Association between the IL-35 rs583911 polymorphism and hepatocellular carcinoma risk in patients infected with chronic hepatitis B virus

Abstract

Abstract Background The immunoregulatory cytokine interleukin (IL)-35 has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). Here, we explored the association between single-nucleotide polymorphisms (SNPs) in the IL-35 gene and the occurrence of HCC in patients with chronic hepatitis B virus (HBV). Methods We selected 39 patients with chronic hepatitis B (HBV) and 52 patients with HBV-related hepatocellular carcinoma (HCC) as the case groups, along with 42 healthy individuals as the control group. We genotyped five IL-35-related single-nucleotide polymorphisms (SNPs) and analyzed their association with HCC risk. In addition, serum IL-35 levels, lymphocyte counts, and regulatory T cell (Treg) frequencies were measured in peripheral blood across all groups. Results The frequency of the rs583911 AA genotype tended to increase from healthy controls (4.8%) to patients with chronic HBV (10.3%) to patients with HCC (21.2%) (P for trend = 0.03). When patients with HCC were compared to non-HCC controls (healthy controls + chronic HBV carriers), the rs583911 AA genotype was associated with HCC risk (OR = 3.35; 95% CI: 1.17–9.61, P = 0.020). After adjusting for age, sex, cirrhosis status, and antiviral therapy, the association was no longer statistically significant (adjusted P = 0.085). Serum IL-35 levels were significantly elevated in both the HBV and the HCC groups compared with those in the control group ( P < 0.001), with no significant difference between the HBV and the HCC groups ( P = 0.434). Within the HCC subgroup, patients with the AA genotype tended to have higher IL-35 levels ( P = 0.047). Flow cytometry analysis of a subset of samples (6 controls, 6 patients with HBV, and 28 patients with HCC) revealed that the number of Treg cells was greater in patients with HCC than in those with HBV ( P = 0.038). Conclusion Our findings suggest a potential association between the rs583911 AA genotype and HBV-related HCC risk. However, these exploratory findings did not remain statistically significant after rigorous adjustment for multiple comparisons and potential confounders; therefore, validation in larger, independent cohorts is needed.