Abstract
BackgroundNon-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes.MethodsDNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m2) using the Infinium HumanMethylation450 BeadChip (Illumina). Associations between DNA methylation levels and estimated delta-6 and delta-5 desaturase enzyme activities, liver histology, hepatic mRNA expression, FADS1/2 genotypes, and erythrocyte folate levels were analyzed.ResultsWe found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616.ConclusionsGenetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation.
Highlights
Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene
We investigated in which of these CpG sites DNA methylation correlated with estimated delta-6 desaturase and delta-5 desaturase enzyme activities based on liver and serum fatty acids analysis
We discovered that methylation at two CpG sites in the FADS2, cg06781209 and cg07999042, correlated significantly with estimated activity of delta-6 desaturase in both liver and serum in all lipid fractions; they were selected for further analysis
Summary
Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. Because changes in DNA methylation affect gene expression and are known to be regulated by both genetic variants and nutritional factors, such as folate [17, 24,25,26,27,28,29,30], DNA methylation is a potential step in gene-diet interaction
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