A common genetic variant may explain why some sickle cell disease patients respond poorly to hydroxyurea, a standard treatment for the condition. Researchers at the University of Pittsburgh have identified a variant in the cytochrome b5 reductase 3 (CYB5R3) gene, called T117S, that is associated with lower fetal hemoglobin production in response to hydroxyurea therapy.
Impact of CYB5R3 Variant on Hydroxyurea Response
The study, published in Blood Advances, found that the CYB5R3 T117S variant is present in approximately 25% of individuals of African ancestry. Homozygous carriers of the variant, who inherit two copies of the mutated gene, exhibited significantly lower rates of fetal hemoglobin production following hydroxyurea treatment. Fetal hemoglobin does not cause sickling and its production is induced by hydroxyurea to dilute adult hemoglobin in red blood cells.
According to Fabliha A. Chowdhury, first author of the study, the variability in fetal hemoglobin induction with hydroxyurea, ranging from 2 to 30%, often leads to higher doses and increased toxicity risks for patients. The presence of the CYB5R3 T117S variant appears to diminish hydroxyurea’s therapeutic effects, potentially explaining this variability.
Clinical Implications and Precision Medicine
Adam C. Straub, a professor at the University of Pittsburgh and director of the Center for Microvascular Research, emphasized the clinical significance of this finding. "One out of four individuals with sickle cell disease will likely be a carrier of the variant and 10% will be homozygous for the variant." Katherine C. Wood, research assistant professor, added that approximately 23,000 sickle cell disease patients in the United States alone could benefit from knowing their CYB5R3 status.
While gene therapies have recently been approved for sickle cell disease, hydroxyurea remains the global standard of care, particularly in sub-Saharan Africa where access to advanced medical infrastructure is limited. Understanding the impact of genetic variants like CYB5R3 T117S on therapeutic response is crucial for precision medicine approaches.
Future Directions
The researchers suggest that identifying patients with the CYB5R3 T117S variant could help guide clinical decision-making, allowing clinicians to select the most appropriate treatment strategy for each individual. This may involve prioritizing newer gene therapies for patients with the variant who are less likely to respond to hydroxyurea.
"As we move forward, it's important that we uncover genetic differences and why we see drug variability among patients," says Straub. "It boils down to can we better predict therapy response through precision medicine?"
