Delta-6-desaturase gene polymorphism is associated with lipoprotein oxidation in vitro

Tiina Solakivi,Tarja Kunnas,Terho Lehtimäki,Olli Jaakkola,Jaana Renko,Seppo T Nikkari

doi:10.1186/1476-511x-12-80

Abstract

BackgroundOxidative modification of low-density lipoprotein (LDL) is a key event in the oxidation hypothesis of atherogenesis. We have previously shown that HDL does not protect LDL from oxidation in vitro, but is in fact oxidized fastest of all lipoproteins due to its rich polyunsaturated fatty acid (PUFA) composition, which is oxidation promoting. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA status. There is a deletion [T/-] in the promoter region of the Δ6 –desaturase gene (FADS2, rs 3834458), which has a direct inhibitory influence on production of PUFA from linoleic and alpha-linolenic acid. To investigate the possible role of rs 3834458 in lipoprotein modification, oxidation of LDL with HDL2 or HDL3 were analyzed from plasma of 58 free-living individuals.ResultsTotal eicosapentaenoic acid and arachidonic acid were significantly decreased in plasma from the 10 subjects homozygous for the deletion in FADS2 rs 3834458. When the isolated LDL and HDL2 were subjected to Cu2+-induced oxidation, these subjects showed decreased rate of appearance (p = 0.027) and the final concentration of conjugated dienes (p = 0.033) compared to the other genotypes. For oxidation of LDL with HDL3, the final concentration of conjugated dienes was also significantly decreased in subjects with [−/−] compared with [T/T] and [T/-] (p = 0.034).ConclusionWe conclude that FADS2 genotype may play a role in peroxidation susceptibility of lipoproteins.

Highlights

Oxidative modification of low-density lipoprotein (LDL) is a key event in the oxidation hypothesis of atherogenesis
When mixtures of isolated LDL and HDL2 were subjected to Cu2+-induced oxidation, the subjects with [−/−] showed decreased rate of appearance (p = 0.027) and the final concentration (P = 0.033) of conjugated dienes, compared with [T/T] and [T/-] (Table 2)
When isolated HDL3 was subjected to Cu2+-induced oxidation with LDL, a similar trend was observed in oxidation rate, but only the final concentration of conjugated dienes was significantly decreased in subjects with [−/−] compared with [T/T] and [T/-] (p = 0.034; p = 0.031 after adjusting for age and gender)

Summary

Introduction

Oxidative modification of low-density lipoprotein (LDL) is a key event in the oxidation hypothesis of atherogenesis. We have previously shown that HDL does not protect LDL from oxidation in vitro, but is oxidized fastest of all lipoproteins due to its rich polyunsaturated fatty acid (PUFA) composition, which is oxidation promoting. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA status. There is a deletion [T/-] in the promoter region of the Δ6 –desaturase gene (FADS2, rs 3834458), which has a direct inhibitory influence on production of PUFA from linoleic and alpha-linolenic acid. The human body can modify fatty acids by Δ6 and Δ5 desaturases and elongases to their respective metabolites along the pathways shown in Figure 1 to meet the metabolic needs. There is a common deletion [T/-] in the promoter region of the Δ6

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