Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, NO. 180 Fenglin Road, Shanghai, 200032, China.
Fudan Institute for Metabolic Diseases, Shanghai, China.
Lipids Health Dis. 2024 Sep 27;23(1):309. doi: 10.1186/s12944-024-02304-9.
Alterations in DNA methylation (DNAm) have been observed in patients with fatty liver, but whether they are cause or consequence remains unknown. The study aimed to investigate longitudinal association of epigenome-wide DNAm with liver fat content (LFC) in Chinese participants, and explore their temporal relationships.
Data were obtained from 2 waves over a four-year time period of the Shanghai Changfeng Study (discovery, n = 407 and replication, n = 126). LFC and peripheral blood DNAm were repeatedly measured using quantitative hepatic ultrasonography and the 850 K Illumina EPIC BeadChip, respectively. Longitudinal and cross-sectional epigenome-wide association studies (EWASs) were conducted with linear mixed model and linear regression model, respectively. Meta-analysis was performed using METAL. Cross-lagged panel analysis (CLPA) was carried out to infer temporal relationships between the significant CpGs and LFC.
Longitudinal EWAS identified cg11024682 (SREBF1), cg06500161 (ABCG1), cg16740586 (ABCG1), cg15659943 (ABCA1) and cg00163198 (SNX19) significantly associated with LFC with P < 1e-7. Another 6 of the 22 previously reported CpGs were replicated in the present longitudinal EWAS. CLPA showed longitudinal effects of cg11024682 (SREBF1) (β = 0.14 [0.06, 0.23]), cg16740586 (ABCG1) (β = 0.17 [0.08, 0.25]), cg06500161 (ABCG1) (β = 0.12 [0.03, 0.20]), cg17901584 (DHCR24) (β = -0.10 [-0.18, -0.02]), cg00574958 (CPT1A) (β = -0.09 [-0.17, -0.01]), cg08309687 (LINC00649) (β = -0.11 [-0.19, -0.03]), and cg27243685 (ABCG1) (β = 0.09 [0.01, 0.18]) on subsequent LFC. The effects were attenuated when further adjusting for body mass index. High levels of LFC led to alterations in DNAm of cg15659943 (ABCA1) (β = 0.13 [0.04, 0.21]), cg07162647 (β = -0.11 [-0.19, -0.03]), cg06500161 (ABCG1) (β = 0.10 [0.02, 0.18]), and cg27243685 (ABCG1) (β = 0.10 [0.02, 0.18]).
Blood DNAm at SREBF1, ABCG1, DHCR24, CPT1A, and LINC00649 may be predictors of subsequent LFC change. The effects of DNAm at SREBF1 and ABCG1 on LFC were partially influenced by obesity. The findings have potential implications in understanding disease pathogenesis and highlight the potential of DNAm for early detection or intervention of fatty liver.
在患有脂肪肝的患者中观察到 DNA 甲基化（DNAm）的改变，但它们是原因还是结果尚不清楚。本研究旨在调查中国参与者中全基因组 DNAm 与肝脂肪含量（LFC）的纵向关联，并探讨它们之间的时间关系。
本研究数据来自上海长风研究（发现组，n=407 和复制组，n=126）的 4 年 2 次随访。使用定量肝超声和 850K Illumina EPIC BeadChip 分别重复测量 LFC 和外周血 DNAm。分别使用线性混合模型和线性回归模型进行纵向和横截面全基因组关联研究（EWASs）。使用 METAL 进行荟萃分析。使用交叉滞后面板分析（CLPA）推断显著 CpG 与 LFC 之间的时间关系。
纵向 EWAS 鉴定出 cg11024682（SREBF1）、cg06500161（ABCG1）、cg16740586（ABCG1）、cg15659943（ABCA1）和 cg00163198（SNX19）与 LFC 显著相关，P 值均小于 1e-7。本纵向 EWAS 还验证了先前报道的 22 个 CpG 中的另外 6 个。CLPA 显示 cg11024682（SREBF1）（β=0.14[0.06, 0.23]）、cg16740586（ABCG1）（β=0.17[0.08, 0.25]）、cg06500161（ABCG1）（β=0.12[0.03, 0.20]）、cg17901584（DHCR24）（β=-0.10[-0.18, -0.02]）、cg00574958（CPT1A）（β=-0.09[-0.17, -0.01]）、cg08309687（LINC00649）（β=-0.11[-0.19, -0.03]）和 cg27243685（ABCG1）（β=0.09[0.01, 0.18]）对随后的 LFC 有纵向影响。当进一步调整体重指数时，这些影响会减弱。较高的 LFC 水平导致 cg15659943（ABCA1）（β=0.13[0.04, 0.21]）、cg07162647（β=-0.11[-0.19, -0.03]）、cg06500161（ABCG1）（β=0.10[0.02, 0.18]）和 cg27243685（ABCG1）（β=0.10[0.02, 0.18]）的 DNAm 发生改变。
SREBF1、ABCG1、DHCR24、CPT1A 和 LINC00649 处的血液 DNAm 可能是随后 LFC 变化的预测因子。SREBF1 和 ABCG1 处的 DNAm 对 LFC 的影响部分受肥胖影响。这些发现可能有助于理解疾病发病机制，并强调了 DNAm 用于早期检测或干预脂肪肝的潜力。
