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Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study
BMC Medicine ( IF 9.3 ) Pub Date : 2021-07-30 , DOI: 10.1186/s12916-021-02041-1
Yuanqing Fu 1, 2, 3 , Fengzhe Xu 1, 2 , Longda Jiang 4 , Zelei Miao 1, 2 , Xinxiu Liang 1, 2 , Jian Yang 1, 2, 3 , Susanna C Larsson 5, 6 , Ju-Sheng Zheng 1, 2, 3
Affiliation  

Circulating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe. We used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes. The MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99). These findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

中文翻译:

循环维生素 C 浓度和癌症风险:孟德尔随机研究

在观察性研究中,循环中的维生素 C 浓度与几种癌症有关,但对这种关联的因果方向知之甚少。本研究旨在探讨循环维生素 C 与欧洲五种最常见癌症风险之间的潜在因果关系。我们在对 52,018 名欧洲人进行的大型维生素 C 全基因组关联研究 (GWAS) 荟萃分析中使用了与血浆维生素 C 相关的遗传变异的汇总数据,以及与肺癌、乳腺癌、前列腺癌、结肠癌和直肠癌的相应关联来自 GWAS 财团,包括多达 870,984 名欧洲血统的参与者。我们使用逆方差加权方法作为主要方法进行了双样本双向孟德尔随机化 (MR) 分析,同时使用了 6 种其他方法(例如,MR-Egger、基于加权中位数和基于模式的方法)作为敏感性分析来检测和调整多效性。我们还对前瞻性队列研究和随机对照试验进行了荟萃分析,以检验维生素 C 摄入量与癌症结局的关系。MR 分析显示没有证据表明循环维生素 C 浓度与任何检查的癌症之间存在因果关系。尽管在英国生物库中,遗传预测的循环维生素 C 浓度每增加一个标准差的优势比 (OR) 为 1.34(95% 置信区间为 1.14 至 1.57),但该关联无法在乳腺癌协会联盟中复制OR 为 1.05(0.94 至 1.17)。吸烟开始,作为我们反向 MR 分析的阳性对照,与循环维生素C浓度呈负相关。然而,没有强有力的证据表明任何检查的癌症与循环维生素 C 之间存在因果关系。使用 6 种不同分析方法的敏感性分析产生了相似的结果。此外,我们的 MR 结果与探索膳食或补充维生素 C 摄入量与癌症风险的前瞻性关联的荟萃分析的无效结果一致,除了较高的膳食维生素 C 摄入量而非维生素 C 补充剂与较低的风险相关肺癌(风险比:0.84,95% 置信区间 0.71 至 0.99)。这些发现没有提供证据支持生理水平的循环维生素 C 对欧洲人群中五种最常见癌症的风险有很大影响,
更新日期:2021-07-30
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