Gao Jiajia, Qiu Xueping, Wang Xuebin, Peng Chunyan, Zheng Fang
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China.
PLoS One. 2016 Jun 9;11(6):e0157128. doi: 10.1371/journal.pone.0157128. eCollection 2016.
Age, gender, diet, gene and lifestyle have been reported to affect metabolic status and disease susceptibility through epigenetic pathway. But it remains indistinct that which factors account for certain epigenetic modifications. Our aim was to identify the influencing factors on inter-individual DNA methylation variations of carbohydrate response element binding protein (ChREBP) and global genome in peripheral blood leucocytes (PBLs). ChREBP DNA methylation was determined by bisulfite sequencing, and genomic 5mdC contents were quantified by capillary hydrophilic-interaction liquid chromatography/ in-source fragmentation/ tandem mass spectrometry system in about 300 healthy individuals. Eleven single nucleotide polymorphisms (SNPs) spanning ChREBP and DNA methyltransferase 1 (DNMT1) were genotyped by high resolution melting or PCR-restriction fragment length polymorphism. DNMT1 mRNA expression was analyzed by quantitative PCR. We found ChREBP DNA methylation levels were statistically associated with age (Beta (B) = 0.028, p = 0.006) and serum total cholesterol concentrations (TC) (B = 0.815, p = 0.010), independent of sex, concentrations of triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C), fasting blood glucose and systolic blood pressure, diastolic blood pressure, PBLs counts and classifications. The DNMT1 haplotypes were related to ChREBP (odds ratio (OR) = 0.668, p = 0.029) and global (OR = 0.450, p = 0.015) DNA methylation as well as LDL-C, but not DNMT1 expression. However, only the relation to LDL-C was robust to correction for multiple testing (ORFDR = 1.593, pFDR = 0.013). These results indicated that the age and TC were independent influential factors of ChREBP methylation and DNMT1 variants could probably influence LDL-C to further modify ChREBP DNA methylation. Certainly, sequential comprehensive analysis of the interactions between genetic variants and blood lipid levels on ChREBP and global DNA methylation was required.
据报道，年龄、性别、饮食、基因和生活方式可通过表观遗传途径影响代谢状态和疾病易感性。但尚不清楚哪些因素导致了特定的表观遗传修饰。我们的目的是确定外周血白细胞（PBL）中碳水化合物反应元件结合蛋白（ChREBP）和全基因组个体间DNA甲基化变异的影响因素。采用亚硫酸氢盐测序法测定ChREBP DNA甲基化，用毛细管亲水相互作用液相色谱/源内裂解/串联质谱系统对约300名健康个体的基因组5mdC含量进行定量分析。通过高分辨率熔解或PCR-限制性片段长度多态性对跨越ChREBP和DNA甲基转移酶1（DNMT1）的11个单核苷酸多态性（SNP）进行基因分型。采用定量PCR分析DNMT1 mRNA表达。我们发现，ChREBP DNA甲基化水平与年龄（β（B）=0.028，p=0.006）和血清总胆固醇浓度（TC）（B=0.815，p=0.010）存在统计学关联，不受性别、甘油三酯浓度、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇（LDL-C）、空腹血糖、收缩压、舒张压、PBL计数和分类的影响。DNMT1单倍型与ChREBP（优势比（OR）=0.668，p=0.029）和全基因组（OR=0.450，p=0.015）DNA甲基化以及LDL-C有关，但与DNMT1表达无关。然而，只有与LDL-C的关系在多重检验校正后仍很显著（ORFDR=1.593，pFDR=0.013）。这些结果表明，年龄和TC是ChREBP甲基化的独立影响因素，DNMT1变异可能通过影响LDL-C进一步改变ChREBP DNA甲基化。当然，需要对ChREBP和全基因组DNA甲基化的基因变异与血脂水平之间的相互作用进行连续综合分析。
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