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Table 2 Representative human studies showing evidence for a role of epigenetics in obesity and related comorbidities

From: Recent developments on the role of epigenetics in obesity and metabolic disease

 

Phenotype

Association with epigenetic marks or changes in epigenetic marksa

Includes validationb

Ref.

Cross-sectional studies

 BMI, WC

Methylation in 37 CpGs associated with BMI and 1 probe with WC in blood (n = 5465); of those 16 CpGs (e.g., CpGs in CPT1A, ABCG1, and SREBPF1) were also associated with BMI in subcutaneous adipose tissue (n = 648)

Yes, 3 other cohorts

[51]

 BMI

DNA methylation of 4979 CpGs (e.g., in FTO, TCF7L2, FASN, PGC1A, CCRL2) in subcutaneous adipose tissue (n = 190). Several BMI-related methylation sites were also associated with age (e.g., ELOVL2), and with gene expression levels

Yes, 2nd cohort

[9]

 BMI

HIF3A methylation 3 CpGs in whole blood (n = 2587) and subcutaneous adipose tissue (n = 635), not in skin (n = 395)

Yes, 3 other cohorts

[52]

 Obesity

LY86 methylation 1 CpG in blood leukocytes adolescents and adults (n = 1534)

Yes, 4 other cohorts

[53]

 Obesity

249 DMRs in subcutaneous adipose tissue (n = 21), methylation in all these 249 regions also changed with high-fat feeding in mice and includes regions overlapping T2DM loci such as in TCF7L2

No, only in mice

[43]

 WHR, blood pressure LDL cholesterol

Association between WHR and ADRB3 methylation in whole blood and between blood pressure and ADRB3 methylation in visceral adipose tissue of obese (n = 25). Association between ADRB3 methylation and LDL cholesterol in whole blood of men with familial hypercholesterolemia (n = 41)

Not validated in 2nd cohort

[55]

 BMI

ADCY3 meQTL in subcutaneous adipose tissue from twins (n = 648)

Yes, technical

[8]

 BMI

Methylation differences at 1236 CpGs in leukocytes of monozygotic twins discordant for BMI and liver fat (n = 13)

Yes, technical

[96]

 Adiposity phenotypes

Methylation in 101 genes in subcutaneous adipose tissue (n = 106) including AOC3, SOD3, DOCK9, AQP7, ANGPT4, ANGPT2, TIMP4, ADAMST4, HOXA3, and LIPE, not found in blood leukocytes same individuals

No validation performed

[56]

 TG, VLDL

CPT1A methylation 1 CpG in CD4+T cells (n = 991) and leukocytes (n = 1261)

Yes, technical and 2nd cohort

[57]

 VLDL and LDL

CPT1A methylation 2 CpGs in CD4+T cells (n = 994)

Yes, in the same cohort

[58]

 Cholesterol and TG

Methylation in 9 CpGs, including in ABCG1, CPT1A and SREBF1, in whole blood (n = 2747), 5 of these CpGs also showed associations in subcutaneous adipose tissue (n = 634)

Yes, 2 other cohorts

[59]

 Insulin and HOMA-IR

ABCG1 1 CpG in CD4+T cells (n = 837)

Yes, in the same cohort

[61]

 HbA1C

DNA methylation of 711 CpGs in subcutaneous adipose tissue (n = 96 males). Not validated in female cohort (n = 94) but 30 CpGs validated in T2DM case-control cohort

Yes, validated in 1 of 2 cohorts

[9]

 T2DM

MALT1 methylation whole blood (n = 27 twins + n = 263 individuals) and other less significant DMRs (FDR < 0.1) overlapping T2DM GWAS loci

Yes, other cohort

[48]

 T2DM

Methylation in 1649 CpG sites, some overlapping T2DM, and obesity GWAS loci such as TCF7L2, FTO, and KCNQ1 in pancreatic islets (n = 49)

Yes, technical

[62]

 T2DM

No differentially methylated sites (after FDR correction) in T2DM discordant monozygotic twins (n = 14 pairs). Differential methylation at 15,627 CpGs, including in T2DM GWAS loci PPARG, KCNQ1, TCF7L2, and IRS1 in subcutaneous adipose tissue (n = 56). 1410 of these CpGs were also differentially methylated (P < 0.05) in the T2DM discordant twins

