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

Daisy C. P. Crick; Sarah L. Halligan; George Davey Smith; Golam M. Khandaker; Hannah J. Jones

doi:10.1093/ije/dyaf065

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

Daisy C. P. Crick
, Sarah L. Halligan
, George Davey Smith
, Golam M. Khandaker
, Hannah J. Jones

Department of Psychology

University of Bristol
MRC Integrative Epidemiology Unit
NIHR Bristol Biomedical Research Centre
Avon and Wiltshire Mental Health Partnership NHS Trust

Research output: Contribution to journal › Article › peer-review

14 Citations (SciVal)

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.

Original language	English
Article number	dyaf065
Journal	International Journal of Epidemiology
Volume	54
Issue number	4
DOIs	https://doi.org/10.1093/ije/dyaf065
Publication status	Published - 1 Aug 2025

Data Availability Statement

Data needed to evaluate the conclusions presented in this paper are provided in the manuscript and/or the Supplementary Material. Additionally, ALSPAC data can be requested from the ALSPAC executive committee and reasonable requests from bona fide researchers. GWAS data is publicly available by using the OpenGWAS website (https://gwas.mrcieu.ac.uk). Part of this research was conducted by using data from UKB project ID: 81499 and project: 30418, a major biomedical database, and can be provided by UKB (http://www.ukbiobank.ac.uk/).

Funding

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 D.C. 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 the Wellcome Trust and the Medical Research Council (MRC) (core) (grant ref.: 76467/Z/05/Z), MRC (grant ref.: MR/L022206/1), and the 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 MRC/UKRI. G.D.S., G.M.K., and H.J. work within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the UK Medical Research Council (MC_UU_00032/1; and MC_UU_00032/6. S.L.H. is funded by the ESRC (grant ES/V002643/1) and MRC (MR/T002816/1). G.M.K. also acknowledges funding support from the Wellcome Trust (grant no.: 201486/Z/16/Z and 201486/B/16/Z), the UK MRC (grant no.: MC_UU_00032/06, MR/W014416/1; MR/S037675/1; MR/Z50354X/1; and MR/Z503745/1), and the UK National Institute of Health Research Bristol Biomedical Research Centre (grant no.: NIHR 203315). H.J. 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.

Funders	Funder number
National Institute for Health and Care Research
University Hospitals Bristol NHS Foundation Trust
University of Bristol
UK Research & Innovation
Economic and Social Research Council	201486/Z/16/Z, MR/T002816/1, 201486/B/16/Z, ES/V002643/1
Medical Research Council	MC_UU_00032/6, MC_UU_00032/1
Mauritius Research Council	MR/W014416/1, MR/S037675/1, MR/Z503745/1, MC_UU_00032/06, MR/Z50354X/1
The Wellcome Trust	8426812/Z/07/Z, 76467/Z/05/Z, MR/N0137941/, MR/L022206/1
The Wellcome Trust	217065/Z/19/Z
NIHR Bristol Biomedical Research Centre	NIHR 203315

Keywords

ALSPAC
CRP
ELOVL2
FADS
GlycA
IL-6
Mendelian randomization
biomarkers
inflammation
polyunsaturated fatty acids

ASJC Scopus subject areas

Epidemiology

Access to Document

10.1093/ije/dyaf065Licence: CC BY

Cite this

@article{e856336d680243feb2f03bec60b0f55e,

title = "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.",

keywords = "ALSPAC, CRP, ELOVL2, FADS, GlycA, IL-6, Mendelian randomization, biomarkers, inflammation, polyunsaturated fatty acids",

author = "Crick, \{Daisy C. P.\} and Halligan, \{Sarah L.\} and Smith, \{George Davey\} and Khandaker, \{Golam M.\} and Jones, \{Hannah J.\}",

year = "2025",

month = aug,

day = "1",

doi = "10.1093/ije/dyaf065",

language = "English",

volume = "54",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - The Relationship between Polyunsaturated Fatty Acids and Inflammation

T2 - Evidence from cohort and Mendelian randomization analyses

AU - Crick, Daisy C. P.

AU - Halligan, Sarah L.

AU - Smith, George Davey

AU - Khandaker, Golam M.

AU - Jones, Hannah J.

PY - 2025/8/1

Y1 - 2025/8/1

N2 - 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.

AB - 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.

KW - ALSPAC

KW - CRP

KW - ELOVL2

KW - FADS

KW - GlycA

KW - IL-6

KW - Mendelian randomization

KW - biomarkers

KW - inflammation

KW - polyunsaturated fatty acids

UR - https://www.scopus.com/pages/publications/105009155728

U2 - 10.1093/ije/dyaf065

DO - 10.1093/ije/dyaf065

M3 - Article

SN - 0300-5771

VL - 54

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 4

M1 - dyaf065

ER -

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

Abstract

Data Availability Statement

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Keywords

ASJC Scopus subject areas

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Caregiver influences on child psychological adjustment following trauma; a longitudinal study of a high adversity population

Psychological and physical heath impacts of childhood trauma: A longitudinal study based on the Drakenstein Child Health Study

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

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

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Caregiver influences on child psychological adjustment following trauma; a longitudinal study of a high adversity population

Psychological and physical heath impacts of childhood trauma: A longitudinal study based on the Drakenstein Child Health Study

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