University of São Paulo, São Paulo, Brazil.
RTI International, Atlanta, Georgia, USA.
Br J Haematol. 2024 Nov;205(5):1974-1984. doi: 10.1111/bjh.19758. Epub 2024 Sep 15.
Sickle cell disease (SCD) is a Mendelian disorder characterized by a point mutation in the β-globin gene that leads to sickling of erythrocytes. Several studies have shown that absolute neutrophil count is strongly associated with clinical severity of SCD, suggesting an apparent role of white blood cells (WBC) in SCD pathology. However, the mechanism by which genetic variants lead to WBC count differences in SCD patients remains unclear.
Genome-wide association (GWA) analyses were carried out amongst a cohort of 2409 Brazil SCD participants. Association of WBC count and genetic markers were investigated in homozygous sickle cell anaemia participants and compound heterozygous sickle cell haemoglobin C participants.
GWA analysis showed that variants in genes TERT, ACKR1, and FAM3C are associated with WBC count variation. The well-studied association between WBC count and Duffy null phenotype (variant in ACKR1) in healthy populations was replicated, reinforcing the influence of the SNP rs2814778 (T>C) in WBC count.
Genetics plays an important role in regulating WBC count in patients with SCD. Our results point to possible mechanisms involved in WBC count variation and as increased WBC count is associated with more severe SCD, these results could suggest potential therapeutic targets for individuals with SCD.
镰状细胞病（SCD）是一种孟德尔遗传病，其特征是β-珠蛋白基因中的一个点突变导致红细胞镰状化。多项研究表明，绝对中性粒细胞计数与 SCD 的临床严重程度密切相关，这表明白细胞（WBC）在 SCD 病理中起着明显的作用。然而，遗传变异如何导致 SCD 患者的 WBC 计数差异的机制尚不清楚。
在 2409 名巴西 SCD 参与者的队列中进行了全基因组关联（GWA）分析。在纯合镰状细胞贫血参与者和复合杂合镰状细胞血红蛋白 C 参与者中，研究了 WBC 计数和遗传标记的关联。
GWA 分析表明，TERT、ACKR1 和 FAM3C 基因中的变异与 WBC 计数的变化有关。在健康人群中，WBC 计数与 Duffy 缺失表型（ACKR1 中的变异）之间的关联已得到充分研究，这进一步证实了 SNP rs2814778（T>C）在 WBC 计数中的影响。
遗传在调节 SCD 患者的 WBC 计数中起着重要作用。我们的结果指出了 WBC 计数变化可能涉及的机制，并且由于 WBC 计数增加与更严重的 SCD 相关，这些结果可能为 SCD 患者提供潜在的治疗靶点。
