Diet-Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People
Authors: Raymond Noordam
Ko Willems van Dijk
Jiao Luo
Leon G Martens
Diana van Heemst
J Wouter Jukema
Journal: Journal of the American Heart Association (2021)
Discipline: CLINICAL MEDICINE
Keywords: antioxidants; cardiovascular disease; diet; ischemic stroke; oxidative stress.
Affiliations: Department of Internal Medicine Section of Gerontology and Geriatrics Leiden University Medical Center Leiden The Netherlands., Department of Human Genetics Leiden University Medical Center Leiden The Netherlands., Department of Cardiology Leiden University Medical Center Leiden The Netherlands.

Abstract:  Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, β-carotene, and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome-wide association studies (P&lt;5×10-8). We used summary statistics for single-nucleotide polymorphisms-stroke associations from 3 European-ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance-weighted analyses and subsequently meta-analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85-1.05) for vitamin C and 1.04 (95% CI, 0.99-1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98-1.03) for retinol and 1.12 (95% CI, 0.88-1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke. 

Retracted: No

PubPeer comments:
 # **Mendelian randomization study on vitamin C and the risk of ischemic stroke may be misleading** Martens et al. concluded that their Mendelian randomization study that among several antioxidants, vitamin C was not u201ccausally associated with a lower risk of ischemic strokeu201d [1]. The Martens et al. study was based on an earlier study, which reported that u201cthe variance of plasma vitamin C explained by the 11 lead SNPs was 1.87% on averageu201d [2, p 102]. However, Martens et al did not give any consideration to the plasma vitamin C levels that 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 11 SNPs 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 meaningful. 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 Martens 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 Martens 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, such as 47.3 vs. 52.7 u03bcM, 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 ischemic stroke. However, the study by Martens et al. is not informative about whether the risk is increased with plasma levels in the 10-20 u03bcM range, compared with higher levels. **References** 1. Martens LG, Luo J, Willems van Dijk K, Jukema JW, Noordam R, van Heemst D. Diet-Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People. J Am Heart Assoc. 2021 Dec 7;10(23):e022567. https: doi.org 10.1161 jaha.121.022567 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 ,