A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease

被引：43

作者：

Ma, Jiantao ^{[1
,2
,3
]}

Nano, Jana ^{[4
,5
,6
]}

Ding, Jingzhong ^{[7
]}

Zheng, Yinan ^{[8
]}

Hennein, Rachel ^{[1
,2
]}

Liu, Chunyu ^{[1
,2
,9
]}

Speliotes, Elizabeth K. ^{[10
]}

Huan, Tianxiao ^{[1
,2
]}

Song, Ci ^{[1
,2
,11
]}

Mendelson, Michael M. ^{[1
,2
,12
]}

Joehanes, Roby ^{[1
,2
]}

Long, Michelle T. ^{[13
]}

Liang, Liming ^{[14
,15
]}

Smith, Jennifer A. ^{[16
]}

Reynolds, Lindsay M. ^{[7
]}

Ghanbari, Mohsen ^{[4
,17
]}

Muka, Taulant ^{[4
]}

van Meurs, Joyce B. J. ^{[4
,18
]}

Alferink, Louise J. M. ^{[19
]}

Franco, Oscar H. ^{[4
]}

Dehghan, Abbas ^{[4
,20
]}

Ratliff, Scott ^{[16
]}

Zhao, Wei ^{[16
]}

Bielak, Lawrence ^{[16
]}

Kardia, Sharon L. R. ^{[16
]}

Peyser, Patricia A. ^{[16
]}

Ning, Hongyan ^{[8
]}

VanWagner, Lisa B. ^{[8
,21
]}

Lloyd-Jones, Donald M. ^{[8
]}

Carr, John Jeffrey ^{[22
]}

Greenland, Philip ^{[8
]}

Lichtenstein, Alice H. ^{[23
]}

Hu, Frank B. ^{[24
]}

Liu, Yongmei ^{[7
]}

Hou, Lifang ^{[8
]}

Murad, Sarwa Darwish ^{[19
]}

Levy, Daniel ^{[1
,2
]}

机构：

[1] NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[2] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA

[3] Tufts Univ, Nutr Data Sci, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA

[4] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[5] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany

[6] German Ctr Diabet Res, Munich, Germany

[7] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA

[8] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA

[9] Boston Univ, Dept Biostat, Boston, MA 02215 USA

[10] Univ Michigan, Sch Med, Ann Arbor, MI USA

[11] Uppsala Univ, Mol Epidemiol, Dept Med Sci, Uppsala, Sweden

[12] Harvard Med Sch, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA

[13] Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA

[14] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[15] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[16] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[17] Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad, Razavi Khorasan, Iran

[18] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[19] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands

[20] Imperial Coll London, Dept Biostat & Epidemiol, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England

[21] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Gastroenterol & Hepatol, Chicago, IL 60611 USA

[22] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA

[23] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Cardiovasc Nutr Lab, Boston, MA 02111 USA

[24] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA

来源：

DIABETES | 2019年 / 68卷 / 05期

基金：

美国国家卫生研究院;

关键词：

EPIGENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; STEATOHEPATITIS;

D O I：

10.2337/DB18-1193

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 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 DNA methylation signatures of NAFLD across racial/ethnic groups.

引用

页码：1073 / 1083

页数：11

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