Polygenic Risk Score of Metabolic Dysfunction-associated Steatotic Liver Disease Amplifies the Health Impact on Severe Liver Disease and Metabolism-related Outcomes

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Jul 12

PMID 38997780

Authors

Lushan Xiao

Yan Li

Chang Hong

Pengcheng Ma

Hongbo Zhu

Hao Cui

Xuejing Zou

Jiaren Wang

Ruining Li

Jingzhe He

Shengxing Liang

Zeyang Li

Lin Zeng

Li Liu

Affiliations

Soon will be listed here.

Abstract

Background: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes.

Methods: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes.

Results: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes.

Conclusions: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.

Citing Articles

Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease.

Pei Y, Goh G Gut Liver. 2025; 19(1):8-18.

PMID: 39774124 PMC: 11736312. DOI: 10.5009/gnl240407.

References

Unalp-Arida A, Ruhl C . Patatin-Like Phospholipase Domain-Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population. Hepatology. 2019; 71(3):820-834. DOI: 10.1002/hep.31032. View

Eslam M, Sanyal A, George J . MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020; 158(7):1999-2014.e1. DOI: 10.1053/j.gastro.2019.11.312. View

Liu Z, Suo C, Shi O, Lin C, Zhao R, Yuan H . The Health Impact of MAFLD, a Novel Disease Cluster of NAFLD, Is Amplified by the Integrated Effect of Fatty Liver Disease-Related Genetic Variants. Clin Gastroenterol Hepatol. 2021; 20(4):e855-e875. DOI: 10.1016/j.cgh.2020.12.033. View

He H, Liao S, Zeng Y, Liang L, Chen J, Tao C . Causal relationships between metabolic-associated fatty liver disease and iron status: Two-sample Mendelian randomization. Liver Int. 2022; 42(12):2759-2768. DOI: 10.1111/liv.15455. View

Hsu C, Loomba R . From NAFLD to MASLD: implications of the new nomenclature for preclinical and clinical research. Nat Metab. 2024; 6(4):600-602. PMC: 11262457. DOI: 10.1038/s42255-024-00985-1. View

Eslam M, Newsome P, Sarin S, Anstee Q, Targher G, Romero-Gomez M . A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020; 73(1):202-209. DOI: 10.1016/j.jhep.2020.03.039. View

Yonezawa Y, Takahashi I, Ohseto H, Ueno F, Onuma T, Noda A . Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study. BMC Pregnancy Childbirth. 2024; 24(1):209. PMC: 10953086. DOI: 10.1186/s12884-024-06376-4. View

Anstee Q, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D . Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort. J Hepatol. 2020; 73(3):505-515. DOI: 10.1016/j.jhep.2020.04.003. View

Akbarzadeh M, Alipour N, Moheimani H, Zahedi A, Hosseini-Esfahani F, Lanjanian H . Evaluating machine learning-powered classification algorithms which utilize variants in the GCKR gene to predict metabolic syndrome: Tehran Cardio-metabolic Genetics Study. J Transl Med. 2022; 20(1):164. PMC: 8994379. DOI: 10.1186/s12967-022-03349-z. View

10.

Eslam M, Valenti L, Romeo S . Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol. 2017; 68(2):268-279. DOI: 10.1016/j.jhep.2017.09.003. View

11.

Wang J, Zeng L, Hong C, Cui H, Wang W, Zhu H . Lower creatinine to cystatin C ratio is associated with an increased risk of MASLD: A cross-sectional and prospective study of 368,634 UK Biobank participants. Clin Endocrinol (Oxf). 2023; 100(2):116-123. DOI: 10.1111/cen.14990. View

12.

Pashos E, Park Y, Wang X, Raghavan A, Yang W, Abbey D . Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci. Cell Stem Cell. 2017; 20(4):558-570.e10. PMC: 5476422. DOI: 10.1016/j.stem.2017.03.017. View

13.

Kaya E, Yilmaz Y . Metabolic-associated Fatty Liver Disease (MAFLD): A Multi-systemic Disease Beyond the Liver. J Clin Transl Hepatol. 2022; 10(2):329-338. PMC: 9039705. DOI: 10.14218/JCTH.2021.00178. View

14.

Esteve-Luque V, Padro-Miquel A, Fanlo-Maresma M, Corbella E, Corbella X, Pinto X . Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia. Nutrients. 2021; 13(2). PMC: 7914661. DOI: 10.3390/nu13020552. View

15.

Speliotes E, Yerges-Armstrong L, Wu J, Hernaez R, Kim L, Palmer C . Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011; 7(3):e1001324. PMC: 3053321. DOI: 10.1371/journal.pgen.1001324. View

16.

Maldonado-Gonzalez M, Hernandez-Nazara Z, Torres-Castillo N, Martinez-Lopez E, De la Cruz-Color L, Ruiz-Madrigal B . Association between the rs3812316 Single Nucleotide Variant of the Gene and Alpha-Linolenic Acid Intake with Triglycerides in Mexican Mestizo Women. Nutrients. 2022; 14(22). PMC: 9692638. DOI: 10.3390/nu14224726. View

17.

Ghodsian N, Abner E, Emdin C, Gobeil E, Taba N, Haas M . Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med. 2021; 2(11):100437. PMC: 8606899. DOI: 10.1016/j.xcrm.2021.100437. View

18.

Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M . Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2015; 64(1):73-84. DOI: 10.1002/hep.28431. View

19.

Hsu C, Chang S, Nfor O, Lee K, Ho C, Liu C . Association of Metabolic Syndrome with Aerobic Exercise and LPL rs3779788 Polymorphism in Taiwan Biobank Individuals. Diabetes Metab Syndr Obes. 2021; 14:3997-4004. PMC: 8449547. DOI: 10.2147/DMSO.S328308. View

20.

Onuma H, Tabara Y, Kawamoto R, Shimizu I, Kawamura R, Takata Y . The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population. J Hum Genet. 2010; 55(9):600-4. DOI: 10.1038/jhg.2010.75. View