General Updates | Pharmacogenomics in sickle cell disease: factors influencing treatment response to hydroxurea

So pharmacogenomics is really a field that tries to understand how genetic factors may influence treatment response outcomes. So that means how the genetic makeup of an individual may actually influence how they respond to a particular intervention, being it a drug or gene therapy or whatever. And this is because, as we all know, genes are the origins of different proteins in the body, including different enzymes that are used in metabolism of drugs. 

So there are different factors. So there are social factors, environmental factors, but also of late we have been looking at how genetic factors may influence hydroxyurea response. And hydroxyurea is quite a unique intervention or drug because one: it is a drug that is really needed widely, globally, for therapy for sickle cell disease individuals. But number two, it’s a drug that is known to increase the levels of fetal hemoglobin, which is a known major modifier of sickle cell disease. And again, it’s unique because fetal hemoglobin levels are known to be significantly influenced by genetic factors. But we also know hydroxyurea itself as a drug is metabolized by very specific enzymes, which again are a result of different genes. 

So when you look at hydroxyurea in relation to pharmacogenomics, you look at two distinct profiles. So we look at genes that may influence hydroxyurea because they influence fetal hemoglobin levels. And it’s now known that the baseline levels or the levels of HbF or fetal hemoglobin that an individual has prior to hydroxyurea treatment influence how they will respond to hydroxyurea. So the patients who happen to have high levels of fetal hemoglobin have been shown to respond much better to hydroxyurea. But we also know that fetal hemoglobin is more than 80% controlled by genetic factors. So we look at hydroxyurea pharmacogenomics, one from an angle of genetic determinants that also influence fetal hemoglobin, but also we look at hydroxyurea pharmacogenomics from an angle of genes that are responsible for synthesizing different enzymes in the different metabolic pathways that are related to hydroxyurea. 

So, so far, there have been studies globally, most of them, of course, in the developed countries. And some of our key genes have been identified, including those that are associated with fetal hemoglobin. But also in Africa, we have initiated these initiatives, and I led a team that also looked at the genetic determinants of hydroxyurea response. And as I said, based on the knowledge that we already have, we looked at a number of regions that, in one way, are related to fetal hemoglobin levels and in another in the known metabolic pathways of drug metabolism.

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