Alpha thalassemia, but not βS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort

Abstract

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia −3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia −3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

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Acknowledgements

The authors would like to thank the sickle cell anemia patients and their families who made this research possible.

Funding

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

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Authors

Contributions

BLDH performed experiments, analyzed and interpreted data, and drafted the manuscript; DAP-M. and IFD performed experiments, analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; MNNS performed experiments, analyzed and interpreted data, and reviewed the manuscript; DAF, LPLP, ASA, MAM, BVA, ABLMR, DMLS, FPA, performed experiments, recruited patients, and updated the clinical data; ICCF, JMFO, GSA, THCB, MJS, and RMS recruited patients, updated the clinical data, and reviewed the manuscript; JVGFB updated the clinical data, analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; ARL-A and JLCS analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; IW drafted and reviewed the manuscript. ACA, FFC, ASA, and MACB conceived and designed the study and reviewed the manuscript; MACB gave the final approval of the version to be submitted.

Corresponding author

Correspondence to Betânia Lucena Domingues Hatzlhofer.

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Informed consent was obtained from all patients for being included in the study.

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The authors declare no competing interests.

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Hatzlhofer, B.L.D., Pereira-Martins, D.A., de Farias Domingos, I. et al. Alpha thalassemia, but not βS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort. Ann Hematol (2021). https://doi.org/10.1007/s00277-021-04450-x

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Keywords

  • Genetic modifies
  • Anemia
  • Haplotypes
  • α-Thalassemia
  • Sickle cell disease
  • Cholelithiasis
  • Stroke
  • Priapism