Diet‐Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People

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 <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.

Adherence to oxidative balance score is inversely associated with the prevalence of stroke: results from National Health and Nutrition Examination Survey 1999–2018

“…Earlier studies have shown that the intake of certain dietary antioxidants is associated with a reduced risk of stroke ( 33 , 34 ). However, recent evidence suggests that dietary antioxidants are not associated with stroke risk and even increase the risk of certain stroke types ( 35 , 36 ). However, these studies only examined the relationship between one or specific dietary antioxidants and the risk of stroke, unlike the integrated assessment of dietary antioxidants and pro-oxidants in our study.…”

Genetically Predicted Vegetable Intake and Cardiovascular Diseases and Risk Factors: An Investigation with Mendelian Randomization

“…Luo et al investigated five antioxidants, i.e., vitamin C, vitamin E, retinol, carotene, and lycopene, in both absolute circulating levels and relative metabolite levels, and found null evidence for any associations with incident CHD [53]. Similarly, Martens et al found that the five antioxidants were not associated with stroke [54]. However, these studies focused on a single nutrient and ignored the potential additive and synergistic effects of various antioxidants, as well as those between antioxidants and minerals, fiber, and other phytochemicals, which could be a more plausible mechanism for CVD risk reduction due to increased vegetable intake [49,55].…”

Vegetable intake and metabolic risk factors: A Mendelian randomization study

“…Previous MR using serum antioxidants as exposures also showed similar results. For example, serum vitamin C was not associated with multiple cardiovascular diseases [44,47,48]; other antioxidants (vitamin E, carotene, lycopene and retinol) were not associated with risk of ischemic stroke [49] and CHD [50].…”