Association Between Selected Single Nucleotide Polymorphisms in Globin and Related Genes and Response to Hydroxyurea Therapy in Ghanaian Children with Sickle Cell Disease
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Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
Pharmacogenomics and Personalized Medicine
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Description
Research Article
Keywords
hydroxyurea, single nucleotide polymorphism, sickle cell disease, haemoglobin F