Pharmacogenomics of Sickle Cell Disease: Pain and Drug metabolism associated Gene Variants, and hydroxyurea-induced miRNAs

Background: The major therapeutic benefit of hydroxyurea (HU), the only FDA-approved pharmacologic treatment for sickle cell disease (SCD), is directly related to fetal hemoglobin (HbF) production that leads to significant... [ view full abstract ]

Background: The major therapeutic benefit of hydroxyurea (HU), the only FDA-approved pharmacologic treatment for sickle cell disease (SCD), is directly related to fetal hemoglobin (HbF) production that leads to significant reduction of morbidity and mortality. However, potential adverse effects such as infertility, susceptibility to infections, or teratogenic effect have been subject for concern. It is therefore important to gain a better understanding of genetic variants affecting the predisposition to specific complications such as stroke and acute chest syndrome, and polymorphisms affecting susceptibility to pain, as well as the pharmacogenomics of commonly prescribed treatments such as HU, malaria prophylaxis and pain medication for future precision medicine in SCD.  In this study we aim to investigate 1) Drug Metabolizing Enzyme and Transporter (DMET) genes variants, and 2) to study changes in miRNA expression linked to treatment with HU, in Sickle Cell Disease.

Objectives: To investigate variants of Drug Metabolizing Enzyme and Transporter (DMET) Genes in SCD; to determine the in vivo post-transcriptomic profile of hydroxyurea-induced miRNA in SCD patients in Cape Town; to determine the in vitro post-transcriptomic profile of hydroxyurea-induced miRNA in human erythroid progenitor cells derived from umbilical cord CD34+ stem cells.

Methods: We will interrogate available exomes data of 150 SCD opioid and hydroxyurea urea naive patients and 50 population-matched controls and determine the differential minor allele frequencies. Analyses of the available miRNA profile (Human miRNA microarrays) from the transcriptome data, pre and post administration of HU will be conducted.  In addition, we will treat human erythroid progenitor cells derived from umbilical cord CD34+ stem cells with HU and investigate the molecular mechanisms of HbF induction through miRNA regulation. Lastly, we will compare the outcomes from in vivo and in vitro experiments, in order to determine that are constantly differentially expressed under HU exposure.

Expected outcomes: This study will help in identifying miRNAs that can be explored as part of therapeutic strategies for sickle cell patients. It will also contribute in the development of a pharmacogenomics model for SCD in the African population.