Effect of UDP‐glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome

Abstract

Variations at the six nucleotides −3279 (T > G), −53 (A[TA]6TAA > A[TA]7TAA), 211 (G > A), 686 (C > A), 1091 (C > T), and 1456 (T > G) in the UDP‐glucuronosyltransferase 1A1 (UGT1A1) gene were determined in 178 Taiwanese patients with Gilbert's syndrome and in 200 healthy adults. Every subject was classified as a genotype depending on variation status of the six nucleotides in the UGT1A1 gene. The UGT1A1 activity for each genotype was calculated and then those genotypes were divided into 10 subgroups (Q1~Q10) according to their UGT1A1 activities, by using 10% as an interval. There were 24 genotypes observed, with UGT1A1 activity ranged 9%~100% of normal. There were two and six subjects with Gilbert's syndrome and none of healthy controls carrying genotypes in the Q1 and Q2 subgroups, respectively. The odds of developing Gilbert's syndrome were significantly higher for subjects carrying genotypes in the Q3, Q4, and Q5 subgroups than for those with genotype in the Q10 subgroup (odds ratios: 240.22, 59.80, and 14.67, respectively, P < .001 for each). Among the 178 patients of Gilbert's syndrome, serum bilirubin value was inversely correlated with UGT1A1 activity (r = −.306, P < .001). The sensitivity was 72.0% and the specificity was 90.5% by using UGT1A1 activity ≦40% of normal as the cut‐off point to distinguish between healthy subjects and patients of Gilbert's syndrome. Our results demonstrate that UGT1A1 activity is certainly a determinate for serum bilirubin value and UGT1A1 activity ≦40% of normal is a proper risk factor for the development of Gilbert's syndrome.

Effects of variation status and enzyme activity for UDP-glucuronosyltransferase 1A1 gene on neonatal hyperbilirubinemia

“…The five SNPs at nucleotides À53, 211, 686, 1091 and 1456 of the UGT1A1 gene were determined by means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), as previously described. 11 The DNAs of the five known variants in the UGT1A1 gene, which had been found in Taiwanese and identified by DNA sequencing methods, 11 were run as positive controls in each performance of genotyping assays.…”

“…The enzyme activity values for 686CA, À53 A(TA) 7 TAA/A(TA) 7 TAA, 1091 TT, 211 GA, 211AA and 1456 GG variants were obtained from previously published studies 4,8,13,14 as shown in Table 1, while those for 686AA, À53 A(TA) 6 TAA/A(TA) 7 TAA, 1091CT and 1456 TG variants were estimated by calculation {UGT1A1 activity for 686AA Z [(activity for 686CA) 2 (square)], while activity for A(TA) 6 TAA/ A(TA) 7 TAA Z [activity for A(TA) 7 TAA/A(TA) 7 TAA] 1/2 and so on}. 11 For subjects carrying multiple SNPs in the UGT1A1 gene, estimated UGT1A1 enzyme-activities were obtained by calculations. 11 However, for subjects carrying two SNPs in close linkage, e.g., 686A/e53 A(TA) 7 TAA, the UGT1A1 enzyme activity of the SNP with lower activity between those two SNPs was estimated, avoiding over-or underestimation.…”

“…11 For subjects carrying multiple SNPs in the UGT1A1 gene, estimated UGT1A1 enzyme-activities were obtained by calculations. 11 However, for subjects carrying two SNPs in close linkage, e.g., 686A/e53 A(TA) 7 TAA, the UGT1A1 enzyme activity of the SNP with lower activity between those two SNPs was estimated, avoiding over-or underestimation. 11…”

“…Grouping on the basis of UGT1A1 activity rather than on the basis of genotypes may reduce the number of potential subgroups, thereby simplifying the analysis of relationship between UGT1A1 gene and certain diseases. 11 Very recently, we found that Taiwanese carrying genotypes with UGT1A1 activity 40% of normal are at high risk for developing Gilbert's syndrome. 11 In contrast, the relationship between UGT1A1 activity and neonatal hyperbilirubinemia has never been evaluated for Taiwanese.…”

“…11 Very recently, we found that Taiwanese carrying genotypes with UGT1A1 activity 40% of normal are at high risk for developing Gilbert's syndrome. 11 In contrast, the relationship between UGT1A1 activity and neonatal hyperbilirubinemia has never been evaluated for Taiwanese.…”