Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in autoimmune rheumatic diseases: a brief research report from a Mendelian randomization study

Abstract

Background: Currently, the association between the consumption of polyunsaturated fatty acids (PUFAs) and the susceptibility to autoimmune rheumatic diseases (ARDs) remains conflict and lacks substantial evidence in various clinical studies. To address this issue, we employed Mendelian randomization (MR) to establish causal links between six types of PUFAs and their connection to the risk of ARDs.

Methods: We retrieved summary-level data on six types of PUFAs, and five different types of ARDs from publicly accessible GWAS statistics. Causal relationships were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the reliability of our research findings, we used four complementary approaches and conducted multivariable MR analysis (MVMR). Additionally, we investigated reverse causality through a reverse MR analysis.

Results: Our results indicate that a heightened genetic predisposition for elevated levels of EPA (OR_IVW: 0.924, 95% CI: 0.666-1.283, P _IVW = 0.025) was linked to a decreased susceptibility to psoriatic arthritis (PsA). Importantly, the genetically predicted higher levels of EPA remain significantly associated with an reduced risk of PsA, even after adjusting for multiple testing using the FDR method (P _{IVW-FDR-corrected} = 0.033) and multivariable MR analysis (P _MV-IVW < 0.05), indicating that EPA may be considered as the risk-protecting PUFAs for PsA. Additionally, high levels of LA showed a positive causal relationship with a higher risk of PsA (OR_IVW: 1.248, 95% CI: 1.013-1.538, P _IVW = 0.037). It is interesting to note, however, that the effects of these associations were weakened in our MVMR analyses, which incorporated adjustment for lipid profiles (P _MV-IVW > 0.05) and multiple testing using the FDR method (P _{IVW-FDR-corrected} = 0.062). Moreover, effects of total omega-3 PUFAs, DHA, EPA, and LA on PsA, were massively driven by SNP effects in the FADS gene region. Furthermore, no causal association was identified between the concentrations of other circulating PUFAs and the risk of other ARDs. Further analysis revealed no significant horizontal pleiotropy and heterogeneity or reverse causality.

Conclusion: Our comprehensive MR analysis indicated that EPA is a key omega-3 PUFA that may protect against PsA but not other ARDs. The FADS2 gene appears to play a central role in mediating the effects of omega-3 PUFAs on PsA risk. These findings suggest that EPA supplementation may be a promising strategy for preventing PsA onset. Further well-powered epidemiological studies and clinical trials are warranted to explore the potential mechanisms underlying the protective effects of EPA in PsA.

Keywords: Mendelian randomization study; autoimmune rheumatic diseases; omega-3; omega-6; polyunsaturated fatty acids.

Figure 1

(A) Three key assumptions of Mendelian randomization (MR) in this study: (1) the instrumental variables (genetic proxies for omega-3 fatty acids, omega-6 fatty acids, EPA, DHA, LA, and AA) are not related to the confounders (dashed line and red ); (2) the instrumental variables (genetic proxies for omega-3 fatty acids, omega-6 fatty acids, EPA, DHA, LA and AA) are related to the exposure factor (solid line), and (3) the instrumental variables (genetic proxies for omega-3 fatty acids, omega-6 fatty acids, EPA, DHA, LA, and AA) are not directly related to the outcome (rheumatic diseases: Juvenile idiopathic arthritis, Gout, Ankylosing spondylitis, Psoriatic arthritis, and Sjögren syndrome) (dashed line and red ). (B) Flowchart of overview of Mendelian randomization (MR) analysis.

Figure 2

Univariable causal effects of (A) total omega3 polyunsaturated fatty acids, (B) DHA, and (C) EPA on investigated outcomes (JIA: light shades of blue, Gout: light shades of orange, AS: light shades of green, PsA: pink and SS: grey); Univariable causal effects of (A) total omega3 polyunsaturated fatty acids, (B) DHA, and (C) EPA on investigated outcomes (JIA: blue, Gout: orange, AS: green, PsA: red and SS: black) via the FADS gene cluster. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FADS, fatty acid desaturase; JIA, Juvenile idiopathic arthritis; AS, Ankylosing spondylitis; SS, Sjögren’s syndrome; PsA, Psoriatic arthritis.

Figure 3

Univariable causal effects of (A) total omega6 polyunsaturated fatty acids, (B) LA, and (C) AA on investigated outcomes (JIA: light shades of blue, Gout: light shades of orange, AS: light shades of green, PsA: pink and SS: grey). Univariable causal effects of (A) total omega6 polyunsaturated fatty acids, (B) LA, and (C) AA on investigated outcomes (JIA: blue, Gout: orange, AS: green, PsA: red and SS: black) via the FADS gene cluster and the C6orf15 gene cluster. LA, Linoleic acid; AA, Arachidonic acid; FADS, fatty acid desaturase; JIA, Juvenile idiopathic arthritis; AS, Ankylosing spondylitis; SS, Sjögren’s syndrome; PsA, Psoriatic arthritis.

Figure 4

Summary of MVMR causal effects for (A) EPA and (B) LA levels on the risk of PsA when controlling for four potential confounders (Unadjusted model: red square; BMI: yellow diamond; HDL: green triangle; LDL: pink circle; triglycerides: blue cross). EPA, Eicosapentaenoic acid; LA, α-linolenic acid; PsA, Psoriatic Arthritis; MVMR, Multivariable MR.