Association analysis of the UGT1A1 polymorphism and unexplained neonatal hyperbilirubinemia

Objective To study the relationship between uridine diphosphate glucuronic acid (UGT1A1) gene polymorphism and unexplained neonatal unconjugated hyperbilirubinemia in Jinhua. Method Full-term infants with unidentified non-binding hyperbilirubinemia were selected as hyperbilirubinemia group from January 2016 to December 2017 in the obstetrics or neonatal intensive care unit of Jinhua Central Hospital, healthy full-term neonates and those with physiological jaundice admitted during the same period were selected as control group. Whole blood DNA was extracted and UGT1A1 was sequenced and then annotated with human gene mutation database. The distribution and frequency of UGT1A1 genotype were analyzed. The correlation between different genotypes and unexplained unconjugated hyperbilirubinemia in neonates was also studied. Result Two hundred and forty cases were enrolled in the hyperbilirubinemia group, and 216 cases were enrolled in the control group. Four single nucleotide variation (SNV) sites associated with the disease were found on UGT1A1, which were c.211G>A (Gly71Arg), c.686C>A (Pro229Gln), c.1091C>T (Pro364Leu) and c.1456T>G (Tyr486Asp), accounting for 83.9%(141/168), 1.8%(3/168), 8.9%(15/168) and 5.4%(9/168) in the experimental group respectively. The genotype frequency and allele frequency analysis showed that the distribution of the two SNV sites of c.211G>A and c.1456T>G were statistically different between the experimental group and the control group (P A and c.1091C>T between the two groups. Binary Logistic regression analysis showed that c.211G>A and c.1456T>G were related to the occurrence of unexplained hyperbilirubinemia, The OR values (95%CI) were 5.412 (3.567~8.212) and 8.377 (1.052~66.670) respectively, but no correlation was found of the other two polymorphic loci. At the different genotypes of c.211G>A locus, the levels of total bilirubin and non-binding bilirubin in infants with homozygous mutant (AA) were higher than those in infants with heterozygous mutant (GA) and wild type (GG), which was statistically significant (P<0.05). Conclusion The most common mutation site of the UGT1A1 gene in Jinhua is c.211G>A. The mutations of c.211G>A and c.1456T>G are risk factors for unconjugated hyperbilirubinemia in neonates. Of the different genotypes of c.211G>A locus, the serum bilirubin level of homozygous mutant group was significantly higher than heterozygous mutant group and wild type group. Key words: Hyperbilirubinemia, neonatal; Uridine diphosphate glucuronic acid; UGT1A1 genes; Gene polymorphism