基于 NMR 代谢组学的 DNA 甲基化死亡率预测因子。

NMR metabolomics-guided DNA methylation mortality predictors.

机构信息

Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; Leiden Computational Biology Center, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; Delft Bioinformatics Lab, TU Delft, Delft, the Netherlands.

Leiden Computational Biology Center, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; Delft Bioinformatics Lab, TU Delft, Delft, the Netherlands.

出版信息

EBioMedicine. 2024 Sep;107:105279. doi: 10.1016/j.ebiom.2024.105279. Epub 2024 Aug 17.

DOI:10.1016/j.ebiom.2024.105279

PMID:39154540

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11378104/

Abstract

BACKGROUND

H-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 H-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.

摘要

背景

血液中的 H-NMR 代谢组学和 DNA 甲基化是广泛已知的预测与年龄相关的生理衰退和死亡率的生物标志物，但它们发挥着相互独立的死亡率和脆弱性信号。

方法

利用来自四个荷兰人群研究的多组学数据（N=5238，其中约 40%为男性），我们研究了 H-NMR 代谢组学捕捉到的死亡率信号是否可以指导基于 DNA 甲基化的死亡率预测因子的构建。

发现

我们训练了基于 DNA 甲基化的 64 种代谢物的替代物，并发现可以使用 DNA 甲基化测定法准确重建标记炎症、液体平衡或 HDL/VLDL 代谢的分析物。有趣的是，先前报道的指示死亡率风险的多分析物评分（MetaboHealth）也可以准确重建。我们的 16 种衍生替代物，包括 MetaboHealth 替代物，与死亡率独立于相关协变量显著相关。