The Relationship between Polyunsaturated Fatty Acids and Inflammation: Evidence from cohort and Mendelian randomization analyses

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(ALSPAC; N=2802) and UK Biobank (N=12,401)) using multivariable analyses. We investigated causality using two-sample Mendelian Randomization (MR). In addition to the inverse-variance weighted (IVW) method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR (MVMR) to investigate causal effects of n-3 andn-6 on inflammation, accounting for the low-density lipoprotein (LDL)-cholesterol, triglycerides, mono-unsaturated 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% 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 andGlycA remained in the MVMR analysis, after accounting for LDL-cholesterol, triglycerides, mono-unsaturated FAs and saturated FAs.

Conclusions:
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 mechanisms underlying the effects of PUFAs on specific immune biomarkers