Song et al. constructed a novel model to stratify hepatocellular carcinoma (HCC) risk in the general population without established risk factors for chronic liver disease 1. Our previous analyses demonstrated genetic susceptibility to HCC among patients with chronic hepatitis B (CHB) 2. In addition, emerging evidence indicates that HCC risk is associated with air pollution exposure 3. We therefore integrated individual-level estimates of air pollution exposure and single-nucleotide polymorphisms (SNPs) to evaluate incident HCC using Cox proportional hazards regression. This cohort was based on data from our previous study 2. After adjustment for age, sex, body mass index, cirrhosis status, and relevant SNPs, two factors remained independently associated with HCC development: the GCKR rs1260326 TT genotype (hazard ratio HR 13.64, 95% confidence interval CI 2.57–72.40; p = 0.002) and NO2 exposure (HR 1.12 per unit increase, 95% CI 1.01–1.25; p = 0.04). Notably, our preliminary Cox regression analysis revealed that, in addition to genetic susceptibility, elevated NO2 exposure was an independent significant predictor of HCC, suggesting that environmental factors may play a crucial role in the progression from cirrhosis to HCC. We further identified a statistically significant interaction between NO2 exposure and the GCKR rs1260326 TT genotype (Table 1). When NO2 exposure was categorized into quartiles and combined with genotype status, a clear exposure–response relationship was observed, with progressively increasing HCC risk among individuals carrying the TT genotype at higher NO2 exposure levels. The GCKR rs1260326 variant is known to influence hepatic glucose and lipid metabolism and has been implicated in metabolic liver disease. In addition, accumulating evidence supports a direct link between air pollution and hepatocarcinogenesis. Notably, prior studies in CHB patients receiving nucleotide/nucleoside analogue therapy have demonstrated that long-term exposure to ambient air pollution is independently associated with HCC development, underscoring the oncogenic potential of air pollutants beyond viral and metabolic risk factors 3. In summary, together with the published evidence linking air pollution to fatty liver and cirrhosis, our data support a disease continuum in which long-term exposure to air pollution contributes to liver injury 4, fibrosis 5, and ultimately HCC, particularly in genetically susceptible individuals. These findings underscore the importance of incorporating environmental exposures and gene–environment interactions into liver cancer risk stratification and prevention strategies. This study was supported by the Ministry of Health and Welfare, Pingtung Hospital, and Kaohsiung Medical University Hospital. The authors thank the secretaries of the Hepatobiliary Division in Kaohsiung Medical University Hospital. The author declares no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Tyng‐Yuan Jang (Fri,) studied this question.