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

Dietary polyunsaturated fatty acids (PUFAs) are thought to influence the risk of various chronic diseases by modulating systemic inflammation. Omega-3 and omega-6 FAs are thought to have anti- and pro-inflammatory roles, respectively, but it is unclear whether these associations are causal. We tested associations of PUFAs with three blood-based biomarkers of systemic inflammation, namely C-reactive protein (CRP), glycoprotein acetyls (GlycA) and interleukin 6 (IL-6), in a population cohort (n=2748) and using Mendelian randomization analysis (a genetic causal inference method). We provide consistent evidence that omega-6 PUFAs increase GlycA levels, but omega-3 FAs do not lower levels of inflammatory markers. Additionally, we found that a higher omega-6:omega-3 ratio increases levels of all three inflammatory markers; CRP (mean difference=0.17; 95% CI=0.13, 0.20), GlycA (mean difference=0.16; 95% CI=0.13, 0.20) and IL-6 (mean differene=0.19; 95% CI=0.15, 0.22) in the cohort analysis. Our findings suggest that future public health messaging should encourage reducing the consumption of omega 6 FAs and maintaining a healthy balance between omega 3 and omega 6 FAs, rather than focusing on omega-3 FA supplementation. This is because dietary omega-3 supplementation alone is unlikely to help reduce systemic inflammation or inflammation-related disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The UK Medical Research Council and Wellcome (Grant ref.: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and DC will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by Wellcome Trust and MRC (core) (Grant ref.: 76467/Z/05/Z), MRC (Grant ref.: MR/L022206/1) and Wellcome Trust (Grant ref.: 8426812/Z/07/Z). This work was supported in part by the GW4 BIOMED DTP (D.C., MR/N0137941/), awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. GDS, GMK and HJ work within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC\_UU\_00011/1). GMK acknowledges funding support from the Wellcome Trust (grant no: 201486/Z/16/Z and 201486/B/16/Z), the UK Medical Research Council (grant no: MC\_UU\_00032/06; MR/W014416/1; and MR/S037675/1), and the UK National Institute of Health Research Bristol Biomedical Research Centre (grant no: NIHR 203315). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committee and can be found here: http://www.bristol.ac.uk/alspac/researchers/research-ethics/. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data needed to evaluate the conclusions presented in this paper are provided in the manuscript and/or the supplementary material. Additionaly ALSPAC data can be requested from the ALSPAC executive committee and reasonable requests from bona fide researchers. GWAS data is publicly available using the OpenGWAS website (https://gwas.mrcieu.ac.uk)