Ropero Paloma, Peral Miriam, Sánchez-Martínez Luis Javier, Rochas Sara, Gómez-Álvarez Miguel, Nieto Jorge M, González Fernando A, Villegas Ana, Benavente Celina
Servicio de Hematología y Hemoterapia, Hospital Clínico San Carlos, Madrid, Spain.
Instituto de Investigación Sanitaria Hospital Clínico San Carlos, Madrid, Spain.
Front Med (Lausanne). 2025 Feb 12;12:1347026. doi: 10.3389/fmed.2025.1347026. eCollection 2025.
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.
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: I (rs7482144), BCL11A (rs4671393), and HBS1L-MYB (rs9376092).
We found more SNPs in haplotypes related to higher HbF than those with less HbF, although only the SNP I (rs7482144) showed a statistically significant association.
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.
目的/背景：镰状细胞病（SCD）是一种单基因疾病，其表型高度可变，取决于主要调节因子胎儿血红蛋白（HbF）的含量。患者之间HbF水平的差异受基因调控。HbF既决定了疾病的表型，也决定了对主要治疗药物羟基脲的反应。研究人员的工作重点是发现导致HbF变异的遗传因素，主要描述β基因簇的单倍型以及三个不同位点的单核苷酸多态性（SNP）：BCL11A、HBS1L-MYB和β-珠蛋白基因簇。本研究旨在确定SCD患者队列中SNP数量和单倍型与较高HbF水平之间的可能相关性。阳性关联可以解释为什么某些单倍型，如塞内加尔或阿拉伯-印度单倍型，显示出较高的HbF水平和较轻的疾病。
为了验证这一假设，使用PCR-RFLP技术对单倍型进行表征，并对与HbF变异关联最大的三个位点的三个代表性SNP进行基因分型：I（rs7482144）、BCL11A（rs4671393）和HBS1L-MYB（rs9376092）。
我们发现与较高HbF相关的单倍型中的SNP比HbF较低的单倍型更多，尽管只有SNP I（rs7482144）显示出统计学上的显著关联。
我们发现单倍型与SNP数量之间存在直接相关性。HbF水平较高且表型较轻巧的单倍型显示出更多的SNP。因此，传统上与预后不良相关的贝宁和班图单倍型显示出最少的突变SNP。
