Background/Objectives: Gallbladder cancer (GBC) remains a leading cause of cancer death in Chilean women. Gallstones are present in >90% of GBC cases, but few individuals with gallstones develop cancer, suggesting additional factors are needed. Methods: To determine whether obesity increases the risk of progression from gallstones to high-grade dysplasia (HGD) and GBC, we used data from the Chile Biliary Longitudinal Study, 2016–2025, comprising women with ultrasound-detected gallstones in high-incidence regions of Chile.We measured body mass index (BMI) and waist-to-height ratio (WHtR) at baseline and up to two follow-up visits. We used Cox proportional-hazards models with age as the time scale to quantify associations of time-varying BMI and WHtR with HGD/GBC risk. Results: During a median follow-up of 4.8 years, 116 of 4711 women developed HGD/GBC. Time-varying BMI was not significantly associated with HGD/GBC risk (p-overall = 0.11; p-nonlinearity = 0.20). In contrast, time-varying WHtR showed a non-linear association with HGD/GBC (p-overall = 0.02; p-nonlinearity = 0.02). Baseline WHtR and BMI models showed similar patterns of associations. Based on longitudinal WHtR trajectories among cases and lag sensitivity analyses, preclinical disease-related weight loss is unlikely to fully explain the observed associations. Conclusions: In conclusion, central obesity measured by WHtR was non-linearly associated with HGD/GBC risk in this population, suggesting that central adiposity may impact the progression from gallstones to HGD/GBC.

Background: Gallbladder cancer (GBC) is highly fatal and, unlike most cancers, is more common in women than in men. Most GBC cases have gallstones, but most people with gallstones do not develop GBC. Thus, a critical question is what drives the risk of GBC in the presence of gallstones. Methods: We designed a case–control study to complement the Chile Biliary Longitudinal Study (Chile BiLS) cohort, enriching the number of GBC cases and enhancing our ability to evaluate risk factors for GBC. Starting in July 2022, we began to recruit non-cohort prevalent (diagnosed between January 1, 2016, and July 18, 2022) and incident (diagnosed on or after July 19, 2022) GBC cases, as well as patients with high-grade dysplasia (HGD), in a high-risk area of Chile. Individuals with GBC or HGD are considered cases (HGD +). We are matching gallstone cholecystectomy patients to cases at an approximate 1:1 ratio. We also include unmatched controls (adjudicated) who were initially suspected of having cancer but had benign findings on gallbladder pathology. If a case or control is deceased, we conduct proxy interviews to maximize the potential for detailed epidemiological data collection. Through August 31, 2025, we recruited 196 prevalent and 117 incident HGD + cases. Of these cases, 189 (96%) prevalent and 108 (92%) incident cases were diagnosed with GBC. All prevalent and 98.3% of incident cases have matched controls. Participation rates are 70.8% for HGD + cases and 67.8% for matched controls. Discussion: The Chile BiLS case–control study is conducted in an area with high risk of GBC and a high proportion of people with Mapuche Amerindian ancestry. This study will provide important insights into the factors associated with GBC among people with gallstones. Here, we provide a thorough description of the design of the study, field procedures, and biological resources, as well as research opportunities, which will enable a more complete picture of the etiology of GBC by combining epidemiological, molecular, digital imaging, and clinical data. This study represents a powerful resource for the identification of new targets for cancer prevention and treatment, which are particularly needed in populations at high risk of GBC.