The relationship between polyunsaturated fatty acids and inflammation: evidence from cohort and Mendelian randomization analyses

Abstract Background Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are thought to have anti- and pro-inflammatory roles, respectively, and influence the risk of various chronic diseases. However, it is unclear whether these associations are causal. Methods We examined the associations of dietary polyunsaturated FAs with biomarkers of systemic inflammation: C-reactive protein (CRP), glycoprotein acetyls (GlycA), and interleukin 6 (IL-6) in two cohort datasets—Avon Longitudinal Study of Parents and Children (N = 2802) and UK Biobank (N = 12 401)—by using multivariable analyses. We investigated causality by using two-sample Mendelian randomization (MR). In addition to the inverse-variance weighted (IVW) method, we used sensitivity analyses to strengthen the causal inference. We conducted multivariable MR (MVMR) to investigate the causal effects of n-3 and n-6 on inflammation, accounting for the low-density lipoprotein (LDL) cholesterol, triglycerides, monounsaturated FAs, and saturated FAs. Results Cohort analyses show a positive association between the n-6:n-3 ratio and each biomarker. Total n-3 and n-6 PUFAs were associated with higher GlycA levels [mean difference = 0.33; 95% confidence interval (CI) = 0.29, 0.36, and 0.52; 95% CI = 0.48, 0.55, respectively]. The MR results suggest that total n-3 FAs cause higher circulating CRP (IVW = 0.09; 95% CI = 0.03, 0.16) and GlycA levels (0.12; 95% CI = 0.04, 0.21). The positive association between n-3 FAs and GlycA remained in the MVMR analysis after accounting for LDL cholesterol, triglycerides, monounsaturated FAs, and saturated FAs. Conclusion We find no convincing evidence of a simple pro- and anti-inflammatory dichotomy regarding the function of n-6 and n-3 PUFAs. Further research is needed to better understand the mechanisms underlying the effects of PUFAs on specific immune biomarkers.