Laboratory and genetic characteristic associated with gallbladder-related outcomes in sickle cell disease in Brazil: results from the REDS-III multicenter cohort study

Sickle cell disease (SCD) is a hereditary disorder characterized by HBB variants, leading to chronic hemolytic anemia and vaso-occlusion. Hepatobiliary complications, including cholelithiasis, are common but underreported. This study investigated the rates and risk factors for cholelithiasis, cholecystitis, and cholecystectomy in a large Brazilian SCD cohort. Data from 2,778 individuals across six referral centers in the REDS-III Brazilian SCD cohort were analyzed. Clinical, laboratory, and genetic data were obtained retrospectively at enrollment and prospectively during follow-up. Gallbladder-related outcomes were assessed through medical records and imaging. Whole-genome sequencing was performed via the TOPMed program. Genome-wide association analyses used logistic mixed models adjusted for age, sex, genotype, and the first 10 principal components. Cholelithiasis, cholecystitis, and cholecystectomy occurred in 35.9%, 25.1%, and 10.6% of participants, respectively. Indirect bilirubin was consistently associated with all outcomes, while associations with other laboratory variables varied by genotype. Genetic analyses confirmed associations between UGT1A1 variants and bilirubin levels and identified genome-wide associations with cholecystectomy. Novel loci, including FER1L6, LRFN5, and SDK2, were also implicated. These findings indicate a high burden of gallbladder-related disease in Brazilian individuals with SCD and highlight both established and novel genetic pathways that may inform risk stratification and preventive strategies.