AUTHOR=Xu Xiao , Xu Xu , Zakeri Mohammad Ali , Wang Shu-Yun , Yan Min , Wang Yuan-Hong , Li Li , Sun Zhi-ling , Wang Rong-Yun , Miao Lin-Zhong 

TITLE=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

JOURNAL=Frontiers in Nutrition

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1356207

DOI=10.3389/fnut.2024.1356207

ISSN=2296-861X

ABSTRACT=<sec id="sec1"><title>Background</title><p>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.</p></sec><sec id="sec2"><title>Methods</title><p>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.</p></sec><sec id="sec3"><title>Results</title><p>Our results indicate that a heightened genetic predisposition for elevated levels of EPA (OR<sub>IVW</sub>: 0.924, 95% CI: 0.666–1.283, <italic>P</italic><sub>IVW</sub> = 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 (<italic>P</italic><sub><italic>IVW</italic>–FDR–corrected</sub> = 0.033) and multivariable MR analysis (<italic>P</italic><sub>MV-IVW</sub> &lt; 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<sub>IVW</sub>: 1.248, 95% CI: 1.013–1.538, <italic>P</italic><sub>IVW</sub> = 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 (<italic>P</italic><sub>MV-IVW</sub><italic>&gt;</italic> 0.05) and multiple testing using the FDR method (<italic>P</italic><sub>IVW–FDR–corrected</sub> = 0.062). Moreover, effects of total omega-3 PUFAs, DHA, EPA, and LA on PsA, were massively driven by SNP effects in the <italic>FADS</italic> 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.</p></sec><sec id="sec4"><title>Conclusion</title><p>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.</p></sec>