Joint associations of TyG-BMI and SIRI with incident gallstone disease: a cohort study

Background Insulin resistance and chronic low-grade inflammation have been associated with gallstone disease, but their joint associations remain unclear. This study aimed to investigate the independent and joint associations of the triglyceride-glucose body mass index (TyG-BMI) and the systemic inflammation response index (SIRI) with incident gallstone disease. Methods This observational cohort study was based on the Dalian Health Management Cohort and included 52,196 adults who underwent at least two health examinations between 2014 and 2023. Gallstone disease was diagnosed by abdominal ultrasonography. Cox proportional hazards regression models were used to evaluate the associations of TyG-BMI and SIRI with incident gallstone disease, individually and jointly. Restricted cubic spline (RCS) analyses were performed to assess dose–response relationships. Additive and multiplicative interaction analyses and incremental predictive value analyses were then conducted. In addition, an exploratory mediation analysis was performed to examine potential indirect associations involving TyG-BMI and SIRI in relation to incident gallstone disease. Results During a mean follow-up of 3.18 ± 1.93 years, 1,412 participants developed incident gallstone disease. After multivariable adjustment, both TyG-BMI and SIRI were independently associated with an increased risk of incident gallstone disease (TyG-BMI: hazard ratio (HR) = 1.30, 95% confidence interval (CI): 1.22–1.39; SIRI: HR = 1.13, 95% CI: 1.07–1.18). Compared with the lowest tertile, participants in the highest tertile of TyG-BMI (HR = 1.60, 95% CI: 1.37–1.88) and SIRI (HR = 1.35, 95% CI: 1.19–1.54) had significantly higher risks of incident gallstone disease. Joint analysis showed that participants with both high TyG-BMI and high SIRI had approximately a 2.20-fold higher risk of gallstone disease than those with both low TyG-BMI and low SIRI (HR = 2.20, 95% CI: 1.75–2.78). RCS analyses showed approximately linear positive associations between both biomarkers and gallstone disease risk. No statistically significant additive or multiplicative interaction was observed. Incremental predictive value analysis indicated that incorporating both TyG-BMI and SIRI into the base model increased the area under the curve (AUC) to 0.597 (ΔAUC = 0.025; Holm-adjusted p < 0.001). Exploratory mediation analysis identified statistically significant estimated indirect associations under both model specifications, each accounting for a small proportion of the respective total association. Conclusion Both TyG-BMI and SIRI were independently associated with incident gallstone disease, and individuals with concomitantly elevated levels of both markers had a higher risk of developing gallstone disease. These findings highlight the relevance of jointly considering metabolic and inflammatory status in epidemiological studies of gallstone disease.