Analysis of the UGT1A1 Genotype in Hyperbilirubinemia Patients: Differences in Allele Frequency and Distribution.

Xiao-Xiao Mi,Ge-Li Zhu,Xiao-Wen Kong,Jun-Ping Shi,Wen-Jun Yang,Gong-Ying Chen,Ling Gong,Jian Yan,Yi-Dan Gao,Xiao-Jie Ma

doi:10.1155/2019/6272174

Xiao-Xiao Mi, Ge-Li Zhu + Show 8 more

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https://doi.org/10.1155/2019/6272174

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Abstract

Objective The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3–76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype–phenotype correlations in hyperbilirubinemia patients.

Highlights

Hereditary unconjugated hyperbilirubinemia is autosomal recessive disorder and can be categorized as Crigler–Najjar syndrome type I (CN-I; OMIM#218800), Crigler–Najjar syndrome type II (CN-II; OMIM#606785), or Gilbert syndrome (GS; OMIM#143500) based on serum bilirubin levels
These results indicated that 83.3% of GS patients heterozygous for the c.-3279T>G variation harbored heterozygous variation in the UDP-glucuronyl transferase A (UGT A) promoter region (Figure 1(a󸀠)), suggesting that c.-3279T>G heterozygosity is mostly accompanied by heterozygous variations in the UDP-glucuronyl transferase (UGT) A promoter in our patient cohort
We identified UGT A variants in 60 patients with unconjugated hyperbilirubinemias, including 55 GS

Summary

Introduction

Hereditary unconjugated hyperbilirubinemia is autosomal recessive disorder and can be categorized as Crigler–Najjar syndrome type I (CN-I; OMIM#218800), Crigler–Najjar syndrome type II (CN-II; OMIM#606785), or Gilbert syndrome (GS; OMIM#143500) based on serum bilirubin levels. The concentration of serum total bilirubin (TBIL) in CN-I, CNII, and GS ranges from 513 μM to 855 μM, 102.6μM to 342 μM, and 17 μM to 85 μM, respectively [1]. These hyperbilirubinemias result from increased water-insoluble unconjugated bilirubin in the liver in the absence of liver dysfunction or hemolysis [2]. UDP-glucuronyl transferase (UGT), encoded by UGT A , is the only enzyme in liver that glucuronidates bilirubin. Hereditary unconjugated hyperbilirubinemia, including CN-I, CN-II, and GS, is, respectively, caused by mutations in UGT A (OMIM∗191740), which is a member of the UGT1 superfamily and located on chromosome (2q37). UGT1A1 enzyme activity can be increased by phenobarbital administration, which induces UGT A expression by binding to the phenobarbital-responsive module (PBREM) in the distal

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