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Influence of UGT1A1 promoter polymorphism, α-thalassemia and βs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort

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Abstract

Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and βS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, −3.7 kb alpha thalassemia deletion and βS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with βS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.

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Acknowledgments

The authors acknowledge all patients and their parents for their collaboration in this study.

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #483714/2013–5).

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Author notes

  1. Jéssica V. G. F. Batista and Gabriela S. Arcanjo contributed equally to this work.

Authors and Affiliations

  1. Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil

    Jéssica V. G. F. Batista, Gabriela S. Arcanjo, Thais H. C. Batista, Marcondes J. Sobreira, Rodrigo M. Santana, Igor F. Domingos, Betânia L. Hatzlhofer, Diego A. Falcão, Jéssica M. Oliveira, Amanda S. Araujo, Luana P. M. Laranjeira, Antonio R. Lucena-Araujo & Marcos A. Bezerra

  2. Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, Brazil

    Igor F. Domingos

  3. Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, Recife, Brazil

    Betânia L. Hatzlhofer

  4. Department of Internal Medicine, Medical School of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil

    Diego A. Pereira-Martins

  5. Aggeu Magalhães Institute/Oswaldo Cruz Foundation, Recife, Brazil

    Fernanda S. Medeiros

  6. Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil

    Flávia P. Albuquerque, Dulcinéia M. Albuquerque, Magnun N. Santos & Fernando F. Costa

  7. Department of Internal Medicine, Hematology and Hemotherapy Foundation of Pernambuco, Recife, Brazil

    Manuela F. Hazin, Ana C. dos Anjos & Aderson S. Araujo

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  1. Jéssica V. G. F. Batista
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Contributions

J.V.G.F.B. performed experiments, updated the clinical data, performed statistical analyses, analyzed and interpreted data, and drafted the manuscript. G.S.A. performed experiments, updated the clinical data, analyzed and interpreted data, and drafted the manuscript. T.H.C.B., M.J.S., R.M.S., I.F.D., B.L.H., D.A.F, D.A.P-M., J.M.O., A.S.A., L.P.M.L., F.S.M., F.P.A., D.M.A, and M.N.S. updated the clinical data, performed experiments, and reviewed the manuscript. M.F.H, A.C.A., F.F.C., and A.S.A recruited patients, assured the access to patients' samples, and updated the clinical data. A.R.L-A. and M.A.B. conceived and designed the study and reviewed the manuscript. M.A.B. gave the final approval of the version to be submitted. The manuscript was reviewed and approved by all authors.

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Correspondence to Marcos A. Bezerra.

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The local research ethics board approved this study (#0035/10) and, in accordance with the Declaration of Helsinki, informed consent was obtained from all participants before study commencement. For those under the age of 18 years, informed consent was obtained from their parents or legal guardian.

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Batista, J.V.G.F., Arcanjo, G.S., Batista, T.H.C. et al. Influence of UGT1A1 promoter polymorphism, α-thalassemia and βs haplotype in bilirubin levels and cholelithiasis in a large sickle cell anemia cohort. Ann Hematol 100, 903–911 (2021). https://doi.org/10.1007/s00277-021-04422-1

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