Relations of circulating long chain polyunsaturated fatty acids, lipid peroxidation product and FADS2 gene variants differentiate between patients with relapsing-remitting and secondary progressive multiple sclerosis

Abstract

Introduction: Long chain polyunsaturated fatty acids (LC-PUFA), commonly omega-6, are involved in key pathogenic processes in multiple sclerosis (MS), through participating in the production of proinflammatory mediators and undergoing the lipid peroxidation, thus contributing to oxidative stress and triggering the recently described iron-mediated cell death, ferroptosis, which relates to neuronal and oligodendrocyte loss in MS. Objectives/Aims: Therefore, the aim of this study was to investigate relations of circulating LC-PUFA levels with lipid peroxidation product and with variants in gene coding for the key omega-6 and omega-3 LC-PUFA biosynthesis enzyme, fatty acid desaturase 2 (FADS2), in regard to clinical course of MS. Methods: The study involved 144 patients, 95 with relapsing-remitting (RR) and 49 with secondary progressive (SP) course of MS. LC-PUFA concentrations were determined in erythrocytes by gas chromatography. Lipid peroxidation product 4-hydroxynonenal (4-HNE) was quantified in plasma, by enzyme linked immunosorbent assay. FADS2 intronic variants, rs174576 (C/A), rs174593 (T/C) and rs174616 (G/A), were detected using TaqMan® SNP genotyping assays. Statistical analysis included T-test/Mann-Whitney U test, Analysis of Covariance and Factorial Analysis of Variance Results: 4-HNE was decreased in SP, compared to RR MS patients (median, 1304.23 vs. 1748.78 pg/ml, p = 2x10-5). Inverse relation between omega-3 eicosapentaenoic acid and 4-HNE levels was established only in SPMS (p = 0.003), suggesting favourable omega-3 antioxidant action in SP course. In comparison to RRMS, SPMS patients homozygous for rs174616 alternative, A, allele had lower omega-6 linoleic acid and higher omega-3 docosahexaenoic acid levels, relative to the reference, GG, genotype (p = 0.007 and p = 0.04, respectively), implying GG as adverse in terms of increasing the omega-6 to omega-3 fatty acid ratio. Conclusion: Regarding the course of disease and LC-PUFA, supplementation with omega-3 fatty acids might be particularly beneficial for SPMS patients, notably those with rs174616 GG genotype. By enabling a favourable omega-6 to omega-3 ratio, omega-3 supplementation would contribute to multiple health benefits, which are beyond known and include lowering of lipid peroxidation products and protection against neuronal and oligodendrocyte damage associated with oxidative stress and potentially ferroptosis.