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Co-methylation analyses identify CpGs associated with lipid traits in Chinese discordant monozygotic twins

生物 DNA甲基化 混淆 甲基化 单卵双胞胎 遗传力缺失问题 遗传学 高密度脂蛋白 双胞胎研究 内科学 基因 遗传关联 内分泌学 遗传力 胆固醇 肿瘤科 单核苷酸多态性 基因表达 医学 基因型
作者
Zhaoying Li,Weijing Wang,Weilong Li,Haiping Duan,Chunsheng Xu,Xiaocao Tian,Na Feng,Dongfeng Zhang
出处
期刊:Human Molecular Genetics [Oxford University Press]
标识
DOI:10.1093/hmg/ddad207
摘要

To control genetic background and early life milieu in genome-wide DNA methylation analysis for blood lipids, we recruited Chinese discordant monozygotic twins to explore the relationships between DNA methylations and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). 132 monozygotic (MZ) twins were included with discordant lipid levels and completed data. A linear mixed model was conducted in Epigenome-wide association study (EWAS). Generalized estimating equation model was for gene expression analysis. We conducted Weighted correlation network analysis (WGCNA) to build co-methylated interconnected network. Additional Qingdao citizens were recruited for validation. Inference about Causation through Examination of Familial Confounding (ICE FALCON) was used to infer the possible direction of these relationships. A total of 476 top CpGs reached suggestively significant level (P < 10-4), of which, 192 CpGs were significantly associated with TG (FDR < 0.05). They were used to build interconnected network and highlight crucial genes from WGCNA. Finally, four CpGs in GATA4 were validated as risk factors for TC; six CpGs at ITFG2-AS1 were negatively associated with TG; two CpGs in PLXND1 played protective roles in HDL-C. ICE FALCON indicated abnormal TC was regarded as the consequence of DNA methylation in CpGs at GATA4, rather than vice versa. Four CpGs in ITFG2-AS1 were both causes and consequences of modified TG levels. Our results indicated that DNA methylation levels of 12 CpGs in GATA4, ITFG2-AS1, and PLXND1 were relevant to TC, TG, and HDL-C, respectively, which might provide new epigenetic insights into potential clinical treatment of dyslipidemia.
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