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

Christiansen, Colette ; Tomlinson, Max ; Eliot, Melissa ; Nilsson, Emma LU orcid ; Costeira, Ricardo ; Xia, Yujing ; Villicaña, Sergio ; Mompeo, Olatz ; Wells, Philippa and Castillo-Fernandez, Juan , et al. (2022) In Genome Medicine 14(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adiposity, DNA methylation, Integrative omics, Visceral fat
in
Genome Medicine
volume
14
issue
1
article number
75
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85134539396
  • pmid:35843982
ISSN
1756-994X
DOI
10.1186/s13073-022-01077-z
language
English
LU publication?
yes
id
cdf6532f-dbcf-48d5-b538-af934ac8ede0
date added to LUP
2022-10-10 11:31:55
date last changed
2024-06-13 13:06:40
@article{cdf6532f-dbcf-48d5-b538-af934ac8ede0,
  abstract     = {{<p>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.</p>}},
  author       = {{Christiansen, Colette and Tomlinson, Max and Eliot, Melissa and Nilsson, Emma and Costeira, Ricardo and Xia, Yujing and Villicaña, Sergio and Mompeo, Olatz and Wells, Philippa and Castillo-Fernandez, Juan and Potier, Louis and Vohl, Marie Claude and Tchernof, Andre and Moustafa, Julia El Sayed and Menni, Cristina and Steves, Claire J. and Kelsey, Karl and Ling, Charlotte and Grundberg, Elin and Small, Kerrin S. and Bell, Jordana T.}},
  issn         = {{1756-994X}},
  keywords     = {{Adiposity; DNA methylation; Integrative omics; Visceral fat}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Medicine}},
  title        = {{Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers}},
  url          = {{http://dx.doi.org/10.1186/s13073-022-01077-z}},
  doi          = {{10.1186/s13073-022-01077-z}},
  volume       = {{14}},
  year         = {{2022}},
}