title: Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  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.
authors.affiliation: UMR S-458 INSERM/Université des Antilles et de la Guyane, France.
authors.forename: Vicky
authors.initials: V
authors.lastname: Chaar
authors.forename: Lysiane
authors.initials: L
authors.lastname: Kéclard
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Diara
authors.forename: Claudine
authors.initials: C
authors.lastname: Leturdu
authors.forename: Jacques
authors.initials: J
authors.lastname: Elion
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Krishnamoorthy
authors.forename: John
authors.initials: J
authors.lastname: Clayton
authors.forename: Marc
authors.initials: M
authors.lastname: Romana
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002769:Cholelithiasis / Q000150:complications* / Q000235:genetics*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D006454:Hemoglobins; D000099148:UGT1A1 Enzyme