A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease

Jiantao Ma, Jana Nano, Jingzhong Ding, Yinan Zheng, Rachel Hennein, Chunyu Liu, Elizabeth K. Speliotes, Tianxiao Huan, Ci Song, Michael M. Mendelson, Roby Joehanes, Michelle T. Long, Liming Liang, Jennifer A. Smith, Lindsay M. Reynolds, Mohsen Ghanbari, Taulant Muka, Joyce B.J. Van Meurs, Louise J.M. Alferink, Oscar H. Franco & 17 others Abbas Dehghan, Scott Ratliff, Wei Zhao, Lawrence Bielak, Sharon L.R. Kardia, Patricia A. Peyser, Hongyan Ning, Lisa Beth VanWagner, Donald M Lloyd-Jones, John Jeffrey Carr, Philip Greenland, Alice H. Lichtenstein, Frank B. Hu, Yongmei Liu, Lifang Hou, Sarwa Darwish Murad, Daniel Levy*

*Corresponding author for this work

Research output: Contribution to journal › Article

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNAmethylation signatures of NAFLD across racial/ethnic groups.

Original languageEnglish (US)
Pages (from-to)1073-1083
Number of pages11
JournalDiabetes
Volume68
Issue number5
DOIs
StatePublished - Jan 1 2019

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DNA Methylation
Fats
Liver
Type 2 Diabetes Mellitus
Mendelian Randomization Analysis
Hispanic Americans
Ethnic Groups
Non-alcoholic Fatty Liver Disease
Monocytes
Ultrasonography
Cohort Studies
Biomarkers
Tomography
Population

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ma, Jiantao ; Nano, Jana ; Ding, Jingzhong ; Zheng, Yinan ; Hennein, Rachel ; Liu, Chunyu ; Speliotes, Elizabeth K. ; Huan, Tianxiao ; Song, Ci ; Mendelson, Michael M. ; Joehanes, Roby ; Long, Michelle T. ; Liang, Liming ; Smith, Jennifer A. ; Reynolds, Lindsay M. ; Ghanbari, Mohsen ; Muka, Taulant ; Van Meurs, Joyce B.J. ; Alferink, Louise J.M. ; Franco, Oscar H. ; Dehghan, Abbas ; Ratliff, Scott ; Zhao, Wei ; Bielak, Lawrence ; Kardia, Sharon L.R. ; Peyser, Patricia A. ; Ning, Hongyan ; VanWagner, Lisa Beth ; Lloyd-Jones, Donald M ; Carr, John Jeffrey ; Greenland, Philip ; Lichtenstein, Alice H. ; Hu, Frank B. ; Liu, Yongmei ; Hou, Lifang ; Murad, Sarwa Darwish ; Levy, Daniel. / A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease. In: Diabetes. 2019 ; Vol. 68, No. 5. pp. 1073-1083.
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title = "A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease",
abstract = "Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNAmethylation signatures of NAFLD across racial/ethnic groups.",
author = "Jiantao Ma and Jana Nano and Jingzhong Ding and Yinan Zheng and Rachel Hennein and Chunyu Liu and Speliotes, {Elizabeth K.} and Tianxiao Huan and Ci Song and Mendelson, {Michael M.} and Roby Joehanes and Long, {Michelle T.} and Liming Liang and Smith, {Jennifer A.} and Reynolds, {Lindsay M.} and Mohsen Ghanbari and Taulant Muka and {Van Meurs}, {Joyce B.J.} and Alferink, {Louise J.M.} and Franco, {Oscar H.} and Abbas Dehghan and Scott Ratliff and Wei Zhao and Lawrence Bielak and Kardia, {Sharon L.R.} and Peyser, {Patricia A.} and Hongyan Ning and VanWagner, {Lisa Beth} and Lloyd-Jones, {Donald M} and Carr, {John Jeffrey} and Philip Greenland and Lichtenstein, {Alice H.} and Hu, {Frank B.} and Yongmei Liu and Lifang Hou and Murad, {Sarwa Darwish} and Daniel Levy",
year = "2019",
month = "1",
day = "1",
doi = "10.2337/DB18-1193",
language = "English (US)",
volume = "68",
pages = "1073--1083",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "5",

