Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan 250012, China.
Nutrients. 2022 Aug 8;14(15):3237. doi: 10.3390/nu14153237.
Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank-the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608-0.985, = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623-0.936, = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen-the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529-0.940, = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584-0.955, = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.
分子机制和观察性研究发现，饮食来源的抗氧化剂与消化系统癌症有关，而随机临床试验缺乏因果证据。在这项研究中，我们旨在通过孟德尔随机化（MR）研究评估这些关联的因果关系。饮食来源的循环抗氧化剂（即 α-和 γ-生育酚、抗坏血酸、视黄醇、β-胡萝卜素、番茄红素和尿酸）的单核苷酸多态性，通过绝对水平和相对代谢物浓度来评估，被用作遗传工具。消化系统癌症的汇总统计数据来自英国生物库和芬兰基因研究。在两个结果数据库中分别进行了两样本 MR 分析，然后进行了荟萃分析。采用逆方差加权 MR 作为主要分析方法。对于来自不同来源的结果，还使用了另外五种 MR 方法（似然 MR、MR-Egger、加权中位数、惩罚加权中位数和 MR-PRESSO）和复制 MR 分析作为敏感性分析。在进行多次检验校正后，遗传决定的抗氧化剂与五种消化系统癌症并无显著关联。然而，我们发现了一些有意义的证据表明，绝对抗坏血酸水平与英国生物库中的结肠癌呈负相关，抗坏血酸每增加一个单位，比值比（OR）为 0.774（95%置信区间 0.608-0.985， = 0.037），这与芬兰基因的结果一致，合并 OR 为 0.764（95%置信区间 0.623-0.936， = 0.010）。同样，较高的绝对视黄醇水平提示降低了芬兰基因中的胰腺癌风险，ln 转换后视黄醇每增加 10%单位，OR 为 0.705（95%置信区间 0.529-0.940， = 0.017），这与英国生物库的结果一致，合并 OR 为 0.747（95%置信区间，0.584-0.955， = 0.020）。敏感性分析验证了上述有意义的证据。我们的研究结果表明，除了抗氧化剂对结肠癌的保护作用和视黄醇对胰腺癌的保护作用有提示意义外，较高水平的抗氧化剂不太可能成为大多数消化系统癌症的因果保护因素。
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