A Polymorphic Mutation, c.-3279T>G, in the UGT1A1 Promoter Is a Risk Factor for Neonatal Jaundice in the Malay Population

Abstract

ABSTRACT:The uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes the enzyme responsible for bilirubin glucuronidation. To evaluate the contribution of UGT1A1 promoter mutations to neonatal jaundice, we determined the genotypes of c.-3279TϾG, c.-3156GϾA, and A(TA)7TAA in Malay infants with neonatal jaundice (patients) and in infants without neonatal jaundice (controls). In our population study, only c.-3279TϾG was associated with neonatal jaundice. The genotype distributions between both groups were significantly different (p ϭ 0.003): the frequency of homozygosity for c.-3279G was much higher in patients than those in controls. Allele frequency of c.-3279G was significantly higher in patients than those in controls (p ϭ 0.006). We then investigated changes in transcriptional activity because of c.-3279TϾG. Luciferase reporter assay in HepG2 cells demonstrated that transcriptional activity of the c.-3279G allele was significantly lower than that of the c.-3279T allele in both the absence and presence of bilirubin. Luciferase reporter assay in COS-7 cells elucidated that c.-3279TϾG modified the synergistic effects of the nuclear factors associated with transcriptional machinery. In conclusion, the c.-3279TϾG mutation in the UGT1A1 promoter is a genetic risk factor for neonatal jaundice. T he uridine diphospho (UDP)-glucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes bilirubin UDPglucuronosyltransferase (UGT1A1), which is the enzyme responsible for bilirubin glucuronidation. A decrease in UGT1A1 activity leads to unconjugated hyperbilirubinemia. Inherited UGT1A1 deficiencies because of UGT1A1 mutations are classified into three forms based on clinical severity: Crigler-Najjar syndrome type 1 (CN-1, a severe form), Crigler-Najjar syndrome type 2 (CN-2, an intermediate form), and Gilbert's syndrome (GS, a mild form) (1,2). Such inherited UGT1A1 deficiencies may cause neonatal jaundice.A mutant TATA box with an additional TA insertion, A(TA)7TAA, was first found in patients with CN-1, CN-2, and GS (3-5). GS with homozygosity for A(TA)7TAA accelerates or prolongs neonatal jaundice (6). This mutation is frequently observed in whites and Africans (7). Another GScausing gene mutation, c.211GϾA, is frequent in the East Asian population (8). The c.211GϾA mutation causes an amino acid change, glycine to arginine at codon 71.Recently, polymorphic mutations, c.-3279TϾG and c.-3156GϾA, were identified in the UGT1A1 promoter region (9,10). The c.-3279TϾG mutation is located in the phenobarbital responsive enhancer module (gtPBREM), which is activated by a nuclear receptor, constitutive androstane receptor (CAR) (11). Sugatani et al. (9) showed using luciferase reporter assay that mutant gtPBREM with c.-3279TϾG decreases the transcriptional activity of the UGT1A1 promoter by 60%. The c.-3156GϾA mutation is located between the gtPBREM and TATA box. A haplotype analysis showed that there is a high extent of linkage disequilibrium between c.-3156GϾA and A(TA)7TAA (10,12). However, it is unknown ...

Association of neonatal hyperbilirubinemia with uridine diphosphate‐glucuronosyltransferase 1A1 gene polymorphisms: Meta‐analysis

“…There were 18 studies focusing on the relationships between UGT1A1 TATA promoter polymorphisms and neonatal hyperbilirubinemia (Table 4). 11–14,17,18,21–25,27,30,32–36 Analysis of these studies indicated that TATA promoter variations were not associated with an increased risk of neonatal hyperbilirubinemia (7/7 + 6/7 vs 6/6: OR, 1.13; P = 0.23; 95%CI: 0.93–1.37; I 2 = 80.0%; P heterogeneity = 0.00; Fig. 3a).…”

“…Of these, 205 were subsequently excluded after screening of abstracts or full texts. Ultimately, 28 articles were included in the meta‐analysis 9–14,16–37 . The flow diagram of study identification is given in Figure 1.…”

Genetic Variations in Bilirubin Metabolism Genes and Their Association with Unconjugated Hyperbilirubinemia in Adults

“…Recently, ‐3279 T→G and ‐3156 G→A polymorphisms upstream in the UGT1A1 promoter have also been reported to be risk factors involved in the development of hyperbilirubinemia (Borucki et al., ) and occurs in linkage disequilibrium with TA repeats promoter variants. Further, studies showed the association of ‐3279 (T→G) variant in the promoter region of the UGT1A1 gene with hyperbilirubinemia in Taiwanese and Malay populations (Huang et al., ; Yusoff et al., ). In the present study, it was found that the adults who carry ‐3279 (T→G) variant are also at the higher risk to develop hyperbilirubinemia.…”

High resolution melting analysis of the NR1I3 genetic variants: Is there an association with neonatal hyperbilirubinemia?

“…A higher incidence of neonatal hyperbilirubinemia in the Asians compared with the Caucasians suggests that genetic factors could be the underlying cause for the disease occurrence (Huang et al, 2004;Morioka et al, 2010). Genetic factors that predispose to neonatal hyperbilirubinemia including the UGT1A1, G6PD and SLCO1B1 variants have been extensively explored in various ethnicities (Watchko and Lin, 2010;Yusoff et al, 2010;Liu et al, 2013;D'Silva et al, 2014;Tiwari et al, 2014). Generally, these variants contribute to neonatal hyperbilirubinemia by disrupting the balance between bilirubin production and elimination (Kaplan et al, 2002).…”