Omega-6 fatty acids and the risk of cardiovascular disease: insights from a systematic review and meta-analysis of randomized controlled trials and a Mendelian randomization study

Introduction: Omega-6 polyunsaturated fatty acids (PUFAs) represent almost 15% of the total energy intake in Western countries. Their effects on the cardiovascular (CV) risk factors are still controversial. Thus, we performed a systematic review and meta-analysis of randomized control trials (RCTs) as well as a Mendelian randomization (MR) analysis to evaluate the links and possible causality between supplementation or serum levels of omega-6 PUFA, CV disease (CVD) and cardiometabolic risk factors. Material and methods: Selected databases were searched until September 2019 to identify prospective studies investigating the effects of omega-6 PUFA supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. The inverse variance weighted (IVW) method, weighted median-based method, MR-Egger and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied for MR. Results: The pooled estimate risk ratio (RR) of omega-6 PUFA supplementation was 0.94 for any CVD event (95% CI: 0.77–1.15, I² = 66.2%), 1.06 for CVD death (95% CI: 0.73–1.55, I² = 66.2%), 0.84 for coronary heart disease (CHD) events (95% CI: 0.61–1.16, I² = 79.4%), 0.87 for myocardial infarction (MI) (95% CI: 0.74–1.01, I² = 2.3%) and 1.36 for stroke (95% CI: 0.45–4.07, I² = 55.3%). In contrast, MR showed that individuals with higher serum omega-6 acid – adrenic acid (AA) levels had a greater risk for CHD events (IVW β = 0.526), MI (IVW β = 0.606) and large artery stroke (IVW β = 1.694), as well as increased levels of fasting blood glucose (FBG) (IVW β = 0.417), low-density lipoprotein cholesterol (LDL-C) (IVW β = 0.806), high-density lipoprotein cholesterol (HDL-C) (IVW β = 0.820), and lower levels of triglycerides (TG) (IVW β = –1.064) and total cholesterol (TC) (IVW β = –1.064). Conclusions: Omega-6 PUFA supplementation did not affect the risk for CVD morbidity and mortality. Additionally, based on MR analysis we found that higher AA levels might even significantly increase the risk of CHD, MI and large artery stroke, as well as the levels of FBG and LDL-C, whereas they were negatively associated with TC and TG. Since a considerable chance of heterogeneity was observed for some of the results, further research is needed to elucidate the effects of omega-6 PUFAs on cardiometabolic outcomes.