Genetics and epigenetics of NAFLD and NASH: Clinical impact
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Several other gene variants are also likely to modify MASH disease.
“while several other gene variants are also likely to modify disease(221).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [221]
Cites
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487 · see citing works
Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease
Miele, L., Valenza, V., La Torre, G., Montalto, M., Cammarota, G., Ricci, R., Mascianà, R., Forgione, A., Gabrieli, M. L., Perotti, G., et al. (2009) · Hepatology · doi:10.1002/hep.22848 · Cited by 1,434 · see citing works
Kozlitina, J., Smagris, E., Stender, S., Nordestgaard, B. G., Zhou, H. H., Tybjærg-Hansen, A., Vogt, T. F., Hobbs, H. H., & Cohen, J. C. (2014) · Nature Genetics · doi:10.1038/ng.2901 · Cited by 1,234 · see citing works
Liu, Y.-L., Reeves, H. L., Burt, A. D., Tiniakos, D., McPherson, S., Leathart, J. B. S., Allison, M. E. D., Alexander, G. J., Piguet, A.-C., Anty, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms5309 · Cited by 623 · see citing works
Buch, S., Stickel, F., Trépo, E., Way, M., Herrmann, A., Nischalke, H. D., Brosch, M., Rosendahl, J., Berg, T., Ridinger, M., et al. (2015) · Nature Genetics · doi:10.1038/ng.3417 · Cited by 565 · see citing works
Dongiovanni, P., Petta, S., Maglio, C., Fracanzani, A. L., Pipitone, R., Mozzi, E., Motta, B. M., Kaminska, D., Rametta, R., Grimaudo, S., et al. (2015) · Hepatology · doi:10.1002/hep.27490 · Cited by 533 · see citing works
Self-citationRelationship Between Methylome and Transcriptome in Patients With Nonalcoholic Fatty Liver Disease
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., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.07.047 · Cited by 391 · see citing works
BasuRay, S., Smagris, E., Cohen, J. C., & Hobbs, H. H. (2017) · Hepatology · doi:10.1002/hep.29273 · Cited by 302 · see citing works
Multigenerational epigenetic adaptation of the hepatic wound-healing response
Zeybel, M., Hardy, T., Wong, Y. K., Mathers, J. C., Fox, C. R., Gackowska, A., Oakley, F., Burt, A. D., Wilson, C. L., Anstee, Q. M., et al. (2012) · Nature Medicine · doi:10.1038/nm.2893 · Cited by 279 · see citing works
PNPLA3 I148M polymorphism and progressive liver disease
Dongiovanni, P. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i41.6969 · Cited by 252 · see citing works
Hardy, T., Zeybel, M., Day, C. P., Dipper, C., Masson, S., McPherson, S., Henderson, E., Tiniakos, D., White, S., French, J., et al. (2017) · Gut · doi:10.1136/gutjnl-2016-311526 · Cited by 216 · see citing works
Telomerase gene mutations are associated with cirrhosis formation
Hartmann, D., Srivastava, U., Thaler, M., Kleinhans, K. N., N'Kontchou, G., Scheffold, A., Bauer, K., Kratzer, R. F., Kloos, N., Katz, S.-F., et al. (2011) · Hepatology · doi:10.1002/hep.24217 · Cited by 173 · see citing works
Gariani, K., Ryu, D., Menzies, K. J., Yi, H.-S., Stein, S., Zhang, H., Perino, A., Lemos, V., Katsyuba, E., Jha, P., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2016.08.024 · Cited by 167 · see citing works
Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria
Berardi, M. J., & Chou, J. J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.004 · Cited by 76 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Eslam, M., Newsome, P. N., Sarin, S. K., Anstee, Q. M., Targher, G., Romero-Gomez, M., Zelber-Sagi, S., Wai-Sun Wong, V., Dufour, J.-F., Schattenberg, J. M., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.03.039 · Cited by 4,472 · see citing works
Self-citationMechanisms of NAFLD development and therapeutic strategies
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018) · Nature Medicine · doi:10.1038/s41591-018-0104-9 · Cited by 4,354 · see citing works
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 · see citing works
Self-citationRinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667 · see citing works
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement
Neeland, I. J., Ross, R., Després, J.-P., Matsuzawa, Y., Yamashita, S., Shai, I., Seidell, J., Magni, P., Santos, R. D., Arsenault, B., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30084-1 · Cited by 1,603 · see citing works
Ye, Q., Zou, B., Yeo, Y. H., Li, J., Huang, D. Q., Wu, Y., Yang, H., Liu, C., Kam, L. Y., Tan, X. X. E., et al. (2020) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(20)30077-7 · Cited by 925 · see citing works
Krishnan, S., Ding, Y., Saedi, N., Choi, M., Sridharan, G. V., Sherr, D. H., Yarmush, M. L., Alaniz, R. C., Jayaraman, A., & Lee, K. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.109 · Cited by 679 · see citing works
Mantovani, A., Csermely, A., Petracca, G., Beatrice, G., Corey, K. E., Simon, T. G., Byrne, C. D., & Targher, G. (2021) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00308-3 · Cited by 674 · see citing works
Determinants of Fibrosis Progression and Regression in NASH
Schuppan, D., Surabattula, R., & Wang, X. Y. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.11.012 · Cited by 479 · see citing works
NAFLD as a driver of chronic kidney disease
Byrne, C. D., & Targher, G. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.013 · Cited by 449 · see citing works
