Manu Gloria Pokuaa, Segbefia Catherine, N'guessan Benoit Banga, Coffie Shadrack Asiedu, Adjei George Obeng
Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra, Ghana.
Department of Child Health, University of Ghana Medical School, Accra, Ghana.
Pharmgenomics Pers Med. 2022 Mar 10;15:205-214. doi: 10.2147/PGPM.S351599. eCollection 2022.
Sickle cell disease (SCD) is a group of genetic disorders affecting the structure and function of haemoglobin. Hydroxyurea (HU) stimulates fetal haemoglobin (HbF) and reduces sickle erythrocyte-endothelial cell interaction. However, the degree of HbF response to HU varies, with HbF expression-associated single nucleotide polymorphisms (SNPs) in quantitative trait loci (QTL) been implicated. We investigated the relationship between four SNPs (rs11886868, rs6706648, rs7606173 and 158C/T Xmn1) in two QTL (B-cell lymphoma 11A (BCL11A) and Xmn1) and HbF levels in children with SCD in Accra, Ghana.
A total of 110 children with SCD in steady-state, comprising 64 and 46 SCD children treated with HU (HU+) or with no history of HU therapy (HU-), respectively, were recruited. HbF levels were measured in peripheral blood by alkali denaturation and SNPs were genotyped using polymerase chain reaction and restriction fragment length polymorphism.
The presence of SNPs (rs11886868, rs6706648, rs7606173 and -158C/T Xmn1) was identified. Observed heterozygosity and homozygosity for the derived alleles were 45.7%, 82.6%, 21.7% and 39.1% in rs11886868, rs6706648, rs7606173 and -158C/T Xmn1 polymorphisms, respectively, for the HU+ population. Observed frequencies of the minor alleles were 0.204, 0.477, 0.171 and 0.190 for rs11886868, rs6706648, rs7606173 and -158C/T Xmn1 polymorphisms, respectively. The three BCL11A SNPs in the HU+ population showed homozygous individuals for rs11886868 (CC), rs6706648 (CC) and heterozygous or homozygous mutant individuals for rs7606173 (CG/GG) having higher HbF values. The combined effect of the SNPs was associated with variance in HbF levels in the HU+ population. The BCL11A SNP, rs6706648 was strongly associated with HbF levels and the C allele frequency, with significantly elevated HbF levels.
An association between the various variants and combined effect of SNPs and HbF among children with SCD was found and confirms the known association between HU intake and increased HbF in SCD.
镰状细胞病（SCD）是一组影响血红蛋白结构和功能的遗传性疾病。羟基脲（HU）可刺激胎儿血红蛋白（HbF）并减少镰状红细胞与内皮细胞的相互作用。然而，HbF对HU的反应程度各不相同，数量性状位点（QTL）中与HbF表达相关的单核苷酸多态性（SNP）被认为与之有关。我们调查了加纳阿克拉SCD儿童中两个QTL（B细胞淋巴瘤11A（BCL11A）和Xmn1）中的四个SNP（rs11886868、rs6706648、rs7606173和158C/T Xmn1）与HbF水平之间的关系。
共招募了110名病情稳定的SCD儿童，其中分别有64名和46名接受HU治疗（HU+）或无HU治疗史（HU-）的SCD儿童。通过碱变性法测量外周血中的HbF水平，并使用聚合酶链反应和限制性片段长度多态性对SNP进行基因分型。
鉴定出了SNP（rs11886868、rs6706648、rs7606173和-158C/T Xmn1）的存在。对于HU+人群，rs11886868、rs6706648、rs7606173和-158C/T Xmn1多态性中观察到的衍生等位基因杂合度和纯合度分别为45.7%、82.6%、21.7%和39.1%。rs11886868、rs6706648、rs7606173和-158C/T Xmn1多态性的次要等位基因观察频率分别为0.204、0.477、0.171和0.190。HU+人群中的三个BCL11A SNP显示，rs11886868（CC）、rs6706648（CC）的纯合个体以及rs7606173（CG/GG）的杂合或纯合突变个体具有较高的HbF值。SNP的联合效应与HU+人群中HbF水平的差异相关。BCL11A SNP rs6706648与HbF水平和C等位基因频率密切相关，HbF水平显著升高。
发现了SCD儿童中各种变体以及SNP与HbF联合效应之间的关联，并证实了已知的HU摄入与SCD中HbF增加之间的关联。
