Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese

Abstract

Neonatal hyperbilirubinemia, which is prevalent among Asian peoples, has been considered as a physiological phenomenon, and its metabolic basis has not been clearly explained. Gilbert syndrome is a common inherited disease of unconjugated hyperbilirubinemia due to decreased bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT), and its role in neonatal jaundice has recently been considered. We have previously reported that the Gly71Arg mutation of the B-UGT gene associated with Gilbert syndrome is prevalent in Japanese, Korean, and Chinese populations and was more frequently detected in neonates with severe hyperbilirubinemia than in control subjects. We have studied 159 Japanese full-term neonates, evaluating the relationship between the B-UGT genotype and the severity of jaundice, as assessed with a transcutaneous bilirubinometer. The gene frequency of the Gly71Arg mutation in these neonates was 0.19, and neonates carrying the Gly71Arg mutation had significantly increased bilirubin levels on days 2-4, manifested in a gene dose-dependent manner. The frequency of the Gly71Arg mutation was 0.47 in the neonates who required phototherapy (i.e., those with more severe hyperbilirubinemia), significantly higher than 0.16 in the neonates who did not require the therapy. The gene frequency of the TA repeat promoter polymorphism, the (TA) 7 mutation, was 0.07, and neonates carrying this mutation did not have an increase in bilirubin. These results suggested that the Gly71Arg mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese.

Neonatal Hyperbilirubinemia in Japanese Neonates: Analysis of the Heme Oxygenase-1 Gene and Fetal Hemoglobin Composition in Cord Blood

“…Theoretically, indirect hyperbilirubinemia may be caused by either overproduction or impaired metabolism of bilirubin, or both. In 1998, we elucidated that the G71R mutation of the B-UGT gene is very common among Japanese, Koreans, and Chinese and is associated with the high incidence and severity of neonatal hyperbilirubinemia in Japanese infants (4,5). However, we noticed that half of the neonates with severe neonatal hyperbilirubinemia did not carry the G71R mutation.…”

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…Arrows highlight variants previously shown to be associated with human-health phenotypes in either multiple human subject studies or in individual association studies involving more than 100 human subjects; these include the UGT1A8*2 allele, 70,71 the three non-synonymous coding SNPs in UGT1A7 (*2,*3,*10), 69,72,73,81,82 two nsSNPs in UGT1A6 (*2,*3), 67,68,70 rs887829 -the SNP revealing the strongest association with tranilast-induced hyperbilirubinemia, 28 and the UGT1A1*6 allele. 10,24,25,[50][51][52][53][54][55][56][57][83][84][85][86][87] Figure 4 Two-point LD maps for variants of UGT1A1, UGT1A6, and UGT1A9 mapped by population. The patterns of pairwise LD, summarized by |D 0 |, include 60 variants in African-Americans (left), 52 in European-Americans (center), and 49 in Asians (right).…”

Compound heterozygosity of a novel exon 3 frameshift (p.R357P fs*24) mutation and Y486D mutation in exon 5 of the UGT1A1 gene in a Thai infant with Crigler-Najjar syndrome type 2

“…In addition, its gene frequency is related to neonatal hyperbilirubinemia as a common variation among the Japanese populations. For instance, a higher frequency of mutated UGT1A1 gene is related to more severe hyperbilirubinemia as a clinical manifestation (Akaba et al, 1999).…”

“…Mutations in exons 3 and 5 were compound heterozygotes. The c.211G>A (p.G71R) mutation is a common variation in the Japanese population (Akaba et al, 1999;Maruo et al, 2000); c.1456T>G (p.Y486D) has also been identified (Nakagawa et al, 2011).…”