评估系统铁状态与表观遗传钟之间的关联：一项遗传关联和双向孟德尔随机化研究。

Appraising the Associations Between Systemic Iron Status and Epigenetic Clocks: A Genetic Correlation and Bidirectional Mendelian Randomization Study.

机构信息

School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China.

Beidahuang Industry Group General Hospital, Harbin, China.

出版信息

Am J Clin Nutr. 2023 Jul;118(1):41-49. doi: 10.1016/j.ajcnut.2023.05.004. Epub 2023 May 3.

DOI:10.1016/j.ajcnut.2023.05.004

PMID:37146762

Abstract

BACKGROUND

Genetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational studies have suggested systemic iron status is associated with human aging.

OBJECTIVES

We explored the genetic correlations and bidirectional causal effects between systemic iron status and epigenetic clocks.

METHODS

Leveraging large-scale genome-wide association study summary-level statistics for 4 systemic iron status biomarkers (ferritin, serum iron, transferrin, and transferrin saturation) (N = 48,972) and 4 measures for epigenetic age (GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge) (N = 34,710), genetic correlations, and bidirectional causal effects were estimated between them mainly by applying linkage disequilibrium score (LDSC) regression, Mendelian randomization (MR), and MR based on Bayesian model averaging. The main analyses were conducted employing multiplicative random-effects inverse-variance weighted MR. MR-Egger, weighted median, weighted mode, and MR-PRESSO were performed as sensitivity analyses to support the robustness of causal effects.

RESULTS

The LDSC results illustrated Rg between serum iron and PhenoAge (Rg = 0.1971, P = 0.048) and between transferrin saturation and PhenoAge (Rg = 0.196, P = 0.0469). We found that increased ferritin and transferrin saturation significantly increased all 4 measures of epigenetic age acceleration (all P < 0.0125, β > 0). Each standard deviation genetically increases in serum iron only significantly associated with increased IEAA (β: 0.36; 95% CI: 0.16, 0.57; P = 6.01 × 10) and increased HannumAge acceleration (β: 0.32; 95% CI: 0.11, 0.52; P = 2.69 × 10). Evidence showed a suggestively significant causal effect of transferrin on epigenetic age acceleration (all 0.0125 <P < 0.05). Additionally, reverse MR study indicated no significant causal effect of epigenetic clocks on systemic iron status.

CONCLUSIONS

All 4 iron status biomarkers had a significant or suggestively significant causal effect on epigenetic clocks, whereas reverse MR studies did not.

摘要

背景

尽管观察性研究表明，全身铁状态与人类衰老有关，但遗传相关性（Rg）和全身铁状态与表观遗传时钟之间的双向因果关系尚未得到充分研究。

目的

我们探讨了全身铁状态和表观遗传时钟之间的遗传相关性和双向因果关系。

方法

利用大规模全基因组关联研究汇总统计数据，对 4 种全身铁状态生物标志物（铁蛋白、血清铁、转铁蛋白和转铁蛋白饱和度）（N=48972）和 4 种表观遗传年龄测量值（GrimAge、PhenoAge、内在表观遗传年龄加速（IEAA）和 HannumAge）（N=34710），主要通过应用连锁不平衡评分（LDSC）回归、孟德尔随机化（MR）和基于贝叶斯模型平均的 MR 进行遗传相关性和双向因果关系的估计。主要分析采用乘法随机效应逆方差加权 MR。MR-Egger、加权中位数、加权众数和 MR-PRESSO 作为敏感性分析，以支持因果关系的稳健性。

结果

LDSC 结果表明血清铁与 PhenoAge 之间存在 Rg（Rg=0.1971，P=0.048），转铁蛋白饱和度与 PhenoAge 之间存在 Rg（Rg=0.196，P=0.0469）。我们发现，铁蛋白和转铁蛋白饱和度的增加显著增加了所有 4 种表观遗传年龄加速测量值（均 P < 0.0125，β>0）。血清铁的每个标准偏差仅显著增加与 IEAA 增加相关（β：0.36；95%CI：0.16，0.57；P=6.01×10）和 HannumAge 加速（β：0.32；95%CI：0.11，0.52；P=2.69×10）。证据表明，转铁蛋白对表观遗传年龄加速有显著的因果作用（均 0.0125<P<0.05）。此外，反向 MR 研究表明，表观遗传时钟对全身铁状态没有显著的因果作用。