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; Abbas Dehghan; Scott Ratliff; Wei Zhao; Lawrence Bielak; Sharon L.R. Kardia; Patricia A. Peyser; Hongyan Ning; Lisa B. 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

doi:10.2337/DB18-1193

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. FrancoAbbas Dehghan, Scott Ratliff, Wei Zhao, Lawrence Bielak, Sharon L.R. Kardia, Patricia A. Peyser, Hongyan Ning, Lisa B. 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 › peer-review

9 Scopus citations

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 language	English (US)
Pages (from-to)	1073-1083
Number of pages	11
Journal	Diabetes
Volume	68
Issue number	5
DOIs	https://doi.org/10.2337/DB18-1193
State	Published - 2019

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/DB18-1193

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Ma, J., Nano, J., Ding, J., Zheng, Y., Hennein, R., Liu, C., Speliotes, E. K., Huan, T., Song, C., Mendelson, M. M., Joehanes, R., Long, M. T., Liang, L., Smith, J. A., Reynolds, L. M., Ghanbari, M., Muka, T., Van Meurs, J. B. J., Alferink, L. J. M., ... Levy, D. (2019). A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for nonalcoholic fatty liver disease. Diabetes, 68(5), 1073-1083. https://doi.org/10.2337/DB18-1193

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 B. ; 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.

@article{17d1ed65b1fd4ba5acb4b5ab13e2c445,

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 B.} 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",

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 B.; 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, 2019, p. 1073-1083.

Research output: Contribution to journal › Article › peer-review

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 B.

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

Y1 - 2019

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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JF - Diabetes

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