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New research assessed whether the T117S gene variant could be useful as a marker for predicting sickle cell disease patients' might responses to hydroxyurea treatment.
The loss of cytochrome b5 reductase 3 (Cyb5R3) activity was found to negatively affect fetal hemoglobin (HbF) and hematocrit (HCT) in sickle cell disease patients treated with hydroxyurea (HU), a new study shows.
The study was designed to test for whether the T117S gene variant could function as a marker for prediction of which sickle cell patients could have positive HbF and HCT responses to HU treatment.
This research was presented at the American Society of Hematology (ASH) Annual Meeting and Exposition. It was led by Katherine C Wood, PhD, from the Heart, Lung, Blood and Vascular Medicine Institute in the University of Pittsburgh Department of Medicine.
Over 40 variants of Cyb5R3 have been noted, including one particular variant known as T117S which has a threonine to serine substitution in the flavoprotein. This variant also lessens the reductase’s activity by about half, as compared to the wild-type, and is known to frequently occur in those with African ancestry.
“Nothing is known about the role of Cyb5R3 in the anemia of sickle cell disease,” Wood and colleagues wrote. “We hypothesized that Cyb5R3 may act as a modifier of HbF induction by HU in sickle cell anemia.”
The study recruited both female and male sickle cell patients from 12 to 70 years of age (n=633), drawing them from the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) trial and genetically analyzed.
The investigators genotyped rs1800457 (T117S SNP), in addition to making several comparisons of HbF levels by Cyb5R3 genotype and by status of HU treatment. They also conducted intrapatient correlation analyses of HCT and of HbF.
The research team compared HbF levels by Cyb5R3 genotype (CC, wild-type; CG, heterozygous wild-type and T117S; GG, homozygous T117S) and HU treatment status, divided into treated versus untreated) at baseline.
The investigators wrote that HU was found to be a less potent HbF inducer for the GG patient group (4.32 mean diff, P=0.344) when compared to the CC and CG groups (CC: 6.027 mean diff, P<0.0001 and CG: 6.914 mean diff, P<0.0001).
For every sickle cell patient, regardless of Cyb5R3 genotype, the analyses demonstrated that HCP tended to decrease as HbF levels rose with patients not treated with HU (CC: r= -0.336, P<0.0001, n=320; CG: r= -0.437 P<0.0001, n=120; GG: r= -0.253, P=0.136, n=36).
With HU, however, the inverse relationship between HCT and HbF was found to be less negative for participants with at least a single wild-type Cyb5R3 gene copy.
“These data indicate that the positive relationship between HbF and HCT is subject to uncoupling by loss of Cyb5R3 function,” they wrote. “In vitro studies with human erythroleukemic K562 cells reveal loss of gamma globin induction by HU treatment when wild-type Cyb5R3 is knocked down by siRNA, indicating a requirement for Cyb5R3 in HU-stimulated HbF induction.”
This led to the investigators’ realization that the T117S variant could be helpful as a marker for predicting which sickle cell patients might incur the best responses to HU treatment, helping to then improve drug decision-making for clinicians.
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