Genome-wide association study identifies three PNPLA3/SAMM50 SNPs associated with HCC development in non-viral liver disease.
Journal
JHEP reports : innovation in hepatology
Journal Volume
8
Journal Issue
2
Start Page
101673
ISSN
2589-5559
Date Issued
2026-02
Author(s)
Liu, Xia-Rong
Yang, Tsai-Hsuan
Yin, Szu-Ching
Chen, Yi-Ting
Chen, Fen-Fang
Pang, See-Tong
Hou, Ming-Chih
Peng, Yen-Chun
Yang, Shun-Fa
Huang, Peng-Ju
Lee, Sing-Lian
Huang, Chih-Yang
Chen, Ming
Chang, Ya-Hsuan
Chen, Hsuan-Yu
Yang, Hwai-I
Yu, Ming-Lung
Chen, Chien-Jen
Lee, Mei-Hsuan
Abstract
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: Ten SNPs in PNPLA3/SAMM50 were significantly associated with HCC risk (p <1.62 × 10-7) 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: This study identified PNPLA3/SAMM50 variants significantly associated with long-term HCC risk in individuals without viral hepatitis. These findings highlight their potential utility as biomarkers for HCC risk stratification and underscore the need for further research into underlying mechanisms.
Impact and implications: Variants in the PNPLA3/SAMM50 locus were significantly associated with hepatocellular carcinoma (HCC) risk in individuals seronegative for HBsAg and anti-HCV. The stepwise increase in HCC risk with higher numbers of risk alleles suggests their potential utility as biomarkers to identify high-risk individuals without a history of chronic hepatitis B or C virus infection. These findings provide a foundation for genetic risk stratification and precision prevention strategies in populations where non-viral etiologies of HCC are becoming increasingly important.
Subjects
Steatosis
biobank
long-term risk
prospective cohort
susceptibility
Type
journal article