RESUMO
BACKGROUND AND OBJECTIVES: High levels of erythrocyte destruction in sickle cell anemia (SCA) result in chronic hyperbilirubinemia, with cholelithiasis occurring in a subset of patients. We investigated whether susceptibility to cholelithiasis in SCA was associated with the promoter polymorphism of the 5?-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene encoding a key enzyme in bilirubin catabolism. DESIGN AND METHODS: We determined the frequencies of UGT1A1 promoter alleles in 171 SCA children and 153 SCA adults regularly followed for a number of years at the Guadeloupe sickle cell center. These patients had undergone liver/biliary tree ultrasound scans every year. We analyzed the relationships between the various UGT1A1 promoter alleles and hemoglobin levels, steady-state total and unconjugated bilirubin concentrations and the frequency of cholelithiasis. RESULTS: In both children and adults, (TA)6 was less frequent and (TA)7 more frequent in patients with cholelithiasis than in those without this condition. Total and unconjugated bilirubin levels and the frequency of cholelithiasis were significantly higher in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes than in those with other genotypes. Those homozygous for (TA)6 or carrying at least one (TA)5 allele had the lowest total and unconjugated bilirubin levels and were least likely to have cholelithiasis. Patients with (TA)6/(TA)7 and (TA)6/(TA)8 genotypes presented intermediate values. Kaplan-Meier analysis of cholelithiasis-free survival in children demonstrated an early age-at-onset for cholelithiasis in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes. INTERPRETATIONS AND CONCLUSIONS: This study shows that the UGT1A1 gene promoter polymorphism is a major genetic risk factor modifying the frequency and age-at-onset of cholelithiasis in SCA patients.
Assuntos
Anemia Falciforme/complicações , Anemia Falciforme/genética , Colelitíase/complicações , Colelitíase/genética , Glucuronosiltransferase/genética , Polimorfismo Genético , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Genótipo , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
Enhanced erythrocyte destruction in sickle cell anemia results in chronic hyperbilirubinemia. Only a subset of patients develop cholelithiasis. UGT1A1 promoter polymorphism is associated both with unconjugated bilirubin level and elevated risk for cholelithiasis in such subset. Here, we investigated the role of alpha-thalassemia, yet another genetic factor that modulates hemolysis, in conferring protection from cholelithiasis. We show that, although alpha-thalassemia is associated with modest reduction in hemolysis and unconjugated bilirubin level, UGT1A1 polymorphism outweighs its effect on cholethiogenesis in sickle cell anemia patients.