Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

Tina Rönn; Petr Volkov; Linn Gillberg; Milana Kokosar; Alexander Perfilyev; Anna Louisa Jacobsen; Sine W Jørgensen; Charlotte Brøns; Per-Anders Jansson; Karl-Fredrik Eriksson; Oluf Pedersen; Torben Hansen; Leif Groop; Elisabet Stener-Victorin; Allan Vaag; Emma Nilsson; Charlotte Ling

doi:10.1093/hmg/ddv124

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

Tina Rönn, Petr Volkov, Linn Gillberg, Milana Kokosar, Alexander Perfilyev, Anna Louisa Jacobsen, Sine W Jørgensen, Charlotte Brøns, Per-Anders Jansson, Karl-Fredrik Eriksson, Oluf Pedersen, Torben Hansen, Leif Groop, Elisabet Stener-Victorin, Allan Vaag, Emma Nilsson, Charlotte Ling

Institut for Klinisk Medicin

156 Citationer (Scopus)

Abstract

Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28–46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	24
Udgave nummer	13
Sider (fra-til)	3792-813
Antal sider	22
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddv124
Status	Udgivet - 1 jul. 2015

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10.1093/hmg/ddv124

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Rönn, T., Volkov, P., Gillberg, L., Kokosar, M., Perfilyev, A., Jacobsen, A. L., Jørgensen, S. W., Brøns, C., Jansson, P-A., Eriksson, K-F., Pedersen, O., Hansen, T., Groop, L., Stener-Victorin, E., Vaag, A., Nilsson, E., & Ling, C. (2015). Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Human Molecular Genetics, 24(13), 3792-813. https://doi.org/10.1093/hmg/ddv124

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. / Rönn, Tina; Volkov, Petr; Gillberg, Linn et al.

I: Human Molecular Genetics, Bind 24, Nr. 13, 01.07.2015, s. 3792-813.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Rönn, T, Volkov, P, Gillberg, L, Kokosar, M, Perfilyev, A, Jacobsen, AL, Jørgensen, SW, Brøns, C, Jansson, P-A, Eriksson, K-F, Pedersen, O , Hansen, T, Groop, L, Stener-Victorin, E, Vaag, A, Nilsson, E & Ling, C 2015, 'Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood', Human Molecular Genetics, bind 24, nr. 13, s. 3792-813. https://doi.org/10.1093/hmg/ddv124

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title = "Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood",

abstract = "Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28–46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue. ",

author = "Tina R{\"o}nn and Petr Volkov and Linn Gillberg and Milana Kokosar and Alexander Perfilyev and Jacobsen, {Anna Louisa} and J{\o}rgensen, {Sine W} and Charlotte Br{\o}ns and Per-Anders Jansson and Karl-Fredrik Eriksson and Oluf Pedersen and Torben Hansen and Leif Groop and Elisabet Stener-Victorin and Allan Vaag and Emma Nilsson and Charlotte Ling",

year = "2015",

month = jul,

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doi = "10.1093/hmg/ddv124",

language = "English",

volume = "24",

pages = "3792--813",

journal = "Human Molecular Genetics",

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TY - JOUR

T1 - Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

AU - Rönn, Tina

AU - Volkov, Petr

AU - Gillberg, Linn

AU - Kokosar, Milana

AU - Perfilyev, Alexander

AU - Jacobsen, Anna Louisa

AU - Jørgensen, Sine W

AU - Brøns, Charlotte

AU - Jansson, Per-Anders

AU - Eriksson, Karl-Fredrik

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Groop, Leif

AU - Stener-Victorin, Elisabet

AU - Vaag, Allan

AU - Nilsson, Emma

AU - Ling, Charlotte

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28–46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.

AB - Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28–46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.

U2 - 10.1093/hmg/ddv124

DO - 10.1093/hmg/ddv124

M3 - Journal article

C2 - 25861810

SN - 0964-6906

VL - 24

SP - 3792

EP - 3813

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 13

ER -

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

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