Circulating vitamin C and the risk of cardiovascular diseases: A Mendelian randomization study

https://doi.org/10.1016/j.numecd.2021.04.023Get rights and content

Highlights

  • The evidence for the effect of vitamin C supplementation on the risk of cardiovascular diseases is inconsistent.

  • Genetically determined vitamin C levels were not related to the risk of coronary artery disease, atrial fibrillation, heart failure, and stroke.

  • Genetically determined vitamin C levels were not related to blood lipids, blood pressure, and body composition.

Abstract

Background and aims

The impact of vitamin C supplementation on the risk of cardiovascular diseases (CVDs) remains uncertain with inconsistent evidence obtained from observational studies and randomized clinical trials (RCTs). We aimed to assess possible causal associations of vitamin C with major CVD events as well as their risk factors using Mendelian randomization (MR) design.

Methods and results

Nine genetic variants associated with vitamin C at genome-wide significance (p < 5 × 10−8) were used as instrumental variables to predict plasma vitamin C levels. The primary outcomes were coronary artery disease (Ncase = 122,733 and Ncontrol = 424,528), atrial fibrillation (Ncase = 60,620 and Ncontrol = 970,216), heart failure (Ncase = 47,309 and Ncontrol = 930,014), and ischemic stroke (Ncase = 40,585 and Ncontrol = 406,111). Several CVD risk factors were also evaluated in secondary analyses. Two-sample MR analyses were performed using the inverse variance weighted method, with several sensitivity analyses. Genetically determined higher levels of plasma vitamin C were not significantly associated with any of the four examined CVD events. Likewise, there is no convincing evidence for the associations between genetically determined vitamin C and CVD risk factors, including higher blood lipids, higher blood pressure, and abnormal body composition. Sensitivity analyses using different analytical approaches yielded consistent results. Additionally, MR assumptions did not seem to be violated.

Conclusion

This MR study does not support a causal protective role to circulate vitamin C levels on various types of CVD events. In combination with previous RCT results, our findings suggest that vitamin C supplementation to increase circulating vitamin C levels may not help in CVD prevention.

Section snippets

Background

Globally, deaths from cardiovascular disease (CVD) increased by 14.5% from 2006 to 2016, ranking the first leading cause of death [1]. Dietary factors such as high levels of fruit and vegetable intake have been reported to be related to a lower risk of CVD incidence and mortality [2,3]. Circulation levels of vitamin C are considered good biomarkers of fruit and vegetable intake for its antioxidation effects and anti-inflammatory functions [[4], [5], [6]]. Vitamin C may protect low-density

Study design

In this study, we employed a two-sample MR design (Fig. 1), in which summary statistics for exposure (i.e., plasma vitamin C levels) and outcome (i.e., CVDs and their risk factors) were derived from a different sample. There are three core assumptions for MR analysis: (1) the genetic variants must be robustly associated with the exposure of interest; (2) the genetic variants should not be related to potential confounders of the exposure-outcome association; (3) the genetic variants should only

Statistical power

With a type 1 error rate of 0.003, when the expected odds ratio (OR) was ≤0.85, our study had >99% power to detect it for coronary artery disease, >99% power for atrial fibrillation, >96% power for heart failure, and >90% power for ischemic stroke. In the analysis of the association between vitamin C and CVD risk factors, our study is also sufficiently powered to investigate very weak associations. Detailed information on a priori power calculation is presented in the Supplementary Table S4.

Vitamin C and four CVD events

As

Discussion

In the present study, we examined the causal association between genetically predicted plasma vitamin C concentration with a risk of four CVD outcomes (i.e., coronary artery disease, atrial fibrillation, heart failure, and ischemic stroke) and 11 CVD risk factors (i.e., HDL-cholesterol, LDL-cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, BMI, waist circumference, WHR, fat mass, and fat-free mass) using the two-sample MR analysis. Our principal

Conclusions

Using comprehensive two-sample MR analyses, our finding provided little evidence for linear causal associations between genetically predicted plasma vitamin C concentrations and risk of coronary artery disease, atrial fibrillation, heart failure, and ischemic stroke. Additionally, no evidence was revealed for the associations between vitamin C and CVD risk factors, including higher blood lipids, higher blood pressure, and abnormal body composition. In combination with previous RCT results, our

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgments

The authors thank all the relevant consortiums and investigators for the management and sharing of summary-level data.

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