NMR metabolomics-guided DNA methylation mortality predictors.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-09-01 Epub Date: 2024-08-17 DOI:10.1016/j.ebiom.2024.105279

Daniele Bizzarri, Marcel J T Reinders, Lieke Kuiper, Marian Beekman, Joris Deelen, Joyce B J van Meurs, Jenny van Dongen, René Pool, Dorret I Boomsma, Mohsen Ghanbari, Lude Franke, Pieternella E Slagboom, Erik B van den Akker

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Abstract

Background: ¹H-NMR metabolomics and DNA methylation in blood are widely known biomarkers predicting age-related physiological decline and mortality yet exert mutually independent mortality and frailty signals.

Methods: Leveraging multi-omics data in four Dutch population studies (N = 5238, ∼40% of which male) we investigated whether the mortality signal captured by ¹H-NMR metabolomics could guide the construction of DNA methylation-based mortality predictors.

Findings: We trained DNA methylation-based surrogates for 64 metabolomic analytes and found that analytes marking inflammation, fluid balance, or HDL/VLDL metabolism could be accurately reconstructed using DNA-methylation assays. Interestingly, a previously reported multi-analyte score indicating mortality risk (MetaboHealth) could also be accurately reconstructed. Sixteen of our derived surrogates, including the MetaboHealth surrogate, showed significant associations with mortality, independent of relevant covariates.

Interpretation: The addition of our metabolic analyte-derived surrogates to the well-established epigenetic clock GrimAge demonstrates that our surrogates potentially represent valuable mortality signal.

Funding: BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

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核磁共振代谢组学指导下的 DNA 甲基化死亡率预测。

背景：血液中的 1H-NMR 代谢组学和 DNA 甲基化是众所周知的预测与年龄相关的生理衰退和死亡率的生物标志物，但它们却发出相互独立的死亡率和虚弱信号：利用四项荷兰人口研究（N = 5238，其中男性占 40%）中的多组学数据，我们研究了 1H-NMR 代谢组学捕获的死亡率信号能否指导构建基于 DNA 甲基化的死亡率预测指标：我们对 64 种代谢组学分析物进行了基于 DNA 甲基化的替代物训练，发现利用 DNA 甲基化检测可以准确重建炎症、体液平衡或高密度脂蛋白/低密度脂蛋白代谢的分析物。有趣的是，以前报道过的一种显示死亡风险的多分析物评分（MetaboHealth）也可以准确地重建。在我们得出的代用指标中，包括MetaboHealth代用指标在内的16个指标都显示与死亡率有显著关联，且不受相关协变量的影响：解释：将我们的代谢分析物衍生代用指标添加到成熟的表观遗传时钟 GrimAge 中，表明我们的代用指标可能代表有价值的死亡率信号：BBMRI-NL, X-omics, VOILA, Medical Delta, NWO, ERC.

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.