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UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia
Matthew M Heeney1, Thad A Howard, Sherri A Zimmerman
1Pediatric Sickle Cell Program and Division of Pediatric Hematology/Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. matthew.heeney@TCH.harvard.edu.
Insights
Hydroxyurea therapy improves sickle cell anemia (SCA) by reducing hemolysis. However, the uridine diphosphoglucuronate glucuronosyltransferase 1A (UGT1A) genotype impacts how effectively it lowers bilirubin levels, affecting gallstone prevention.
Area of Science:
- Genetics
- Hematology
- Pharmacogenomics
Background:
- Sickle cell anemia (SCA) is characterized by hemolysis and elevated bilirubin, increasing gallstone risk.
- Hydroxyurea therapy is a standard treatment that reduces hemolysis and bilirubin levels in SCA patients.
- A UGT1A gene promoter polymorphism influences baseline bilirubin levels and gallstone incidence in SCA.
Purpose of the Study:
- To investigate the impact of UGT1A gene promoter polymorphism on hydroxyurea's therapeutic efficacy in children with SCA.
- To determine if UGT1A genotype influences hydroxyurea's ability to normalize bilirubin levels and potentially prevent gallstones.
Main Methods:
- Analysis of a large cohort of children with SCA receiving maximum tolerated hydroxyurea dose.
- Genotyping of the UGT1A gene promoter polymorphism (6/6, 6/7, 7/7).
- Assessment of hemolysis markers and serum bilirubin levels in relation to UGT1A genotype and hydroxyurea treatment.
Main Results:
- Hydroxyurea significantly reduced hemolysis in all SCA patients, irrespective of UGT1A genotype.
- Hydroxyurea's effect on serum bilirubin levels was dependent on UGT1A genotype.
- Patients with the wild-type 6/6 UGT1A genotype showed normalized bilirubin levels, while those with 6/7 or 7/7 genotypes did not.
- Individuals with the 7/7 genotype (Gilbert syndrome phenotype) maintained high bilirubin levels (>3 mg/dL) despite hydroxyurea therapy.
Conclusions:
- The UGT1A promoter polymorphism is a significant non-globin genetic modifier in SCA, affecting baseline and hydroxyurea-modulated bilirubin levels.
- UGT1A genotype influences the therapeutic response to hydroxyurea regarding bilirubin reduction.
- UGT1A polymorphisms may impact hydroxyurea's effectiveness in preventing gallstone formation in SCA patients.
Abstract:
Hydroxyurea therapy reduces hemolysis and decreases serum bilirubin levels in children and adults with sickle cell anemia (SCA) and may therefore help prevent the development of cholelithiasis in this patient population. We recently reported that a promoter polymorphism in the uridine diphosphoglucuronate glucuronosyltransferase 1A (UGT1A) gene affects steady-state bilirubin levels and the incidence of gallstones in children with SCA. We have now analyzed the influence of the UGT1A genotype on the therapeutic response to hydroxyurea. A large cohort of children with SCA taking hydroxyurea therapy at the maximum tolerated dose demonstrated significant reductions in hemolysis independent of UGT1A promoter polymorphism genotype, but the hydroxyurea-related decreases in serum bilirubin levels were significantly different. Children with the wild-type 6/6 UGT1A genotype demonstrated normalized bilirubin levels with hydroxyurea therapy, but children with the heterozygous 6/7 or abnormal 7/7 genotypes did not. Children with the abnormal 7/7 genotype, which confers the phenotype of Gilbert syndrome, had bilirubin levels greater than 3 mg/dL despite full-dose hydroxyurea therapy. These data indicate the UGT1A promoter polymorphism is a powerful nonglobin genetic modifier in SCA that influences serum bilirubin both at baseline and on hydroxyurea therapy. UGT1A promoter polymorphisms may therefore influence the ability of hydroxyurea to prevent gallstone formation in patients with SCA.