Newly identified single-nucleotide polymorphism associated with the transition from nonalcoholic fatty liver disease to liver fibrosis: results from a nested case-control study in the UK biobank

• Published in: Annals of medicine (Helsinki) Vol. 57; no. 1; p. 2458201
• Main Authors: Ling, Yitong, Yang, Yu Xuan, Chen, Yan Chun, Wang, Jing Hao, Feng, Dong Ge, Xiang, Shi Jian, Zhang, Xiaoyu, Lyu, Jun, Li, Sha Sha
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.12.2025; Taylor & Francis Group
• Subjects: Adult; Aged; Biological Specimen Banks; Case-Control Studies; Cell Line; Collagen Type I, alpha 1 Chain; Disease Progression; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Hepatic Stellate Cells - metabolism; Hepatology; Humans; liver cirrhosis; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Male; Middle Aged; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; nonalcoholic fatty liver disease; Oxidative Stress - genetics; Polymorphism, Single Nucleotide; SAMM50-rs2073080; Single-nucleotide polymorphism; UK Biobank; United Kingdom - epidemiology; United Kingdom; SAMM50-rs2073080; nonalcoholic fatty liver disease; Single-nucleotide polymorphism; liver cirrhosis
• ISSN: 0785-3890; 1365-2060; 1365-2060
• DOI: 10.1080/07853890.2025.2458201

Genetic factors may have a significant influence on the likelihood of liver fibrosis in individuals with nonalcoholic fatty liver disease (NAFLD). The present study was conducted to explore how single-nucleotide polymorphism (SNP) impacts the development of fibrosis in those suffering from NAFLD. Utilizing the UK Biobank dataset, we conducted a nested case-control analysis among NAFLD participants, defining the case group as those with liver fibrosis and cirrhosis during follow-up. For our investigations, we employed the LX-2 human hepatic stellate cell line. Our procedures included cultivating these cells, employing SAMM50-rs2073080 plasmid techniques to enhance the expression of recently discovered SNPs, and conducting biochemical assays. To quantify gene expression, we used real-time PCR with fluorescence detection. The study analyzed data from 5467 participants (1094 cases and 4373 controls). Genome-wide association analysis identified nine significant loci, including the novel rs2073080 variant, strongly associated with NAFLD-associated hepatic fibrosis. TGF-β modeling revealed significant upregulation of α-SMA and COL1A1, confirming model effectiveness. Oxidative stress markers like elevated malondialdehyde (MDA) and reduced catalase (CAT) and superoxide dismutase (SOD) levels indicated liver damage in the TGF-β group. SAMM50-rs2073080 was upregulated in the NAFLD-associated fibrosis model. experiments on LX-2 cells showed that SAMM50-rs2073080 overexpression led to increased fibrosis, as indicated by higher cellular MDA levels and lower CAT and SOD levels, compared to the vector group. Our research highlights a significant association of SAMM50-rs2073080 with the progression of NAFLD to hepatic fibrosis, and the experiments further corroborated these findings.