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ORIGINAL RESEARCH article

Front. Med.
Sec. Hematology
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1347026

Phenotype of Sickle Cell Disease. Correlation of Haplotypes and Polymorphisms in Cluster β, BCL11A, and HBS1L-MYB. Pilot Study

Provisionally accepted
PALOMA ROPERO PALOMA ROPERO 1,2*Miriam Peral Miriam Peral 3Luis Javier Sánchez Martínez Luis Javier Sánchez Martínez 4Sara Rochas Sara Rochas 5,6Miguel Gómez-Álvarez Miguel Gómez-Álvarez 5Jorge M Nieto Jorge M Nieto 5,6Fernando A González Fernando A González 5,6Ana Villegas Ana Villegas 5Celina Benavente Celina Benavente 2,5
  • 1 Servicio de Hematología y Hemoterapia. Hospital Clínico San Carlos. Madrid., Madrid, Spain
  • 2 Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC). Madrid., Madrid, Spain
  • 3 Instituto de Biología y Genética Molecular (IBGM)., Valladolid, Spain
  • 4 Departamento de Biodiversidad, Ecología y Evolución. Facultad de Biología. Universidad Complutense de Madrid., Madrid, Spain
  • 5 Servicio de Hematología y Hemoterapia. Hospital Clínico San Carlos, Madrid, Asturias, Spain
  • 6 Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Madrid, Spain

The final, formatted version of the article will be published soon.

    Objective/Background: Sickle cell disease (SCD) is a monogenic disease with a highly variable phenotype depending on the amount of fetal hemoglobin (HbF), the main modulator. Variation of HbF levels among patients is genetically regulated. HbF determines both the phenotype of the disease and the response to treatment with the main drug used, hydroxyurea. The efforts of the researchers have focused on discovering the genetic factors responsible for HbF variation, mainly describing the haplotypes of the β cluster and single nucleotide polymorphisms (SNPs) at three different loci: BCL11A, HBS1L-MYB, and the β-globin cluster. This study aimed to determine the possible correlation between the number of SNPs and haplotypes with higher HbF levels in a cohort of patients with SCD. A positive association could explain why certain haplotypes, such as Senegal or Arab-Indian, show higher HbF levels and less severe disease. Methods: To test this hypothesis, the characterization of haplotypes was performed using the PCR-RFLP technique and genotyping of three SNPs representative of the three loci with the greatest association with HbF variation: XmnI (rs7482144), BCL11A (rs4671393), and HBS1L-MYB (rs9376092). Results: We found more SNPs in haplotypes related to higher HbF than those with less HbF, although only the SNP XmnI (rs7482144) showed a statistically significant association. Conclusions: We found a direct correlation between haplotypes and the number of SNPs. Haplotypes with higher levels of HbF and less severe phenotypes showed a higher number of SNPs. Thus, the Benin and Bantu haplotypes traditionally associated with poor prognosis showed the fewest mutated SNPs.

    Keywords: Sickle Cell Disease, cluster haplotypes β, XmnI, Bcl11A, HBS1L-MYB, Fetal Hemoglobin

    Received: 30 Nov 2023; Accepted: 14 Jan 2025.

    Copyright: © 2025 ROPERO, Peral, Sánchez Martínez, Rochas, Gómez-Álvarez, Nieto, González, Villegas and Benavente. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: PALOMA ROPERO, Servicio de Hematología y Hemoterapia. Hospital Clínico San Carlos. Madrid., Madrid, Spain

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