RESUMO
BACKGROUND: Severe neonatal hyperbilirubinemia could lead to kernicterus and neonatal death. This study aimed to analyze the association between single nucleotide polymorphisms in genes involved in bilirubin metabolism and the incidence of severe hyperbilirubinemia. METHODS: A total of 144 neonates with severe hyperbilirubinemia and 50 neonates without or mild hyperbilirubinemia were enrolled in 3 institutions between 2019 and 2020. Twelve polymorphisms of 5 genes (UGT1A1, SLCO1B1, SLCO1B3, BLVRA, and HMOX1) were analyzed by PCR amplification of genomic DNA. Genotyping was performed using an improved multiplex ligation detection reaction technique based on ligase detection reaction. RESULTS: The frequencies of the A allele in UGT1A1-rs4148323 and the C allele in SLCO1B3-rs2417940 in the severe hyperbilirubinemia group (30.2% and 90.6%, respectively) were significantly higher than those in the controls (30.2% vs.13.0%, 90.6% vs. 78.0%, respectively, both p < 0.05). Haplotype analysis showed the ACG haplotype of UGT1A1 were associated with an increased hyperbilirubinemia risk (OR 3.122, p = 0.001), whereas the GCG haplotype was related to a reduced risk (OR 0.523, p = 0.018). CONCLUSION: The frequencies of the A allele in rs4148323 and the C allele in rs2417940 are highly associated with the incidence of severe hyperbilirubinemia in Chinese Han neonates. TRIAL REGISTRATION: Trial registration number:ChiCTR1800020424; Date of registration:2018-12-29.
Assuntos
Hiperbilirrubinemia Neonatal , Polimorfismo de Nucleotídeo Único , Recém-Nascido , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Alelos , Hiperbilirrubinemia Neonatal/genética , Glucuronosiltransferase/genética , China/epidemiologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismoRESUMO
BACKGROUND: Hyperbilirubinemia is a common disorder in neonates, with premature infants at higher risk of developing the disorder. OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD) gene detection was used to determine the incidence of G6PD deficiency and analyze the etiologies of G6PD deficiency in neonates with hyperbilirubinemia in the Zunyi region with the aim of providing scientific evidence for the clinical diagnosis and treatment. METHODS: For the gene detection, 64 neonates with hyperbilirubinemia were selected as the observation group and 30 normal neonates were selected as the control group, and the risk factors for hyperbilirubinemia were investigated by using multivariate logistic regression analysis. RESULTS: Among the neonates in the observation group, 59 cases had the G1388A mutation (92.19%) and 5 cases had the G1376T mutation (7.81%). No mutation was detected in the control group. In the observation group, the proportion of neonates who were born prematurely, with artificial feeding, with the age of starting feeding of more than 24 h, the time of first bowel movement of more than 24 h, premature rupture of membranes, infection, scalp hematoma, and perinatal asphyxia was higher than that in the control group, and the difference was statistically significant (p< 0.05). Multivariate logistic regression analysis showed that prematurity, infection, scalp hematoma, perinatal asphyxia, the age of starting feeding of more than 24 h, and the time of first bowel movement over 24 h were risk factors for the development of neonatal hyperbilirubinemia (p< 0.05). CONCLUSION: The G1338A and G1376T mutations were important features of the genetics of neonatal hyperbilirubinemia, and genetic detection together with the prevention of prematurity, infection, scalp hematoma, perinatal asphyxia, the age of starting feeding, and the time of first bowel movement would help reduce the incidence of this disease.
