Gilbert's syndrome is a common hereditary chronic or recurrent, mild unconjugated hyperbilirubinemia. Polymorphisms in the bilirubin uridine diphosphate glucuronosyl transferase gene (UGT1A1) causing a decreased enzyme activity are associated with susceptibility to the syndrome. Homozygosity for TA7 allele of the A(TA)nTAA promoter polymorphism is found in the majority of Caucasian patients. We sought to investigate the role of three UGT1A1 polymorphisms (A[TA]nTAA, -3279T→G, and G71R) in the susceptibility to Gilbert's syndrome in 53 Italian pediatric subjects compared to 83 unaffected controls. Carriage of two TAn risk alleles (TA7 and TA8) and -3279G homozygosity were similarly associated with hyperbilirubinemia (odds ratio [OR] = 11.59, 95% confidence interval [CI] = 4.80-27.98; p <0.001, and OR = 11.51, 95% CI = 5.06-26.19; p <0.001, respectively). Homozygosity for both TA7 and -3279G was associated with the highest relative risk estimate (OR = 19.23, 95% CI = 7.34-50.4; p <0.001), but a significant association was found also for TA7 heterozygosity combined with -3279G/G genotype (OR = 7.98, 95% CI = 2.54-25.06; p <0.001). The G71R variant was found only in two controls. Our results demonstrate that genotyping of both UGT1A1 A(TA)nTAA and -3279T→G polymorphisms best defines genetic susceptibility to Gilbert's syndrome in Caucasian pediatric patients, and the TA7 heterozygous genotype combined with homozygosity for the -3279G allele can also be associated with pediatric mild hyperbilirubinemia.
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