Department of Clinical Nutrition, Faculty of Health Sciences, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210, Kuopio, Finland.
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70211, Kuopio, Finland.
Clin Epigenetics. 2019 Jan 17;11(1):10. doi: 10.1186/s13148-019-0609-1.
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 now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes.
DNA 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/m) 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.
We 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.
Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation.
非酒精性脂肪性肝病与肝脏中 FADS2 的 mRNA 表达增加以及血清中 delta-6 去饱和酶的估计活性有关，该基因由 FADS2 基因编码。由于 FADS1/2/3 基因簇中的 DNA 甲基化先前与遗传变异和去饱和酶活性有关，我们现在旨在发现调节 FADS1/2 基因注释的 CpG 位点 DNA 甲基化的因素。
使用 Infinium HumanMethylation450 BeadChip（Illumina）分析了来自 95 名肥胖的 Kuopio 肥胖手术研究参与者（34 名男性和 61 名女性，年龄 49.5±7.7 岁，BMI 43.0±5.7 kg/m）肝脏样本中 FADS2 和 FADS1 注释的 CpG 位点的 DNA 甲基化水平。分析了 DNA 甲基化水平与估计的 delta-6 和 delta-5 去饱和酶活性、肝组织学、肝 mRNA 表达、FADS1/2 基因型和红细胞叶酸水平之间的关系。
我们发现 cg06781209 和 cg07999042 的 DNA 甲基化水平与肝 FADS2 mRNA 表达呈负相关（均 p<0.05），并且与基于肝和血清脂肪酸的估计的 delta-6 去饱和酶活性呈负相关（均 p<0.05）。有趣的是，cg07999042 的甲基化水平（p=0.001）而不是 cg06781209 的甲基化水平（p=0.874）与 FADS2 变体 rs174616 相关。
FADS2 的遗传变异可能通过改变 DNA 甲基化而导致非酒精性脂肪性肝病的发病机制。
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