Assuntos
Deficiência de Glucosefosfato Desidrogenase , Hiperbilirrubinemia Neonatal , Recém-Nascido , Humanos , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/terapia , Asfixia , Hiperbilirrubinemia Neonatal/epidemiologia , Hiperbilirrubinemia Neonatal/genética , Fatores de Risco , HematomaRESUMO
INTRODUCTION: Neonatal hyperbilirubinemia is common and remains a clinical concern in China. Since neonatal hyperbilirubinemia is linked to genetic factors, we aimed to identify the gene variants of the red blood cell membrane (RBCM) and evaluate the clinical risk factors in Chinese neonates with hyperbilirubinemia. METHODS: 117 hyperbilirubinemia neonates (33 cases of moderate hyperbilirubinemia and 84 cases of severe hyperbilirubinemia) and 49 controls with normal bilirubin levels were selected as our study subjects. A customized 22-gene panel with next-generation sequencing (NGS) was designed to characterize genetic variations among the neonates. Sanger sequencing was used to verify the accuracy of the NGS. The clinical risk factors and potential effects of genetic variations in neonates with hyperbilirubinemia were subsequently assessed. RESULTS: After data filtering, suspected pathogenic variants of UGT1A1, SLCCO1B1, and RBCM-associated gene were identified in neonates, the combined numbers of RBCM-associated gene variants were found to have differences between the hyperbilirubinemia group and the controls (p = 0.008), they were also different between severe hyperbilirubinemia and moderate hyperbilirubinemia (p = 0.008), and were correlated with an increased risk of hyperbilirubinemia (odds ratio = 9.644, p = 0.006). The UGT1A1-rs4148323 variant in neonates with hyperbilirubinemia was significantly increased as compared with the controls (p < 0.001). However, there was no statistical difference for the SLCO1B1-rs2306283 variant between the hyperbilirubinemia group and the controls. In addition, breastfeeding contributed to an increased risk of hyperbilirubinemia. CONCLUSION: Our study highlights that the RBCM-related gene variants are an underestimated risk factor, which may play an important role in developing hyperbilirubinemia in Chinese newborns.
Assuntos
Hiperbilirrubinemia Neonatal , Humanos , Recém-Nascido , Membrana Celular , China/epidemiologia , População do Leste Asiático , Glucuronosiltransferase/genética , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Fatores de RiscoRESUMO
BACKGROUND: Free bilirubin (Bf) is a better marker than total serum bilirubin (TSB) for predicting bilirubin encephalopathy (BE). To date, two UGT1A1 genetic variants (rs4148323 and rs3064744) have been associated with neonatal hyperbilirubinemia; however, the direct association between UGT1A1 variants and Bf levels in newborns has not been elucidated. METHODS: We retrospectively analyzed the clinical data of 484 infants, including the genotype data of two UGT1A1 genetic variants. We divided the infants into a high Bf group (Bf ≥ 1.0 µg/dL, n = 77) and a non-high Bf group (Bf < 1.0 µg/dL, n = 407), based on the peak Bf values. Logistic regression analysis was performed to calculate the odds ratios (ORs) for each variant allele compared to wild-type alleles. RESULTS: The frequencies of the A allele in rs4148323 and (TA)7 allele in rs3064744 in the high Bf group (29% and 4%, respectively) were significantly different from those in the non-high Bf group (16% and 12%, respectively). In logistic regression analysis, for rs4148323, the A allele was significantly associated with an increased risk of hyper-free bilirubinemia over the G allele (adjusted OR: 1.80, 95% confidence interval [CI]: 1.19-2.72, p < 0.01). However, for rs3064744, the (TA)7 allele was significantly associated with a decreased risk of hyper-free bilirubinemia over the (TA)6 allele (adjusted OR: 0.42, 95% CI: 0.18-0.95, p = 0.04). CONCLUSIONS: This study is the first to show that the A allele in rs4148323 is a risk factor and that the (TA)7 allele in rs3064744 is a protective factor for developing hyper-free bilirubinemia in Japanese newborns.
Assuntos
Glucuronosiltransferase , Hiperbilirrubinemia Neonatal , Humanos , Lactente , Recém-Nascido , Alelos , Bilirrubina/análise , Genótipo , Glucuronosiltransferase/genética , Hiperbilirrubinemia Neonatal/genética , Japão , Estudos RetrospectivosRESUMO
OBJECTIVES: To study the characteristics of UGT1A1 gene mutations in Dong neonates in Sanjiang County of Liuzhou and its association with the pathogenesis of hyperbilirubinemia in Dong neonates. METHODS: A prospective analysis was performed on 84 neonates who were diagnosed with unexplained hyperbilirubinemia in the Department of Neonatology, Sanjiang County People's Hospital, from January 2021 to January 2022. Sixty healthy neonates born during the same period were enrolled as the control group. Peripheral blood genomic DNA was extracted for both groups, and UGT1A1 exon 1 was amplified by PCR and sequenced. RESULTS: In the case group, 33 neonates were found to have G71R missense mutation, with a mutation rate of 39%. The case group had a significantly higher frequency of A allele than the healthy control group (21% vs 10%, P<0.05). The risk of hyperbilirubinemia in Dong neonates carrying G71R missense mutation was 2.588 times as high as that in healthy neonates carrying wild-type UGT1A1 gene (P<0.05). Hardy-Weinberg equilibrium testing showed that the UGT1A1 G71R locus was in genetic equilibrium in both groups (P>0.05). CONCLUSIONS: UGT1A1 G71R mutation is a high-frequency gene mutation type in Dong neonates in Sanjiang County, and G71R missense mutation is associated with hyperbilirubinemia in Dong neonates.
