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 | |
| State | Published - 2019 |
| Externally published | Yes |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
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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
N1 - Funding Information: Infrastructure for the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grant R01- HL-105756. This work was supported in part by the Intramural Research Program of the NIH: NHLBI; National Institute on Aging (NIA); and National Institute of Environmental Health Sciences. The FHS is funded by NIH contract N01- HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, Bethesda, MD. The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH. The generation and management of the Illumina HumanMethylation450K BeadChip array data (EWAS data) for the RS was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center, and by the Netherlands Organization for Scientific Research (NWO) (project number 184021007) and made available as a Rainbow Project (RP3 [Biobank-based Integrative Omics Study (BIOS)]) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The RS is funded by Erasmus University Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (Directorate-General XII); and the Municipality of Rotterdam. MESA and the MESA SHARe (SNP Health Association Resource) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts NIH N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC- 95169, UL1-TR-001079, UL1-TR-000040, and DK063491. The MESA Epigenomics and Transcriptomics Study was funded by NIA grant 1R01HL101250-01 to Wake Forest University Health Sciences. CARDIA is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C and grant R01-HL098445 for the year 25 CT exam (J.J.C.) from the NHLBI. The laboratory work and analytical component were funded by the American Heart Association (17SFRN33700278 and 14SFRN20790000 [L.H.]). L.B.V. is supported by NHLBI grant K23-HL-136891. Support for GENOA was provided by the NHLBI of the NIH (HL-054464, HL-054457, HL-054481, HL-100185, HL-119443, HL-085571, and HL-133221). Funding Information: Acknowledgments. The authors thank Michael Verbiest, Mila Jhamai, Sarah Higgins, Marijn Verkerk, and Lisette Stolk (Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands) for their help in creating the methylation database. The authors are grateful to the study participants, the staff from the RS, and the participating general practitioners and pharmacists. The authors also thank the families that participated in GENOA. Funding. Infrastructure for the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), grant R01-HL-105756. This work was supported in part by the Intramural Research Program of the NIH: NHLBI; National Institute on Aging (NIA); and National Institute of Environmental Health Sciences. The FHS is funded by NIH contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, Bethesda, MD. The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH. The generation and management of the Illumina HumanMethylation450K BeadChip array data (EWAS data) for the RS was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center, and by the Netherlands Organization for Scientific Research (NWO) (project number 184021007) and made available as a Rainbow Project (RP3 [Biobank-based Integrative Omics Study (BIOS)]) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). The RS is funded by Erasmus University Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (Directorate-General XII); and the Municipality of Rotterdam. MESA and the MESA SHARe (SNP Health Association Resource) project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts NIH N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. The MESA Epigenom-ics and Transcriptomics Study was funded by NIA grant 1R01HL101250-01 to Wake Forest University Health Sciences. CARDIA is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C and grant R01-HL098445 for the year 25 CT exam (J.J.C.) from the NHLBI. The laboratory work and analytical component were funded by the American Heart Association (17SFRN33700278 and 14SFRN20790000 [L.H.]). L.B.V. is supported by NHLBI grant K23-HL-136891. Support for GENOA was provided by the NHLBI of the NIH (HL-054464, HL-054457, HL-054481, HL-100185, HL-119443, HL-085571, and HL-133221). Publisher Copyright: © 2019 by the American Diabetes Association.
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.
UR - http://www.scopus.com/inward/record.url?scp=85065112934&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065112934&partnerID=8YFLogxK
U2 - 10.2337/DB18-1193
DO - 10.2337/DB18-1193
M3 - Article
C2 - 30936141
AN - SCOPUS:85065112934
SN - 0012-1797
VL - 68
SP - 1073
EP - 1083
JO - Diabetes
JF - Diabetes
IS - 5
ER -