ABSTRACT Background and Aims PNPLA3 variants are associated with increased hepatocellular carcinoma (HCC) risk. We examined the association between a combination of the PNPLA3 I148M genotype and clinical risk factors with HCC risk using data from a large, ongoing, population‐based, prospective cohort study, the Singapore Chinese Health Study. Approach and Results This study included 24,979 participants (54.2% female). The primary outcome was incident HCC. Fine‐Grey models were used to examine the association between a combination of the PNPLA3 I148M genotype and clinical risk factors and risk of HCC. After a median follow‐up of 19.8 years, we identified 214 HCC incident cases. Males who were homozygous carriers for PNPLA3 I148M (adjusted hazard ratio aHR = 9.23, 95% confidence interval CI: 4.81–17.70) had a nine‐fold risk of HCC, while heterozygous male carriers (aHR 4.83, CI: 2.63–8.89) had a five‐fold risk of HCC, compared to non‐carrier females. Homozygous carriers who were overweight (aHR = 2.92, 95% CI: 1.74–4.89) had a three‐fold risk of HCC compared to non‐carriers who were not overweight. Participants with diabetes and who were homozygous carriers (aHR 2.83, 95% CI: 1.21–6.61) had an approximately three‐fold risk of HCC compared to non‐carriers without diabetes. Conclusion The frequency of rs738409‐G alleles was associated with a dose‐dependent increase in HCC risk and was independent of other clinical risk factors. Among participants who were male, overweight, and those with diabetes, the risk of HCC was further elevated among those with rs738409‐G alleles. These data may be helpful for the development of future risk stratification strategies.
Dj et al. (2026) studied this question.