Assuntos
Glucuronosiltransferase , Hiperbilirrubinemia Neonatal , Povo Asiático/genética , China , Éxons , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , MutaçãoRESUMO
Hyperbilirubinemia is the main mechanism that causes neonatal jaundice, and genetics is one of the risk factors of hyperbilirubinemia. Therefore, this study aims to explore the correlation between two genes, UGT1A1 and SLCO1B1, and hyperbilirubinemia in Thai neonates. One hundred thirty seven neonates were recruited from Division of Clinical Chemistry, Ramathibodi Hospital. UGT1A1*28 and *6 were determined by pyrosequencing whereas, SLCO1B1 388A > G and 521 T > C genetic variants were determined by TaqMan® real-time polymerase chain reaction. Neonates carrying with homozygous (AA) and heterozygous (GA) variants in UGT1A1*6 were significantly related to hyperbilirubinemia development compared with wild type (GG; P < 0.001). To the combined of UGT1A1, total bilirubin levels in homozygous variant were higher significantly than heterozygous variant and wild type (P = 0.002, P = 0.003, respectively). Moreover, SLCO1B1 combination was significant differences between the hyperbilirubinemia and the control group (P = 0.041). SLCO1B1 521 T > C variant provide protection for Thai neonatal hyperbilirubinemia (P = 0.041). There are no significant differences in UGT1A1*28 and SLCO1B1 388A > G for the different severity of hyperbilirubinemia. The combined UGT1A1*28 and *6 polymorphism is a strong risk factor for the development of severe hyperbilirubinemia in Thai neonates. Therefore, we suggest neonates with this gene should be closely observed to avoid higher severities of bilirubin.
Assuntos
Hiperbilirrubinemia Neonatal , Icterícia Neonatal , Bilirrubina , Glucuronosiltransferase , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Icterícia Neonatal/complicações , Icterícia Neonatal/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Polimorfismo Genético , TailândiaRESUMO
BACKGROUND: Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation. CASE PRESENTATION: Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped. CONCLUSION: UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.
Assuntos
Síndrome de Crigler-Najjar , Doença de Gilbert , Hiperbilirrubinemia Neonatal , Bilirrubina , Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/genética , Síndrome de Crigler-Najjar/terapia , Feminino , Doença de Gilbert/diagnóstico , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia/genética , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/genética , Hiperbilirrubinemia Neonatal/terapia , Lactente , Recém-Nascido , Mutação , FenobarbitalRESUMO
OBJECTIVE: To investigate the clinical and genetic causes of neonatal unconjugated hyperbilirubinemia. STUDY DESIGN: We included 1412 neonates diagnosed with unconjugated hyperbilirubinemia (total serum bilirubin >95 percentile for age), from the China Neonatal Genomes Project between August 2016 and September 2019, in the current study. Clinical data and targeted panel sequencing data on 2742 genes including known unconjugated hyperbilirubinemia genes were analyzed. RESULTS: Among the 1412 neonates with unconjugated hyperbilirubinemia, 37% had severe unconjugated hyperbilirubinemia, with total serum bilirubin levels that met the recommendations for exchange transfusion. Known clinical causes were identified for 68% of patients. The most common clinical cause in the mild unconjugated hyperbilirubinemia group was infection (17%) and in the severe group was combined factors (21%, with infection combined with extravascular hemorrhage the most common). A genetic variant was observed in 55 participants (4%), including 45 patients with variants in genes associated with unconjugated hyperbilirubinemia and 10 patients with variants that were regarded as additional genetic findings. Among the 45 patients identified with unconjugated hyperbilirubinemia-related variants, the genes were mainly associated with enzyme deficiencies, metabolic/biochemical disorders, and red blood cell membrane defects. G6PD and UGT1A1 variants, were detected in 34 of the 45 patients (76%). CONCLUSIONS: Known clinical causes, which varied with bilirubin levels, were identified in approximately two-thirds of the patients. Genetic findings were identified in 4% of the patients, including in patients with an identified clinical cause, with G6PD and UGT1A1 being the most common genes in which variants were detected.
