表观遗传年龄加速对肾功能的影响:一项孟德尔随机研究。

IF 5.7 2区 医学 Q1 Medicine
Yang Pan, Xiao Sun, Zhijie Huang, Ruiyuan Zhang, Changwei Li, Amanda H Anderson, James P Lash, Tanika N Kelly
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引用次数: 2

摘要

背景:以前的研究已经报道了表观遗传年龄加速(EAA)和肾功能表型之间的横断面关联。然而,这些变量之间的时间和潜在因果关系尚不清楚。我们对EAA和肾功能进行了双向双样本孟德尔随机化研究。EAA和估计肾小球滤过率(eGFR)的遗传工具是从先前的全基因组关联研究(GWAS)对欧洲血统参与者的荟萃分析中确定的。通过基于总结的孟德尔随机化方法评估EAA对肾功能的因果影响以及肾功能对EAA的影响,该方法利用CKDGen GWAS的log-转化估计肾小球滤过率(log-eGFR;n = 5,67,460)和GWAS荟萃分析EAA (n = 34,710)。基于等位基因评分的孟德尔随机化利用来自UK Biobank参与者的个体水平数据(n = 4,33,462)进一步检查了EAA对肾功能的影响。结果:采用基于摘要的孟德尔随机化方法,我们发现每5年内在EAA (IEAA)和GrimAA (GrimAA)增加分别与log-eGFR降低- 0.01和- 0.02个单位相关(P = 0.02和P = 0.09),这一发现得到了基于等位基因的孟德尔随机化研究的有力支持(P均为P)。本研究支持EAA与肾功能之间的双向因果关系,指出潜在的预防和治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.

Background: Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function.

Results: Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR.

Conclusion: This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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