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PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis
Open accessAbstract
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.
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“Overall evidence suggests that the PNPLA3 p.I148M and TM6SF2 p.E167K variants are major risk factors for progressive MASLD, and genotyping helps to noninvasively predict progressive MASH, cirrhosis and HCC when considered alongside clinical factors, 194 -196 but accuracy is suboptimal for prediction of liver disease severity and progression at the individual level.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [194]
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Wang, K., Xiang, S., He, Q., Huang, C., Yang, Z. Y., Li, R., Liu, A., Cai, R., Mi, N., Liang, Z., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6026627/v1 · Cited by 1
Ajmera, V. H. (2023) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.17478
de Souza, M. H. G., Al‐Sharif, L., Diaz, I., Mantovani, A., & Villela‐Nogueira, C. A. (2024) · Research Square · doi:10.21203/rs.3.rs-4118917/v1
Sun, C., Li, R., Shen, C., Zeng, Y., Li, J., Zhang, Q., Xue, H., Li, L., Yu, C.-C., Chen, X., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.5048711
Cirrhose métabolique : une entité en plein essor
Ratziu, V. (2024) · Bulletin de l Académie Nationale de Médecine · doi:10.1016/j.banm.2024.11.012
Yang, T.-H., Liu, X.-R., Su, T., Yin, S., Chen, Y.-T., Chen, F.-F., Pang, S., Hou, M., Peng, Y., Yang, S., et al. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5280175
Editorial: Time to Genotype—Genetic Risk and Prognosis in Steatotic Liver Disease. Authors' Reply
Kubina, M., & Chen, V. L. (2025) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.70361
Shabbir, A., Khatoon, A., Abbas, Z., Srivastava, S., & Mirza, T. (2025) · Medical Sciences · doi:10.3390/medsci13030178
Nádasdi, Á., & Firneisz, G. (2025) · Orvosi Hetilap · doi:10.1556/650.2025.33421
Umais, M., Imtiaz, H., Luqman, M. S., Anwar, S., Iftikhar, M. U., Maheshwari, K., Sara, Z. T., Naseem, N. U. H., Ibnath, F. A., Syed, A. R. S., et al. (2026) · Endocrine · doi:10.1007/s12020-025-04493-4
Nada, A., Elashkar, A. E., Elbahr, O. D., Atef, M., Mohammed, T. M., Elabd, N. S., & Othman, W. (2026) · Egyptian Liver Journal · doi:10.1186/s43066-026-00498-4
Hussain, R., Raut, C., Prabhu, P., Irshaid, A., Hegde, Y. D., Chen, Y., Pant, A., Oliveri, A., Wei, X., Yin, L., et al. (2026) · Journal of Lipid Research · doi:10.1016/j.jlr.2026.101013
Precision medicine in steatotic liver disease
Prasitsumrit, V., & Chen, V. L. (2026) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000001165
Qin, Y., Shuoshuo, M. A., Hong, H., Zhong, D., Liang, Y., Su, Y., Chen, Y., Chen, X., yizhun, Z., & Huang, X. (2026) · Pharmaceuticals · doi:10.3390/ph19030495
Rationale Diagnostik bei metabolischen Lebererkrankungen (MASLD)
Barton, A., & Schattenberg, J. M. (2026) · Die Diabetologie · doi:10.1007/s11428-026-01456-9
Lee, M. K., Stepanova, M., Estep, M., You, Y.-L., Liu, X.-R., de Avila, L., Lam, B., Yu, M., & Younossi, Z. M. (2026) · Liver International · doi:10.1111/liv.70675 · Cited by 1
Giangregorio, F., Civaschi, E., Mazzocchi, S., ROMANO, D., Clini, P., Centenara, E., Casale, U., & Catucci, D. (2026) · World Journal of Hepatology · doi:10.4254/wjh.v18.i5.118817
Metadata
- Authors
- Chen, V. L., Oliveri, A., Miller, M. J., Wijarnpreecha, K., Du, X., Chen, Y., Cushing, K. C., Lok, A. S., & Speliotes, E. K.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Chen, Vincent L.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 164
- Issue
- 6
- Pages
- 966-977.e17
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC10550206
- OpenAlex
- W4319442654
- Cited by
- 108
- References
- 54
- Citations by year
- 2026: 28 · 2025: 32 · 2024: 32 · 2023: 15
- FWCI
- 21.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- Funders
- National Institutes of Health
- NIDDK (K08 DK132312, R01 DK106621, R01 DK107904)
- American Association for the Study of Liver Diseases
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- non-alcoholic fatty liver disease, liver cirrhosis, PNPLA3, rs738409, genetic risk stratification, diabetes mellitus, FIB-4, liver fibrosis, alanine aminotransferase, obesity, disease progression, outcome prediction
- MeSH terms
- Acyltransferases, Diabetes Mellitus, Genotype, Humans, Liver Cirrhosis, Obesity, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Phospholipases A2, Calcium-Independent, Non-alcoholic Fatty Liver Disease
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