Vegetable intake and cardiovascular risk: genetic evidence from Mendelian randomization

Background Observational studies have demonstrated inverse associations between vegetable intake and cardiovascular diseases. However, the results are prone to residual confounding. The separate effects of cooked and raw vegetable intake remain unclear. This study aims to investigate the association between cooked and raw vegetable intake with cardiovascular outcomes using Mendelian randomization (MR). Methods We identified 15 and 28 genetic variants associated statistically and biologically with cooked and raw vegetable intake, which were used as instrumental variables to estimate the associations with coronary heart disease (CHD), stroke, heart failure (HF) and atrial fibrillation (AF). In one-sample analysis using individual participant data from UK Biobank, we adopted two stage least square approach. In two-sample analysis, we used summary level statistics from genome-wide association analyses. The independent effects of cooked and raw vegetable intake were examined with multivariable MR analysis. The one-sample and two-sample estimates were combined via meta-analysis. Bonferroni correction was applied for multiple comparison. Results In the meta-analysis of 1.2 million participants on average, we found null evidence for associations between cooked and raw vegetable intake with CHD, HF, or AF. Raw vegetable intake was nominally associated with stroke (odds ratio [95% confidence interval] 0.82 [0.69 – 0.98] per 1 serving increase daily, p = 0.03), but this association did not pass corrected significance level. Conclusions Cooked and raw vegetable intake was not associated with CHD, AF or HF. Raw vegetable intake is likely to reduce risk of stroke, but warrants more research. Solely increasing vegetable intake may have limited protection, if any, on cardiovascular health. This calls for more rigorous assessment on health burden associated with low vegetable consumption. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors