Association Between Selected Single Nucleotide Polymorphisms in Globin and Related Genes and Response to Hydroxyurea Therapy in Ghanaian Children with Sickle Cell Disease

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.

Exploring Pharmacogenetic Factors Influencing Hydroxyurea Response in Tanzanian Sickle Cell Disease Patients: A Genomic Medicine Approach

“…We observed the same for BCL11A which is a major HbF modifier. The association of these loci with hydroxyurea treatment responses has been reported in other studies [9,[66][67][68], although they have not been applied for hydroxyurea response prediction in clinical settings.…”

“…SNP allele frequencies provide insights into the genetic variability in drug response among different individuals and populations and hence variability in frequencies across the targeted regions. This information is vital for developing personalized medicine and optimizing drug treatments based on individual genetic profiles [66,71] .…”

Population characterization of mutations for sickle cell anemia and its treatment: One step towards personalized medicine for the disease

“…Se han creado bases de datos que permiten almacenar información sobre la ACF y otras hemoglobinopatías, las que son útiles para establecer la personalización de los tratamientos contra la ACF 26 . Algunos ejemplos de personalización del tratamiento de la ACF se han llevado a cabo mediante la caracterización de polimorfismos asociados a la respuesta al tratamiento con hidroxiurea en pacientes pediátricos [27][28][29][30] . Varios estudios han intentado identificar qué población de pacientes mejorará en gran medida sus niveles de HF.…”