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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-026-06800-z.

Keywords: Sickle cell disease, Cholelithiasis, Hemolysis, Genome-wide association study, UGT1A1 variants