Table_4_Plasma Circulating Vitamin C Levels and Risk of Endometrial Cancer: A Bi-Directional Mendelian Randomization Analysis.XLSX

BackgroundObservational studies indicated that circulating vitamin C (VitC) levels may be correlated with the risk of endometrial cancer (EC). However, the causal effects and direction between them were still unclear.
MethodsIn this study, 11 single nucleotide polymorphisms (SNPs) robustly correlated with plasma VitC levels were extracted from the latest genome-wide association study (GWAS), containing 52,018 individuals. Genetic data of EC were obtained from the Endometrial Cancer Association Consortium (ECAC) (12,906 cases and 108,979 controls). An inverse-variance weighted method was utilized as the primary analysis of Mendelian randomization (MR), supplemented by the weighted median, MR Pleiotropy Residual Sum and Outlier test (MR-PRESSO), and MR-Egger methods. Additional sensitivity analyses excluding 3 SNPs with secondary phenotypes were conducted to rule out the possible pleiotropic effects. Potential impacts of several risk factors of EC, such as obesity, body mass index (BMI), hypertension, and diabetes on VitC levels, were assessed. We additionally evaluated the effects of VitC on LDL cholesterol levels, HDL cholesterol levels, and triglycerides levels to probe into the possible mediators in the VitC-EC pathway.
ResultsGenetically predicted higher plasma VitC levels (per 1 SD increase, approximately 20 μmol/L) were causally associated with an increased risk of EC overall [odds ratio (OR) 1.374, 95% CI 1.128–1.674, p = 0.0016], supported by complementary sensitivity analyses. In the subgroup analyses, genetically predicted higher levels of VitC were associated with a tendency of increased risks of both endometrioid (ORSD 1.324, 95% CI 0.959–1.829, p = 0.0881) and non-endometrioid histology (ORSD 1.392, 95% CI 0.873–2.220, p = 0.1647) while without statistical significance. The association remained significant after the exclusion of the three pleiotropic SNPs (ORSD 1.394, 95% CI 1.090–1.784, p = 0.0082). The confounders and mediators were unlikely to affect the VitC-EC relationship. The causal effect of EC on VitC levels was not supported (OR 1.001, 95% CI 0.998–1.004, p = 0.4468).
ConclusionsThis bi-directional MR study demonstrated a causal risk role of higher circulating VitC at physiological levels on an increased risk of EC, which was independent of confounders and mediators. Further studies are warranted to elucidate the possible mechanisms.

Background
观察性研究表明，循环维生素C（vitamin C, VitC）水平可能与子宫内膜癌（endometrial cancer, EC）的发病风险存在关联，但二者之间的因果效应及作用方向仍不明确。
Methods
本研究从纳入52018名受试者的最新全基因组关联研究（genome-wide association study, GWAS）中，提取了与血浆维生素C水平稳健相关的11个单核苷酸多态性（single nucleotide polymorphisms, SNPs）。子宫内膜癌的遗传数据来自子宫内膜癌关联联盟（Endometrial Cancer Association Consortium, ECAC），包含12906例病例与108979例对照。本研究以逆方差加权法作为孟德尔随机化（Mendelian randomization, MR）的主要分析方法，并辅以加权中位数法、MR多效性残差和离群值检验（MR Pleiotropy Residual Sum and Outlier test, MR-PRESSO）以及MR-Egger法。为排除潜在的多效性影响，本研究额外开展了敏感性分析，剔除了3个存在次要表型的SNPs。此外，本研究还评估了子宫内膜癌的若干危险因素（如肥胖、体重指数（body mass index, BMI）、高血压、糖尿病）对维生素C水平的潜在影响，并分析了维生素C对低密度脂蛋白胆固醇、高密度脂蛋白胆固醇及甘油三酯水平的效应，以探究维生素C-子宫内膜癌通路中的潜在中介因子。
Results
遗传预测的血浆维生素C水平升高（每1个标准差升高，约20μmol/L）与总体子宫内膜癌发病风险升高存在因果关联[比值比（odds ratio, OR）=1.374，95%置信区间（confidence interval, CI）=1.128~1.674，p=0.0016]，该结果得到了补充敏感性分析的支持。亚组分析显示，遗传预测的维生素C水平升高与子宫内膜样型组织学（ORSD=1.324，95%CI=0.959~1.829，p=0.0881）及非子宫内膜样型组织学（ORSD=1.392，95%CI=0.873~2.220，p=0.1647）的发病风险升高趋势均存在关联，但未达到统计学显著性。剔除3个多效性SNPs后，该关联仍具有统计学意义（ORSD=1.394，95%CI=1.090~1.784，p=0.0082）。混杂因素与中介因子未对维生素C-子宫内膜癌的关联产生明显影响。未发现子宫内膜癌对维生素C水平存在因果效应（OR=1.001，95%CI=0.998~1.004，p=0.4468）。
Conclusions
本双向孟德尔随机化研究证实，生理水平下循环维生素C水平升高可增加子宫内膜癌的发病风险，且该效应不受混杂因素与中介因子的影响。未来仍需开展进一步研究以阐明其潜在分子机制。