Jones Alana C, Ament Zsuzsanna, Patki Amit, Chaudhary Ninad S, Srinivasasainagendra Vinodh, Kijpaisalratana Naruchorn, Absher Devin M, Tiwari Hemant K, Arnett Donna K, Kimberly W Taylor, Irvin Marguerite R
Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, United States.
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Genet. 2023 Sep 15;14:1184661. doi: 10.3389/fgene.2023.1184661. eCollection 2023.
Metabolic syndrome (MetS) increases the risk of cardiovascular disease and death. Previous '-omics' studies have identified dysregulated serum metabolites and aberrant DNA methylation in the setting of MetS. However, the relationship between the metabolome and epigenome have not been elucidated. In this study, we identified serum metabolites associated with MetS and DNA methylation, and we conducted bidirectional Mendelian randomization (MR) to assess causal relationships between metabolites and methylation. We leveraged metabolomic and genomic data from a national United States cohort of older adults (REGARDS), as well as metabolomic, epigenomic, and genomic data from a family-based study of hypertension (HyperGEN). We conducted metabolite profiling for MetS in REGARDS using weighted logistic regression models and validated them in HyperGEN. Validated metabolites were selected for methylation studies which fit linear mixed models between metabolites and six CpG sites previously linked to MetS. Statistically significant metabolite-CpG pairs were selected for two-sample, bidirectional MR. Forward MR indicated that glucose and serine metabolites were causal on CpG methylation near [B(SE): -0.003 (0.002), = 0.028 and B(SE): 0.029 (0.011), = 0.030, respectively] and that serine metabolites were causal on [B(SE): -0.008(0.003), = 0.006] and [B(SE): -0.009(0.004), = 0.018] methylation which suggested a protective effect of serine. Reverse MR showed a bidirectional relationship between cg06500161 () and serine [B(SE): -1.534 (0.668), = 0.023]. The metabolome may contribute to the relationship between MetS and epigenetic modifications.
代谢综合征（MetS）会增加心血管疾病和死亡风险。以往的“组学”研究已在MetS背景下鉴定出血清代谢物失调和DNA甲基化异常。然而，代谢组与表观基因组之间的关系尚未阐明。在本研究中，我们鉴定了与MetS和DNA甲基化相关的血清代谢物，并进行了双向孟德尔随机化（MR）以评估代谢物与甲基化之间的因果关系。我们利用了来自美国一个老年人群队列（REGARDS）的代谢组学和基因组数据，以及一项基于家庭的高血压研究（HyperGEN）的代谢组学、表观基因组学和基因组数据。我们在REGARDS中使用加权逻辑回归模型对MetS进行代谢物谱分析，并在HyperGEN中进行验证。选择经过验证的代谢物进行甲基化研究，这些研究符合代谢物与先前与MetS相关的六个CpG位点之间的线性混合模型。选择具有统计学意义的代谢物 - CpG对进行两样本双向MR。正向MR表明，葡萄糖和丝氨酸代谢物对[B（标准误）：-0.003（0.002），P = 0.028和B（标准误）：0.029（0.011），P = 0.030]附近的CpG甲基化有因果作用，并且丝氨酸代谢物对[B（标准误）：-0.008（0.003），P = 0.006]和[B（标准误）：-0.009（0.004），P = 0.018]甲基化有因果作用，这表明丝氨酸具有保护作用。反向MR显示cg06500161（）与丝氨酸之间存在双向关系[B（标准误）：-1.534（0.668），P = 0.023]。代谢组可能促成了MetS与表观遗传修饰之间的关系。
