脂肪甲基组学整合组学分析揭示了遗传和饮食代谢健康的驱动因素以及胰岛素抵抗的分类器。

Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers.

机构信息

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Department of Medical & Molecular Genetics, King's College London, London, UK.

出版信息

Genome Med. 2022 Jul 18;14(1):75. doi: 10.1186/s13073-022-01077-z.

DOI:10.1186/s13073-022-01077-z

PMID:35843982

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9290282/

Abstract

BACKGROUND

There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles.

METHODS

Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health.

RESULTS

We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone.

CONCLUSIONS

Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk.

摘要

背景

有大量证据表明 DNA 甲基化组在代谢健康中的重要性，例如，已经有一个强大的甲基化特征与体重指数 (BMI) 相关。然而，内脏脂肪 (VF) 堆积比 BMI 本身更能增加代谢疾病的风险。在这项研究中，我们通过关注 VF 作为代谢疾病的主要危险因素，剖析与代谢健康相关的皮下脂肪组织 (SAT) 甲基化特征。我们将研究结果与遗传、血液甲基化、SAT 基因表达、血液代谢组学、饮食摄入和代谢表型数据相结合，以评估和量化所识别信号的遗传和环境驱动因素，以及它们潜在的功能作用。

方法

我们对来自 538 名 TwinsUK 参与者的 SAT 样本进行了全基因组关联分析，以确定与内脏脂肪量相关的差异甲基化位置 (VF-DMPs)。在来自 3 个独立队列的 333 个人中进行了验证和复制。为了评估 VF-DMPs 的功能影响，在注释到 VF-DMPs 的基因上确定了 VF 与基因表达之间的关联，并进行了关联分析以确定 VF-DMPs 的甲基化是否与基因表达相关。进一步进行了表观遗传学分析，以比较 VF-DMPs 作为反应变量的甲基化水平，并比较了一系列不同的代谢健康表型，包括安卓：女性脂肪比 (AGR)、脂质、血液代谢组学特征、胰岛素抵抗、T2D 和饮食摄入变量。将所有分析的结果整合在一起，以识别表现出改变的 SAT 功能并与代谢健康密切相关的信号。

结果

我们确定了 788 个基因中的 1181 个 CpG 位置与 VF（VF-DMPs）存在差异甲基化，这些基因在胰岛素信号通路中显著富集。对 VF-DMPs 的跨组学分析，包括遗传学、基因表达、代谢组学、饮食和代谢特征，突出了 9 个与代谢疾病机制密切相关的基因中的 VF-DMPs，在 FASN、SREBF1、TAGLN2、PC 和 CFAP410 中复制了信号。PC 甲基化显示出对饮食对 VF 影响的中介效应。FASN 的 DNA 甲基化表现出对 VF 的潜在因果效应，也与胰岛素抵抗强烈相关，FASN 的甲基化水平比 BMI 或 VF 本身更好地分类胰岛素抵抗（AUC=0.91）。