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

. 2026 Feb 16;105(4):115.

doi: 10.1007/s00277-026-06800-z.

Mina Cintho Ozahata 3, Isabel Cristina Gomes Moura 4, Carolina Miranda 5, Anna Bárbara Carneiro-Proietti 5, Ester Cerdeira Sabino 6, Alessandra Ferraz 7, Cláudia Máximo 8, Miriam V Flor-Park 9, Daniela de Oliveira Werneck Rodrigues 5, Rosimere Afonso Mota 5, Brian Custer 10 11, Shannon Kelly 12, Carla Luana Dinardo 13; REDS-III Brazil SCD Cohort study and the TOPMed consortium

Affiliations

André Rolim Belisário et al. Ann Hematol. 2026.

Abstract

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: Cholelithiasis; Genome-wide association study; Hemolysis; Sickle cell disease; UGT1A1 variants.

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Conflict of interest statement

Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare no competing interests.

Figures

Fig. 1

Fig. 1

Cumulative incidence of gallbladder-related outcomes among individuals with sickle cell disease, stratified by genotype. (A) Cumulative incidence of cholelithiasis; (B) Cumulative incidence of cholecystitis; (C) Cumulative incidence of cholecystectomy. Curves are stratified by SCD genotype: HbSS, HbSβ⁰, and HbSβ⁺-severe (blue); HbSC (green); and milder HbSβ⁺ (red). The number at risk is shown below each plot. Among individuals with the HbSS/HbSβ⁰/HbSβ⁺-severe genotypes, the cumulative risk of cholelithiasis was 97.3% (95% CI: 95.1%–99.5%) by age 70; for cholecystitis, 55.0% (95% CI: 46.6%–63.4%) by age 62; and for cholecystectomy, 81.2% (95% CI: 76.1%–86.3%) by age 62. Among individuals with HbSC, the cumulative risk of cholelithiasis was 86.7% (95% CI: 76.5%–96.9%) by age 73; for cholecystitis, 36.4% (95% CI: 28.2%–44.6%) by age 61; and for cholecystectomy, 63.4% (95% CI: 55.7%–71.1%) by age 63. Among individuals with the HbSβ⁺ genotype, the cumulative risk of cholelithiasis was 42.1% (95% CI: 26.9%–57.3%) by age 35, and only one participant experienced cholecystectomy during the study period

Fig. 2

Fig. 2

Genome-wide association analyses for gallbladder-related outcomes in individuals with sickle cell disease. (A) Manhattan plot for indirect bilirubin, displaying the –log₁₀(p-value) for SNP associations across the genome, with a strong association peak observed on chromosome 2. (B) Manhattan plot for cholelithiasis, showing SNP associations across the genome. Three SNPs within the FER1L6 gene (rs77982802, rs142329888, and rs114020220) reached genome-wide significance. Variants at the UGT1A1 region showed p-values substantially lower than those commonly observed in validation cohorts of genotype–phenotype association studies (lowest p-value = 4.4 × 10⁻4). (C) Manhattan plot for cholecystectomy, highlighting a cluster of variants on chromosome 2 that approached or reached genome-wide significance. The dashed horizontal line in all plots represents the genome-wide significance threshold (p = 5 × 10⁻⁸)

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