The effects of omega-6 PUFAs on the CV risk factors are still controversial. Thus, we performed a systematic review and meta-analysis of RCTs as well as a Mendelian Randomization analysis to evaluate the links and possible causality between omega-6 PUFA, 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 PUFAs 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. Inverse variance weighted method (IVW), weighted median-based method, MR-Egger and MR-PRESSO were applied for MR.

The pooled estimate risk ratio (RR) of omega-6 PUFAs 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 adrenic acid (AA) levels had a greater risk for CHD events (IVW=Beta:0.526), MI (IVW=Beta:0.606) and large artery stroke (IVW=Beta:1.694), as well as increased levels of FBG (IVW=Beta:0.417), LDL-C (IVW=Beta:0.806,) HDL-C (IVW=Beta:0.820), and lower levels of triglycerides (TG) (IVW=Beta:-1.064) and total cholesterol (TC) (IVW=Beta:-1.064).

Omega-6 PUFAs supplementation did not affect the risk for CVD morbidity and mortality. Additionally, in MR analysis we showed that higher AA levels might even significantly increase with the risk of CHD, MI and large artery stroke.