Yes, other cohort

[63]

Longitudinal studies

 Adiposity measured annually age 9–14 years

Increase PGC1A promoter methylation in whole blood children measured annually from 5–7 years (n = 40)

No, but measures at multiple time points

[54]

Maternal exposure or phenotype and epigenetic marks in offspring

 Prenatal famine

181 DMRs in adult whole blood (n = 48), including in CDH23, SMAD7, INSR, CPT1A, KLF13, RFTN1 (validated in n = 120)

Yes, technical and 2nd cohort

[68]

 Variation methyl donor intake

Changes in mean methylation across BOLA3, LOC654433, EXD3, ZFYVE28, RBM46, and ZNF678 in blood leukocytes (n = 126) and hair follicles (n = 82) of 2- to 8-month infants

No validation performed

[69]

 Periconceptional BMI

Decreased mean methylation across BOLA3, LOC654433, EXD3, ZFYVE28, RBM46, and ZNF678 in blood leukocytes (n = 126) and hair follicles (n = 82) of 2- to 8-month infants

No validation performed

[69]

 Gestational weight gain early pregnancy

Increased methylation 4 CpGs in MMP7, KCNK4, TRPM5, and NFKB1 in newborn cord blood (n = 88), no association in 2nd cohort (n = 170)

Not validated (technical and 2nd cohort)

[71]

 Preconceptional BMI

Differential methylation in ZCCHC10 in newborn cord blood (n = 308), other less significant sites were found in WNT16, ACPL2, C18orf8, ANGPTL2, SAPCD2, and ADCY3

No

[73]

 Gestational Diabetes

42 CpGs in newborn cord blood (n = 136). ~1/3 of CpGs overlapped with sites that were associated with maternal glucose levels (n = 36) or micronutrient supplementation (n = 59) in 2 other child cohorts

Yes, technical and 2 other cohorts

[70]

 Gestational Diabetes

No differentially methylated sites (after FDR correction) in cord blood and placenta (n = 44) but enrichment of sites in genes metabolic disease pathway

No

[72]

Intervention

 Weight loss surgery

Change in methylation at 3601 CpGs (195 DMRs) in subcutaneous adipose tissue and 15 CpGs in omental adipose tissue (n = 15), some DMRs overlapping known obesity and T2DM loci

Yes, technical

[64]

 Weight loss surgery

227 DMRs, methylation in these regions also changed with high-fat feeding in mice

No, only in mice

[43]

 Weight loss surgery in liver disease

Before surgery 467 differentially methylated CpGs between control (n = 18), healthy obese (n = 18), steatosis (n = 12), and NASH (n = 15) liver samples. After surgery changes in methylation at 113 CpGs, disease-associated methylation was reversible at the HOXB1, PRKCZ, SLC38A10, and SECTM1 loci

No, but for baseline technical and 2nd cohort

[79]

 Weight loss

Methylation profiles of RYR1, TUBA3C and BDNF in PBMCs of successful weight loss maintainers (n = 16) more closely resembled lean (n = 16) than obese subjects (n = 16)

No

[77]

 Endurance and strength exercise

Changes in DNA methylation in skeletal muscle of obese T2DM subjects (n = 17) after 16 weeks, most pronounced with endurance exercise

No

[83]

 High-fat diet (5 days)

PPARGC1A DNA methylation across 4 CpGs increased in subcutaneous adipose tissue of lean adults born with low birth weight (n = 19) but not in controls (n = 26)

No

[76]

  1. BMI body mass index, DMR differentially methylated region, GDM gestational diabetes mellitus, GWAS genome-wide association study, NASH non-alcoholic steatohepatitis, PBMC peripheral blood mononuclear cell, T2DM type 2 diabetes mellitus, TG triglycerides, WC waist circumference, WHR waist-hip ratio
  2. aIf not otherwise stated the number of subjects includes the total number in discovery and validation sets
  3. bValidation refers to validation of at least some epigenetic marks identified in the primary study cohort. This can be either technical validation, using another method for the measurement of epigenetic marks, or validation in another cohort