By Michael H. Crawford, MD, Editor

SYNOPSIS: A study of single nucleotide polymorphisms (SNP) that increase blood levels of diet-derived antioxidants in three large individual subject genetic databases did not demonstrate a relationship between SNPs and coronary artery disease.

SOURCE: Luo J, le Cessie S, van Heemst D, Noordam R. Diet-derived circulating antioxidants and risk of coronary heart disease: A Mendelian randomization study. J Am Coll Cardiol 2021;77:45-54.

Oxidative stress is thought to cause endothelial damage and dysfunction, and to accelerate the development of atherosclerosis. Thus, there has been considerable interest in antioxidants derived from diet or supplements. Luo et al explored the relationship between dietary-derived circulating antioxidants and primary coronary artery disease (CAD) using Mendelian randomization (MR).

The authors retrieved the single-nucleotide polymorphisms (SNP) for five circulating diet-derived antioxidants from published genome-wide association studies (GWAS) data: vitamins E and C, retinol, beta-carotene, and lycopene. Researchers derived the associations of these SNPs with CAD from three large genetic databases: CARDIoGRAMplusC4D, UK Biobank, and FinnGen, encompassing 93,230 CAD cases out of 768,121 subjects.

A meta-analysis of these data demonstrated that genetically predicted circulating antioxidants were not causally associated with CAD risk. Odds ratios ranged from 0.93 to 1.03 for each antioxidant, and none were significant. Sensitivity analyses detected no pleiotropy, and a leave out analysis did not reveal significant changes in the data by excluding individual SNPs. The authors concluded a genetic predisposition to higher levels of dietary-derived antioxidants did not protectively affect the development of CAD. They suggested increasing blood levels of antioxidants by diet or supplements was unlikely to prevent CAD.


The central concept of the antioxidant hypothesis is that for LDL cholesterol to enter the arterial wall, it must be oxidized. Thus, preventing or mitigating this oxidation would be expected to ameliorate or eliminate atherosclerosis. However, trying to study this hypothesis is complicated because those who regularly ingest antioxidant-rich foods or take supplements usually exercise more, eat better, and take better care of themselves generally. In fact, the much-touted Mediterranean diet is rich in antioxidants. However, randomized, controlled trials of antioxidant supplements have been largely negative. Thus, this study is of interest. Other MR studies of vitamin E have been negative, but the genetic variants those authors studied also beneficially affected lipids.1,2 The Luo et al study of genetic variants that raise the blood levels of five antioxidants and does not effect lipids shows no association between these genetic variants and the development of CAD.

The circulating levels of antioxidants produced by the genetic variants that Luo et al studied approximate those achieved in antioxidant supplementation randomized trials. Of course, subjects with these genetic variants maintain these levels their entire life, not just during a randomized study period. In addition, the authors studied SNPs that increase circulating levels of antioxidants and their metabolites. In other words, the authors did not omit antioxidants that have short half-lives in the blood. Finally, they studied these genetic variants in three huge databases. Thus, small effects would be detected easier.

This probably is not the end of the story because there may be subgroups at especially high risk for CAD in whom antioxidants may be beneficial, such as diabetics with familial hypercholesterolemia. Also, it is possible that multiple antioxidants might be synergistic. I expect future MR studies will explore some of these nuances. For now, there does not seem to be any compelling reason to recommend antioxidant supplements broadly for CAD prevention. However, the Luo et al study does not negate the lipid hypothesis. Dietary interventions known to lower lipids, regardless of their effect on antioxidant blood levels, still should be recommended.


  1. Wang T, Xu L. Circulating vitamin E levels and risk of coronary artery disease and myocardial infarction: A Mendelian randomization study. Nutrients 2019;11:2153.
  2. Fan C, Huang T, Kong X. Circulating vitamin E and cardiometabolic measures: A Mendelian randomization analysis. J Clin Biochem Nutr 2019;65:160-169.