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

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.

UGT1A1*6 mutation associated with the occurrence and severity in infants with prolonged jaundice

“…Most homozygous carriers of UGT1A1*6 have benign presentation without severe impairment of liver function, and have a good prognosis after follow-up ( 2 ). Therefore, we speculated that these cases with severe prolonged hyperbilirubinemia might have Gilbert syndrome in infancy.…”

“…The UDP-glucuronosyltransferase 1A1 ( UGT1A1 ) gene encodes UDP-glucuronosyltransferase (UDPGT), an enzyme that plays a crucial role in the metabolism of bilirubin. The UGT1A1 variants in hereditary unconjugated hyperbilirubinemia are distributed differently in different ethnicities and regions ( 1 , 2 ). The homozygous mutation of the TATA box (A(TA) 6 TAA > A(TA) 7 TAA, UGT1A1 *28, rs8175347) is identified as the primary genetic basis of Gilbert's syndrome in Caucasians and Africans ( 1 ).…”

“…The homozygous mutation of the TATA box (A(TA) 6 TAA > A(TA) 7 TAA, UGT1A1 *28, rs8175347) is identified as the primary genetic basis of Gilbert's syndrome in Caucasians and Africans ( 1 ). The incidence of c.211G > A ( UGT1A1*6 ) in East Asia including China, Japan, and Korea, is high (16%–21%) ( 1 , 2 ). The role of c.211G > A in prolonged jaundice was found in Japan and Iran ( 3 , 4 ).…”

Bilirubin metabolism and UDP‐glucuronosyltransferase 1A1 variants in Asians: Pathogenic implications and therapeutic response

“…A total of 66 studies published until December 31, 2021, met the inclusion criteria and were included in this review. Of the 66 studies, 20 included Chinese populations [5][6][7][8][9][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] (two studies also included Chinese Tibetan individuals 9,22 ), 4 included Indian populations, 19,37-39 2 included Indonesian populations, 14,40 12 included Japanese populations 4,10,20,[41][42][43][44][45][46][47][48][49] (one study also included individuals from Uzbekistan 20 ), 4 included Korean populations, 11,12,50,51 3 included Malaysian populations, 15,16,52 1 included Saudi individuals, 21 18 included Taiwanese individuals, 1,3,13,[53][54][55]…”

“…A total of 66 studies published until December 31, 2021, met the inclusion criteria and were included in this review. Of the 66 studies, 20 included Chinese populations 5–9,22–36 (two studies also included Chinese Tibetan individuals 9,22 ), 4 included Indian populations, 19,37–39 2 included Indonesian populations, 14,40 12 included Japanese populations 4,10,20,41–49 (one study also included individuals from Uzbekistan 20 ), 4 included Korean populations, 11,12,50,51 3 included Malaysian populations, 15,16,52 1 included Saudi individuals, 21 18 included Taiwanese individuals, 1,3,13,53–67 1 included Thai individuals, 17 and 1 included Vietnamese individuals 18 . Moreover, we reviewed all the studies examining the relationship between the variants of UGT1A1 and the adverse drug reaction (ADR) or therapeutic efficacy of irinotecan‐based chemotherapy in Asian patients with colon cancer published in PubMed from 2018 to 2021.…”