Dataset Information

The role of UGT1A1 (c.-3279?T?>?G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility.

ABSTRACT: BACKGROUND:Neonatal hyperbilirubinemia (NNH) is a common disease in newborns. This research study aimed to assess the associations between uridine diphospho-glucuronate-glucuronosyltransferase 1A1 (UGT1A1, c.-3279?T?>?G) polymorphisms and NNH risk. METHODS:We searched PubMed, the Cochrane Library, and the Embase electronic databases. All published eligible studies before July 1, 2019, were searched for this meta-analysis. RESULTS:We identified 7 independent studies including 1560 cases. The data showed that in the general population, compared with the GT?+?GG vs TT and GG vs TT, c.-3279?T?>?G (rs4124874) was significantly related to a higher NNH risk (GG vs TT: OR?=?1.865, 95% CI: 1.031-3.373, P?=?0.039; GT?+?GG vs TT: OR?=?1.331, 95% CI: 1.055-1.679, P?=?0.016). Although not statistically significant, the data showed that c.3279?T?>?G had a tendency to be associated with NNH under the allele model and GG vs GT?+?TT in the overall population (G vs T: OR?=?1.288, 95% CI: 0.982-1.689, P?=?0.067; GG vs TT?+?GT: OR?=?1.583, 95% CI: 0.947-2.647, P?=?0.080). CONCLUSION:The UGT1A1 gene c.-3279?T?>?G (rs4124874) polymorphism increased susceptibility to NNH, especially for the comparison of GT?+?GG vs TT and GG vs TT. In the future, we can use homozygous state of the UGT1A1 gene c.-3279?T?>?G (rs4124874) polymorphism for the diagnosis and screening of molecular biomarkers in NNH patients.

SUBMITTER: Li Z

PROVIDER: S-EPMC7648392 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The role of UGT1A1 (c.-3279 T > G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility.

Li Zijin Z Song Li L Hao Lihong L

BMC medical genetics 20201106 1

<h4>Background</h4>Neonatal hyperbilirubinemia (NNH) is a common disease in newborns. This research study aimed to assess the associations between uridine diphospho-glucuronate-glucuronosyltransferase 1A1 (UGT1A1, c.-3279 T > G) polymorphisms and NNH risk.<h4>Methods</h4>We searched PubMed, the Cochrane Library, and the Embase electronic databases. All published eligible studies before July 1, 2019, were searched for this meta-analysis.<h4>Results</h4>We identified 7 independent studies includin ...[more]

PMID: 33158427

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Project description:To retrospectively analyze and quantitatively correlate UGT1A1 (bilirubin UDP- glucuronosyltransferase gene) genotypes and unconjugated hyperbilirubinemia (UCH) phenotypes among Chinese children.We retrospectively reviewed UCH patients, quantitatively analyzed genotype-phenotype correlation by comparing with healthy controls. Pfam database, SWISS-model, and Pymol were used for UGT1A1 protein domain analysis and protein modeling for assessing the effect of novel missense variants on protein structure.Seventy four cases, including 21 prolonged unconjugated hyperbilirubinemia (PUCH), 30 Gilbert syndrome (GS), 22 Crigler-Najjar syndrome type II (CNS-II), and 1 Crigler-Najjar syndrome type I (CNS-I) phenotypes were analyzed. Total of 21 variants, including 7 novel variants (c.764T>A/p.L255Q, c.1112C>T/p.T371I, c.1028C>A/p.S343X, c.1047delG/p.I350YfsX16, c.996?+?5G>C/g.6923G>C, c.287G>A/p.G96E, and c.1142G>A/p.S381N) were found. In the multiple regression model, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. Having only functional polymorphisms in UGT1A1 gene is associated with increased risk of PUCH, and GS with OR values of 5.67 (95% CI: 1.52-21.13), and 3.88 (95% CI: 1.02-14.78), respectively. Having only mutation is associated with significantly increased risk of having GS phenotype (OR: 34.00, 95% CI: 4.65-248.37), but not CNS-II. Polymorphism plus mutation had the strongest association with CNS-II with OR value of 64.80 (95% CI: 7.68-546.41), followed by GS (OR: 4.53, 95% CI: 1.08-19.08).We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. Among Chinese children, G71R and P364L is independently associated with PUCH, A(TA)7TAA is associated with GS, and Y486D or other disease-causing mutations were associated with CNS-II. Multiple alleles were associated with more severe phenotypes. Combined variant of G71R+Y486D is a common occurrence among Chinese children with UCH.

Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

Dataset Information

The role of UGT1A1 (c.-3279?T?>?G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility.

Publications

The role of UGT1A1 (c.-3279 T > G) gene polymorphisms in neonatal hyperbilirubinemia susceptibility.

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