Assuntos
Glucosefosfato Desidrogenase , Glucuronosiltransferase , Hiperbilirrubinemia Neonatal , Bilirrubina , China , Glucosefosfato Desidrogenase/genética , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia/genética , Hiperbilirrubinemia Neonatal/genética , Recém-NascidoRESUMO
BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world. OBJECTIVE: To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia. METHOD: The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal bilirubin was collected and analyzed retrospectively. RESULTS: Seventy four cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubinin of the G6PD-deficient group of hyperbilirubinemia neonates was 334.43 ± 79.27 µmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30 ± 68.62 µmol/L). The most common genotypes of G6PD deficiency were c.1376G > T and c.1388G > A, and the peak bilirubin of neonates with these two variants were 312.60 ± 71.81 µmol/L and 367.88 ± 75.79 µmol/L, respectively. The bilirubin level of c.1388G > A was significantly higher than that of c.1376G > T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55 ± 84.51 µmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50 ± 63.21 µmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63 ± 57.52 µmol/L). CONCLUSION: The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.
Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucuronosiltransferase , Hiperbilirrubinemia Neonatal , Genótipo , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/genética , Glucuronosiltransferase/genética , Heterozigoto , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Mutação , Estudos RetrospectivosRESUMO
Population risks for neonatal hyperbilirubinaemia (NH) vary. Knowledge of local risks permits interventions that may reduce the proportion becoming severe. Between January 2015 and May 2016, in a resource-limited setting on the Thailand-Myanmar border, neonates from 28 weeks' gestation were enrolled into a prospective birth cohort. Each neonate had total serum bilirubin measurements: scheduled (24, 48, 72 and 144 hours of life) and clinically indicated; and weekly follow up until 1 month of age. Risk factors for developing NH were evaluated using Cox proportional hazard mixed model. Of 1710 neonates, 22% (376) developed NH (83% preterm, 19% term). All neonates born <35 weeks, four in five born 35-37 weeks, and three in twenty born ≥38 weeks had NH, giving an overall incidence of 249 per 1000 livebirths [95%CI 225, 403]. Mortality from acute bilirubin encephalopathy was 10% (2/20) amongst the 5.3% (20/376) who reached the severe NH threshold. One-quarter (26.3%) of NH occurred within 24 hours. NH onset varied with gestational age: at a median [IQR] 24 hours [24, 30] for neonates born 37 weeks or prematurely vs 59 hours [48, 84] for neonates born ≥38 weeks. Risk factors for NH in the first week of life independent of gestational age were: neonatal G6PD deficiency, birth bruising, Sgaw Karen ethnicity, primigravidae, pre-eclampsia, and prolonged rupture of membranes. The genetic impact of G6PD deficiency on NH was partially interpreted by using the florescent spot test and further genotyping work is in progress. The risk of NH in Sgaw Karen refugees may be overlooked internationally as they are most likely regarded as Burmese in countries of resettlement. Given high levels of pathological jaundice in the first 24 hours and overall high NH burden, guidelines changes were implemented including preventive PT for all neonates <35 weeks and for those 35-37 weeks with risk factors.
