Genome-wide association study identifies three PNPLA3/SAMM50 SNPs associated with HCC development in non-viral liver disease

作者：Xia-Rong Liu, Tsai-Hsuan Yang, Tung‐Hung Su, Szu‐Ching Yin, Yi-Ting Chen, Fen-Fang Chen, See‐Tong Pang, Ming‐Chih Hou, Yen-Chun Peng, Shun‐Fa Yang, Peng‐Ju Huang, S. Lee, I‐Ming Chen, Chih‐Yang Huang, Ya‐Hsuan Chang, Hsuan‐Yu Chen, Hwai‐I Yang, Ming‐Lung Yu, Chien‐Jen Chen, Jia‐Horng Kao, Mei‐Hsuan Lee · 发表于：JHEP Reports · 年份：2025 · DOI：10.1016/j.jhepr.2025.101673 · 被引用次数：3 · 研究领域：Liver Disease Diagnosis and Treatment、Hepatitis C virus research、Genetic Associations and Epidemiology

Background & Aims: Few genome-wide association studies have examined genetic variants associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV, and the long-term impact of these variants remains uncertain. Methods: This multi-stage study analyzed adults >30 years old who were seronegative for HBsAg and anti-HCV. In the genome-wide association study discovery phase, 765 HCC cases and 9,949 controls were analyzed for 308,693 SNPs, with significant SNPs confirmed in community-based (171 HCC cases, 684 controls) and hospital-based (470 HCC cases, 5,460 controls) validation sets. A cohort of 67,909 participants, followed from 2012 to 2021, was used to evaluate the long-term HCC risk associated with these variants. Results: ) and were in high linkage disequilibrium. Three SNPs (rs738409, rs2281135, rs2235776) were replicated and demonstrated strong associations with HCC, independent of steatosis. Over 267,238 person-years of follow-up, 32 new HCC cases occurred, with elevated risks observed in individuals homozygous for the risk genotypes: GG (rs738409), AA (rs2281135), and TT (rs2235776). The adjusted hazard ratios (95% CI) were 3.37 (1.32-8.63), 2.80 (1.06-7.37), and 2.64 (0.91-7.66), respectively. In allelic models, carriers of the risk allele had higher HCC risk, with adjusted hazard ratios (95% CI) of 1.88 (1.14-3.10) for rs738409, 1.68 (1.02-2.78) for rs2281135, and 1.61 (0.98-2.67) for rs2235776. Conclusions: variants significant...