Role of Insulin Resistance in MAFLD
Sakurai, Y., Kubota, N., Yamauchi, T., & Kadowaki, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084156 · Cited by 448 · see citing works
Update on NAFLD genetics: From new variants to the clinic
Trépo, E., & Valenti, L. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.02.020 · Cited by 393 · see citing works
Self-citationAlcohol consumption and metabolic syndrome: clinical and epidemiological impact on liver disease
Åberg, F., Byrne, C. D., Pirola, C. J., Männistö, V., & Sookoian, S. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.08.030 · Cited by 307 · see citing works
Carlsson, B., Lindén, D., Brolén, G., Liljeblad, M., Bjursell, M., Romeo, S., & Loomba, R. (2020) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15738 · Cited by 169 · see citing works
Self-citationFatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release
Pan, J., Ou, Z., Cai, C., Li, P., Gong, J., Ruan, X. Z., & He, K. (2018) · Cellular Immunology · doi:10.1016/j.cellimm.2018.08.006 · Cited by 132 · see citing works
In Vitro Models for Non-Alcoholic Fatty Liver Disease: Emerging Platforms and Their Applications
Ramos, M. J., Bandiera, L., Menolascina, F., & Fallowfield, J. A. (2022) · iScience · doi:10.1016/j.isci.2021.103549 · Cited by 127 · see citing works
Soto-Angona, Ó., Anmella, G., Valdés-Florido, M. J., De Uribe-Viloria, N., Carvalho, A. F., Penninx, B. W. J. H., & Berk, M. (2020) · BMC Medicine · doi:10.1186/s12916-020-01713-8 · Cited by 122 · see citing works
Atabaki-Pasdar, N., Ohlsson, M., Viñuela, A., Frau, F., Pomares-Millan, H., Haid, M., Jones, A. G., Thomas, E. L., Koivula, R. W., Kurbasic, A., et al. (2020) · PLOS Medicine · doi:10.1371/journal.pmed.1003149 · Cited by 97 · see citing works
Macrophages in metabolic associated fatty liver disease
Alharthi, J., Latchoumanin, O., George, J., & Eslam, M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i16.1861 · Cited by 65 · see citing works
Self-citationEbrahimi, F., Hagström, H., Sun, J., Bergman, D., Shang, Y., Yang, W., Roelstraete, B., & Ludvigsson, J. F. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.08.018 · Cited by 65 · see citing works
The liver as a central "hub" of the immune system: pathophysiological implications
Ronca, V., Gerussi, A., Collins, P., Parente, A., Oo, Y. H., & Invernizzi, P. (2025) · Physiological Reviews · doi:10.1152/physrev.00004.2023 · Cited by 59 · see citing works
Eslam, M., Wong, G. L.-H., Hashem, A. M., Chan, H. L.-Y., Nielsen, M. J., Leeming, D. J., Chan, A. W.-H., Chen, Y., Duffin, K. L., Karsdal, M., et al. (2021) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000001059 · Cited by 53 · see citing works
Self-citationChronic hepatitis B infection with concomitant hepatic steatosis: current evidence and opinion
Shi, Y.-W., Yang, R.-X., & Fan, J.-G. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i26.3971 · Cited by 47 · see citing works
A Model of Hepatic Steatosis with Declined Viability and Function in a Liver-Organ-on-a-Chip
Wiriyakulsit, N., Keawsomnuk, P., Thongin, S., Ketsawatsomkron, P., & Muta, K. (2023) · Scientific Reports · doi:10.1038/s41598-023-44198-0 · Cited by 29 · see citing works
Advancements in MAFLD Modeling with Human Cell and Organoid Models
Wang, S.-X., Yan, J.-S., & Chan, Y.-S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911850 · Cited by 22 · see citing works
From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights
Gatzios, A., Rombaut, M., Buyl, K., De Kock, J., Rodrigues, R. M., Rogiers, V., Vanhaecke, T., & Boeckmans, J. (2022) · Biomedicines · doi:10.3390/biomedicines10010161 · Cited by 15 · see citing works
Liu, Z., Zhang, Y., Graham, S., Pique-Regi, R., Dong, X. C., Chen, Y. E., Willer, C., & Liu, W. (2019) · doi:10.1101/657734 · Cited by 250 · see citing works
- Authors
- Eslam, M., Valenti, L., & Romeo, S.
- Affiliations
- The University of Sydney (AU)
- University of Milan (IT)
- University of Gothenburg (SE)
- Corresponding author
- Eslam, Mohammed
- Valenti, Luca
- Romeo, Stefano
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 68
- Issue
- 2
- Pages
- 268-279
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2767801219
- Cited by
- 971
- References
- 14
- Citations by year
- 2026: 41 · 2025: 99 · 2024: 125 · 2023: 149 · 2022: 153 · 2021: 140 · 2020: 145 · 2019: 71 · 2018: 43 · 2017: 3 · 2015: 1
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NHMRC (1053206, APP1107178, APP1108422)
- AIRC (16888)
- Swedish Research Council (254439006, K2013-54X-11285-19)
- Swedish Heart Lung Foundation (244439007)
- Swedish federal government funding under the Agreement on Medical Training and Medical Research (76290)
- Sahlgrenska University Hospital ALF research (ALFGBG-428911)
- Novonordisk Foundation Grant for Excellence in Endocrinology (244439012)
- Swedish Diabetes Foundation (DIA 2014-052)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, genetic susceptibility, epigenetics, PNPLA3 I148M variant, TM6SF2, MBOAT7, GCKR, disease progression, fibrosis, hepatocellular carcinoma, biomarkers, personalized medicine, therapeutic target
- MeSH terms
- Humans, Prognosis, Disease Progression, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Genome-Wide Association Study, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
