Diet-derived antioxidants do not decrease the risk of ischemic stroke: a Mendelian Randomization Study in over 1 million participants

medRxiv

Abstract

Abstract Background Intake, either as dietary components or as supplements, and blood concentrations of vitamin E, C, lycopene and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot not 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 (MR). Methods For each circulating antioxidant (vitamin E, C, lycopene, β-carotene and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, genetic instrumental variables were generated from earlier genome wide association studies. We used summary statistics for SNP-stroke associations from three European-ancestry cohorts (cases/controls): MEGASTROKE (67,162/454,450), UK Biobank (2,404/368,771) and FinnGen study (8,046/164,286). MR analyses were performed on each exposure per outcome cohort using inverse-variance weighted analyses, and subsequently meta-analyzed. Results In a combined sample of 1,065,119 individuals (77,612 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 (95% CI) ranged between 0.94 (95% CI: 0.85 to 1.05) for vitamin C and 1.04 (95% CI: 0.99 to 1.08) for lycopene. For metabolites, odds ratios ranged between 1.01 (95% CI: 0.98 to 1.03) for retinol and 1.12 (95% CI: 0.88 to 1.42) for vitamin E. Conclusion 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.

Authors 6

1. Leon G. Martens corresponding Aachen Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

2. Jiao Min Luo Aachen Department of Clinical Epidemiology Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

3. Ko Willems van Dijk Aachen Department of Human Genetics Department of Internal Medicine Division of Endocrinology, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

   Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands

   Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands

4. J. Wouter Jukema Aachen Department of Cardiology, Leiden University Medical Center

   Leiden University Medical Center · Netherlands Heart Institute

   Affiliation as printed

   Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

   Netherlands Heart Institute, Utrecht, the Netherlands

5. Raymond Noordam Aachen Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

6. Diana van Heemst Aachen Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands