Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia.
OBJECTIVE
Genetic mutations in the uridine diphosphate (UDP)-glucuronosyltransferase 1A (UGT1A) enzyme promoter have been associated with unconjugated hyperbilirubinemia and Gilbert syndrome. The effects of UGT1A promoter polymorphisms on serum bilirubin levels and symptomatic gallstone formation were studied in a cohort of children with sickle cell anemia (SCA).


METHODS
The UGT1A promoter genotype was deterrmined for 115 consecutive children with SCA. Steady-state laboratory parameters and previous cholecystectomy for symptomatic gallstones were recorded retrospectively, then analyzed according to UGT1A genotype.


RESULTS
Children with SCA had a lower frequency of the normal (TA)6 UGT1A promoter allele (0.413) than the abnormal (TA)7 allele (0.461). A previously described shorter (TA)5 allele (frequency 0.074) and longer (TA)8 allele (frequency 0.052) were also observed. Children with the 7/7 UGT1A genotype had a significantly higher mean bilirubin level (5.8 +/- 3.1 mg/dL) than those with the 6/6 (2.4 +/- 0.8 mg/dL) or 6/7 genotype (3.0 +/- 1.1 mg/dL; P < 0.001 by analysis of variance). Patients with the 7/7 genotype were more likely to have previous cholecystectomy (87.5%) than those with the 6/6 (35.7%) or the 6/7 genotype (36.1%; P = 0.002 by chi2).


CONCLUSIONS
Genetic variation in the UGT1A promoter significantly influences serum bilirubin levels and the development of symptomatic cholelithiasis in children with SCA. The UGT1A promoter polymorphisms represent an important nonglobin genetic modifier of clinical disease expression in SCA.
Passon
R G
RG
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Howard
T A
TA
Zimmerman
S A
SA
Schultz
W H
WH
Ware
R E
RE
D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications*; D001663:Bilirubin / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D002769:Cholelithiasis / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D017931:DNA Primers / Q000737:chemistry; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D017931:DNA Primers; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme