Pictured, from left: Katherine C. Wood, research assistant professor of pharmacology and chemical biology; Fabliha A. Chowdhury, doctoral graduate, pharmacology and chemical biology; and Adam C. Straub, professor of pharmacology and chemical biology and assistant dean for basic science faculty affairs, School of Medicine. Photo by the Straub laboratory.
By Phoebe Ingraham Renda
A single A-to-T typo in the genetic code of adult hemoglobin scrunches red blood cells into sickles that clump and burst as they travel through blood vessels, leading to the characteristic symptoms of sickle cell disease: painful blockages, inflammation, oxidative stress and anemia.
About 1.84 million people struggle with sickle cell disease, which is primarily localized to sub-Saharan Africa and is more common in individuals of African descent. While treatable with hydroxyurea therapy, many patients have a poor fetal hemoglobin response. In new research, published in the October edition of Blood Advances, Pitt researchers have identified a common recessive genetic variant that may be to blame.
“The challenge with hydroxyurea is that it has fetal hemoglobin induction variability between patients; induction varies from 2 to 30%,” says Fabliha A. Chowdhury, first author and a recent doctoral graduate in the laboratory of Adam C. Straub, professor of pharmacology and chemical biology and assistant dean for basic science faculty affairs, School of Medicine. As a result, she says, patients are often prescribed higher doses of hydroxyurea, which pose elevated toxicity risks.
Fetal hemoglobin, which does not cause sickling, is present at birth and naturally declines over the first year of life as it is replaced by the adult sickling form. Hydroxyurea therapy works by inducing fetal hemoglobin production to dilute adult hemoglobin and its sickling tendency in red blood cells.
Studying the genetics of patients with sickle cell disease, Chowdhury noticed one variant in the cytochrome b5 reductase 3 (CYB5R3) gene, called T117S, was frequently present. CYB5R3—which Straub describes as a resilience gene—is a key player in hydroxyurea-induced fetal hemoglobin production. In the study cohorts, the variant was present in 25% of individuals of African ancestry but was rarely present (<1%) in other racial groups.
“This is not a low-frequency variant,” says Straub, who also directs the Center for Microvascular Research, “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.”
When individuals are homozygous, meaning they inherited two genetic copies of the variant (one from each parent), all their CYB5R3 proteins are affected. In the study cohorts, homozygous patients showed low rates of fetal hemoglobin production following hydroxyurea therapy, suggesting that the mutation diminishes hydroxyurea’s therapeutic effects. Validating their hypothesis, they observed a similar pattern of low fetal hemoglobin production following hydroxyurea treatment in hemopoietic stem cells lacking the CYB5R3 gene.