WBCs as a mediator between the TG/HDL ratio and gallstone disease across sex differences: NHANES 2017–2020

Background Gallstone disease (GSD) is associated with insulin resistance (IR) and systemic inflammation, yet the quantitative relationships among these factors remain underexplored. This study investigated the association between IR surrogate indices and the GSD, with a focus on the mediating role of inflammation and potential sex-based differences. Methods Insulin resistance was assessed via biomarkers, including the triglyceride-to-high-density lipoprotein cholesterol (TG/HDL) ratio; TyG, METS-IR, and HOMA-IR, and inflammatory markers, such as white blood cells (WBCs). The associations between TG/HDL and GSD were assessed through logistic regression models and restricted cubic spline (RCS) analysis. Subgroup analyses were conducted on basis of age, sex, marital status, education, poverty-to-income ratio (PIR) and body mass index (BMI). Furthermore, a key focus of the analysis was to investigate the mediating role of WBC count in the relationship between TG/HDL and incident GSD. Additionally, interactions between sex and TG/HDL were tested on both multiplicative and additive scales. Results Among the 3,624 included participants (383 with gallstones and 3,241 without), the mean age was 50.8 ± 17.2 years. Among those diagnosed with gallstone disease, the female-to-male ratio was 2.52:1. The highest quartile (Q4) of TG/HDL was significantly associated with increased GSD risk in the fully adjusted model (OR = 1.63; 95% CI: 1.07–2.49; P = 0.022), whereas TyG, METS-IR, and HOMA-IR did not have significant associations with Q4 (all P > 0.05). RCS analysis revealed a nonlinear, reverse L-shaped relationship between TG/HDL and GSD risk (P = 0.049). Mediation analysis revealed that in the unadjusted model, the WBC count fully mediated the association between the TG/HDL ratio and GSD, accounting for 28.6% of the total effect. After adjusting for sex and age, the WBC count partially mediated this relationship, explaining 17.2% of the effect. Interaction analysis demonstrated a significant additive interaction effect between sex and the TG/HDL ratio (P < 0.05), without a significant multiplicative interaction effect (P > 0.05), suggesting increased GSD risk in females. No significant interactions were observed between WBC count and TG/HDL. Conclusions The TG/HDL ratio is strongly associated with GSD risk, exhibiting a nonlinear relationship partially mediated by inflammation, as indexed by the WBC count. Sex exerts an additive effect on this association, highlighting potential hormonal contributions to gallstone formation.