}

Ma, J, Nano, J, Ding, J, Zheng, Y, Hennein, R, Liu, C, Speliotes, EK, Huan, T, Song, C, Mendelson, MM, Joehanes, R, Long, MT, Liang, L, Smith, JA, Reynolds, LM, Ghanbari, M, Muka, T, Van Meurs, JBJ, Alferink, LJM, Franco, OH, Dehghan, A, Ratliff, S, Zhao, W, Bielak, L, Kardia, SLR, Peyser, PA, Ning, H, VanWagner, LB, Lloyd-Jones, DM, Carr, JJ, Greenland, P, Lichtenstein, AH, Hu, FB, Liu, Y, Hou, L, Murad, SD & Levy, D 2019, 'A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease', Diabetes, vol. 68, no. 5, pp. 1073-1083. https://doi.org/10.2337/DB18-1193

A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease. / Ma, Jiantao; Nano, Jana; Ding, Jingzhong; Zheng, Yinan; Hennein, Rachel; Liu, Chunyu; Speliotes, Elizabeth K.; Huan, Tianxiao; Song, Ci; Mendelson, Michael M.; Joehanes, Roby; Long, Michelle T.; Liang, Liming; Smith, Jennifer A.; Reynolds, Lindsay M.; Ghanbari, Mohsen; Muka, Taulant; Van Meurs, Joyce B.J.; Alferink, Louise J.M.; Franco, Oscar H.; Dehghan, Abbas; Ratliff, Scott; Zhao, Wei; Bielak, Lawrence; Kardia, Sharon L.R.; Peyser, Patricia A.; Ning, Hongyan; VanWagner, Lisa Beth; Lloyd-Jones, Donald M; Carr, John Jeffrey; Greenland, Philip; Lichtenstein, Alice H.; Hu, Frank B.; Liu, Yongmei; Hou, Lifang; Murad, Sarwa Darwish; Levy, Daniel.

In: Diabetes, Vol. 68, No. 5, 01.01.2019, p. 1073-1083.

Research output: Contribution to journal › Article

TY - JOUR

T1 - A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease

AU - Ma, Jiantao

AU - Nano, Jana

AU - Ding, Jingzhong

AU - Zheng, Yinan

AU - Hennein, Rachel

AU - Liu, Chunyu

AU - Speliotes, Elizabeth K.

AU - Huan, Tianxiao

AU - Song, Ci

AU - Mendelson, Michael M.

AU - Joehanes, Roby

AU - Long, Michelle T.

AU - Liang, Liming

AU - Smith, Jennifer A.

AU - Reynolds, Lindsay M.

AU - Ghanbari, Mohsen

AU - Muka, Taulant

AU - Van Meurs, Joyce B.J.

AU - Alferink, Louise J.M.

AU - Franco, Oscar H.

AU - Dehghan, Abbas

AU - Ratliff, Scott

AU - Zhao, Wei

AU - Bielak, Lawrence

AU - Kardia, Sharon L.R.

AU - Peyser, Patricia A.

AU - Ning, Hongyan

AU - VanWagner, Lisa Beth

AU - Lloyd-Jones, Donald M

AU - Carr, John Jeffrey

AU - Greenland, Philip

AU - Lichtenstein, Alice H.

AU - Hu, Frank B.

AU - Liu, Yongmei

AU - Hou, Lifang

AU - Murad, Sarwa Darwish

AU - Levy, Daniel

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNAmethylation signatures of NAFLD across racial/ethnic groups.

AB - Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4. Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNAmethylation signatures of NAFLD across racial/ethnic groups.

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U2 - 10.2337/DB18-1193

DO - 10.2337/DB18-1193

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JO - Diabetes

JF - Diabetes

SN - 0012-1797

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Ma J, Nano J, Ding J, Zheng Y, Hennein R, Liu C et al. A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease. Diabetes. 2019 Jan 1;68(5):1073-1083. https://doi.org/10.2337/DB18-1193

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