cancer prevention remains unclear.
Methods: Based on the Genome-Wide Association Studies (GWAS) datasets from the large prospective UK Biobank and other consortium databases, two-sample mendelian randomization (MR) analysis was conducted to explore the causal effects of statins use on varied site-specific cancer risks. Five MR methods were applied to investigate the causality. The stability, heterogeneity, and pleiotropy of MR results were also evaluated.
Results: The atorvastatin use could increase the risk of colorectal cancer (odd ratio (OR) = 1.041, p = 0.035 by fixed-effects inverse variance weighted (IVW) method (IVWFE), OR = 1.086, p = 0.005 by weighted median; OR = 1.101, p = 0.048 by weighted mode, respectively). According to the weighted median and weighted mode, atorvastatin could modestly decrease the risk of liver cell cancer (OR = 0.989, p = 0.049, and OR = 0.984, p = 0.004, respectively) and head and neck cancer (OR = 0.972, p = 0.020). Besides, rosuvastatin use could reduce the bile duct cancer risk by 5.2% via IVWEF method (OR = 0.948, p = 0.031). No significant causality was determined in simvastatin use and pan-cancers via the IVWFE or multiplicative random-effects IVW (IVWMRE) method if applicable (p > 0.05). There was no horizontal pleiotropy observed in the MR analysis and the leave-one-out analysis proved the stability of the results.
Conclusion: The causalities between statin use and cancer risk were only observed in colorectal cancer and bile duct cancer in the European ancestry population. Future works are warranted to provide more robust evidence for supporting statin repurposing for cancer prevention.

背景：他汀类药物（statins）用于癌症预防已受到广泛关注，但相关结论仍存在争议。他汀类药物的使用是否对癌症预防具有确切的因果效应，目前尚不明确。
方法：本研究基于大型前瞻性队列英国生物银行（UK Biobank）及其他联盟数据库的全基因组关联研究（Genome-Wide Association Studies, GWAS）数据集，开展两样本孟德尔随机化（two-sample mendelian randomization, MR）分析，以探究他汀类药物使用对不同部位特异性癌症风险的因果效应。本研究采用五种MR方法对因果关联进行检验，并对MR结果的稳定性、异质性及多效性进行评估。
结果：阿托伐他汀的使用可升高结直肠癌风险（固定效应逆方差加权法（fixed-effects inverse variance weighted, IVWFE）下比值比（odd ratio, OR）=1.041，P=0.035；加权中位数法下OR=1.086，P=0.005；加权众数法下OR=1.101，P=0.048）。基于加权中位数法与加权众数法结果，阿托伐他汀可轻度降低肝细胞癌（OR=0.989，P=0.049；OR=0.984，P=0.004）与头颈部癌（OR=0.972，P=0.020）的发病风险。此外，瑞舒伐他汀的使用可通过IVW固定效应模型（IVWEF）将胆管癌风险降低5.2%（OR=0.948，P=0.031）。采用IVW固定效应模型或乘性随机效应逆方差加权法（IVWMRE）分析时，未发现辛伐他汀使用与泛癌风险间存在显著因果关联（P>0.05）。MR分析未观察到水平多效性，留一法分析证实了研究结果的稳定性。
结论：在欧洲血统人群中，仅在结直肠癌与胆管癌中观察到他汀类药物使用与癌症风险间存在因果关联。未来仍需开展更多研究，以提供更为可靠的证据，支持他汀类药物重定位用于癌症预防。