The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Relationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease
Open accessAbstract
Background & aims Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting noninvasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression.Methods We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0-1 (mild) and F3-4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome.Results Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P < .05). Methylation at fibroblast growth factor receptor 2, methionine adenosyl methyltransferase 1A, and caspase 1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, and genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and underexpressed.Conclusions Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.
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“Moreover, certain patterns of DNA methylation at fibrosis-related genes, such as those encoding TGFβ1, COL1A1, PDGFα, peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferator-activated receptor delta (PPARδ), can not only distinguish between patients with mild versus advanced MASLD, but also predict future fibrosis progression (169-172).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [169]
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Bioconductor: open software development for computational biology and bioinformatics
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Self-citationDNA methylation and human disease
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MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease
Eslam, M., Sanyal, A. J., George, J., Sanyal, A., Neuschwander-Tetri, B., Tiribelli, C., Kleiner, D. E., Brunt, E., Bugianesi, E., Yki-Järvinen, H., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.312 · Cited by 3,286
Self-citationBoursier, J., Mueller, O., Barret, M., Machado, M., Fizanne, L., Araujo‐Perez, F., Guy, C. D., Seed, P. C., Rawls, J. F., David, L. A., et al. (2016) · Hepatology · doi:10.1002/hep.28356 · Cited by 1,483
“Several other factors that influence the course of the disease have been identified, such as epigenetics,((4)) hormonal status,((5)) or nutrition.”
BackgroundSelf-citationTriggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943
Nonalcoholic fatty liver disease
Brunt, E. M., Wong, V. W., Nobili, V., Day, C. P., Sookoian, S. C., Maher, J. J., Bugianesi, E., Sirlin, C. B., Neuschwander‐Tetri, B. A., & Rinella, M. E. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.80 · Cited by 882
Genetics and epigenetics of NAFLD and NASH: Clinical impact
Eslam, M., Valenti, L., & Romeo, S. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.003 · Cited by 971
Metadata
- Authors
- Murphy, S. K., Yang, H., Moylan, C. A., Pang, H., Dellinger, A., Abdelmalek, M. F., Garrett, M. E., Ashley–Koch, A., Suzuki, A., Tillmann, H. L., Hauser, M. A., & Diehl, A. M.
- Affiliations
- Duke University (US)
- Corresponding author
- Diehl, Anna Mae
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 145
- Issue
- 5
- Pages
- 1076-1087
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC3805742
- OpenAlex
- W2150020322
- Cited by
- 391
- References
- 48
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 36 · 2023: 37 · 2022: 31 · 2021: 35 · 2020: 31 · 2019: 38 · 2018: 40 · 2017: 32 · 2016: 26 · 2015: 28 · 2014: 17 · 2013: 2
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Institutes of Health (5rc2aa019399-02)
- National Institute on Alcohol Abuse and Alcoholism (5RC2-AA019399, RC2-AA019399)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007568)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- non-alcoholic fatty liver disease, DNA methylation, transcriptome, liver fibrosis, disease severity, differentially methylated CpG sites, gene expression, FGF2, MAT1A, caspase-1, one-carbon metabolism, NAFLD progression, non-invasive diagnosis
- MeSH terms
- Adult, Biopsy, Diagnosis, Differential, Fatty Liver, Female, Gene Expression Regulation, Humans, Liver, Male, Methionine Adenosyltransferase, Middle Aged, Severity of Illness Index, Cohort Studies, Disease Progression, CpG Islands, DNA Methylation, Caspase 1, Receptor, Fibroblast Growth Factor, Type 2, Transcriptome, Non-alcoholic Fatty Liver Disease
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