Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study
Authors: Yuanqing Fu
Zelei Miao
Ju-Sheng Zheng
Xinxiu Liang
Fengzhe Xu
Susanna C Larsson
Jian Yang
Longda Jiang
Journal: BMC Medicine (2021)
Discipline: CLINICAL MEDICINE
Keywords: Circulating vitamin C; Mendelian randomization analysis; Site-specific cancers.
Affiliations: Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Rd, Cloud Town, Hangzhou, 310024, China., Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden., Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Rd, Cloud Town, Hangzhou, 310024, China. .

Abstract:  Background: 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. Methods: 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. Results: 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). Conclusions: 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. 

Retracted: No

PubPeer comments:
 # **Mendelian randomization study on vitamin C and cancer may be misleading** Fu et al. concluded from their Mendelian randomization study that there was u201cno evidence of a causal association of circulating vitamin C concentration with any examined canceru201d [1]. The Fu et al. study was based on an earlier study [2], u201cwhich identified 11 plasma vitamin C-associated SNPs explaining 1.87% of the variance of plasma vitamin Cu201d [1]. However, Fu did not consider which kinds of plasma vitamin C levels their Mendelian randomization study would correspond to. From the 1.87% explanation of variance, and the data about the plasma vitamin C means and SD levels available in the earlier paper [2], we calculated that the Mendelian randomization study by Fu et al. would correspond to the comparison of two population groups of equal size with vitamin C levels of 47.3 vs. 52.7 u03bcM [3]. Such a comparison is not clinically relevant. With low dietary vitamin C intakes, plasma levels can fall below 10u2009u03bcM, whereas with high dietary intakes, plasma levels can increase to over 80u2009u03bcM, see Fig. 1C in [4]. It is important to take into account this eightfold range of plasma vitamin C levels when considering the dose-health relationship in the community, but that was not done by Fu et al. [1]. Low plasma vitamin C levels are not uncommon. Levels below 11u2009u03bcM were reported, for example, in 25% of men and 16% of women from low-income populations in the UK [5], and in 13% of a US cohort [6]. In many population groups in less developed countries, such low vitamin C levels are even more common [7]. Thus, large segments of the population have vitamin C levels that are less than one fifth of the u201clowu201d plasma vitamin C level corresponding to the Fu et al. analysis. Based on the large variation in the plasma levels of vitamin C in the population, the most relevant comparison is between low and high plasma levels, e.g., 10u201320u2009u03bcM vs. 60u2013100u2009u03bcM. If a study compares small variations within the high intake range only, the comparison is uninformative about possible effects of vitamin C in the low intake range. Vitamin C may, or may not, influence the risk of some types of cancer. However, the study by Fu et al. is not informative about whether the risk of cancer is increased with plasma vitamin C levels in the lower range of 10-20 u03bcM. **References** 1. Fu Y, Xu F, Jiang L, Miao Z, Liang X, Yang J, Larsson SC, Zheng JS. Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study. BMC Med. 2021;19(1):171. https: doi.org 10.1186 s12916-021-02041-1 http: www.ncbi.nlm.nih.gov pmc articles pmc8323227 2. Zheng JS, et al. Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations. Diabetes Care. 2021;44(1):98-106. https: doi.org 10.2337 dc20-1328 http: www.ncbi.nlm.nih.gov pmc articles pmc7783939 3. Hemilu00e4 H, Chalker E. Assessment of vitamin C effects on pneumonia and COVID-19 using Mendelian randomization: analysis may be misleading. Eur J Clin Nutr. 2022 Feb 14. https: doi.org 10.1038 s41430-022-01091-9 http: www.ncbi.nlm.nih.gov pmc articles pmc8853427 4. Levine M, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. PNAS 1996;93(8):3704-9. https: doi.org 10.1073 pnas.93.8.3704 http: www.ncbi.nlm.nih.gov pmc articles pmc39676 5. Mosdu00f8l A, Erens B, Brunner EJ. Estimated prevalence and predictors of vitamin C deficiency within UK s low-income population. J Public Health (Oxf). 2008;30(4):456-60. https: doi.org 10.1093 pubmed fdn076 6. Schleicher RL, Carroll MD, Ford ES, Lacher DA. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr. 2009;90(5):1252-63. https: doi.org 10.3945 ajcn.2008.27016 7. Rowe S, Carr AC. Global Vitamin C Status and Prevalence of Deficiency: A Cause for Concern? Nutrients. 2020;12(7):2008. https: doi.org 10.3390 nu12072008 http: www.ncbi.nlm.nih.gov pmc articles pmc7400810 ,