Assuntos
Bilirrubina/sangue , Deficiência de Glucosefosfato Desidrogenase/sangue , Hiperbilirrubinemia Neonatal/sangue , Kernicterus/sangue , Estudos de Coortes , Estudos Epidemiológicos , Etnicidade/genética , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/mortalidade , Humanos , Hiperbilirrubinemia Neonatal/genética , Hiperbilirrubinemia Neonatal/mortalidade , Hiperbilirrubinemia Neonatal/patologia , Recém-Nascido , Kernicterus/complicações , Kernicterus/genética , Kernicterus/mortalidade , Masculino , Mianmar/epidemiologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/mortalidade , Gravidez , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Tailândia/epidemiologiaRESUMO
BACKGROUND: Neonatal hyperbilirubinemia causing jaundice is common in East Asian population. Uridine diphosphate glucuronosyltransferase isoenzyme (UGT1A1) glucuronidates bilirubin and converts the toxic form of bilirubin to its nontoxic form. METHOD: A retrospective study was conducted to review clinical information of ABO hemolysis neonates (ABO HDN) admitted to the Department of Neonatology, referred for neonatal hyperbilirubinemia, in a large general hospital of southern China from 2011 to 2017. Variation status of UGT1A1 was determined by direct sequencing or genotype assays. RESULT: Sixty-nine ABO HDNs were included into the final analysis. UGT1A1 c.211 G > A mutation (UGT1A1*6, p.Arg71Gly, rs4148323) was significantly associated with the increased bilirubin level in ABO HDNs, after adjusted by age, sex and feeding method (P = 0.019 for TBIL, P = 0.02 for IBIL). Moreover, heterozygous and/or homozygous UGT1A1 mutations in the coding sequence region were significantly associated with the increased risk of developing hazardous hyperbilirubinemia (as defined by TSB > 427 umol/L) as compared those with a normal UGT1A1 genotype (ORadj = 9.16, 95%CI 1.99-42.08, P = 0.002) in the study cohort. CONCLUSION: UGT1A1 variant in coding region is actively involved in the pathogenesis of ABO hemolysis related neonatal hyperbilirubinemia. Genetic assessment of UGT1A1 may be useful for clinical diagnosis of neonatal unconjugated hyperbilirubinemia.
Assuntos
Hiperbilirrubinemia Neonatal , Bilirrubina , China , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Mutação , Estudos RetrospectivosRESUMO
Objective: The association between a (GT)n dinucleotide length polymorphism in the promoter region of heme oxygenase 1 (HMOX1) and the risk of neonatal hyperbilirubinemia remains controversial. This meta-analysis was, therefore, performed with aims to examine the correlation between the HMOX1 (GT)n repeat length polymorphism and neonatal hyperbilirubinemia susceptibility.Materials and methods: We searched the databases including PubMed, Embase, Cochrane Library, China national knowledge infrastructure (CNKI), and Wanfang Data, with all reviewed studies published before 28 June 2018. After the evaluation of quality, we used RevMan to perform the meta-analyses. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the effect of HMOX1 gene promoter polymorphisms on the risk of neonatal hyperbilirubinemia.Results: Seven studies, involving 584 patients with neonatal hyperbilirubinemia and 1655 controls, were included. A statistically significant association was found between the HMOX1 (GT)n repeat length polymorphism and risk of neonatal hyperbilirubinemia under the allele (allele S vs. allele L: OR = 1.81, 95% CI = 1.22-2.67, p = .003), recessive (genotype SS vs. genotypes LS + LL: OR = 1.38, 95% CI = 1.02-1.86, p = .04), dominant (genotypes SS + LS vs. LL: OR = 1.37, 95% CI = 1.01-1.76, p = .01), and homozygous genetic models (genotype SS vs. genotype LL: OR = 1.47, 95% CI = 1.02-2.11, p = .003), but not under the heterozygous genetic model. Interestingly, subgroup analysis revealed that the cutoffs of the S allele < 25 showed significant associations in any of the five genetic models (allele S vs. allele L: OR = 2.26, 95% CI = 1.68-3.05, p < .00001; genotype SS vs. genotypes LS + LL: OR = 2.56, 95% CI = 1.41-4.65, p = .002; genotypes SS + LS vs. genotype LL: OR = 1.82, 95% CI = 1.28-2.59, p = .0009; genotype SS vs. genotype LL: OR = 3.09, 95% CI = 1.50-6.36, p = .002; genotype LS vs. genotype LL: OR = 1.64, 95% CI = 1.11-2.42, p = .01); however, this association was not observed in the cutoffs of the S allele ≥25.Conclusion: The results of this study indicate that there is a significant association between the HMOX1 (GT)n repeat length polymorphism and susceptibility to neonatal hyperbilirubinemia. Newborns carrying shorter (GT)n repeats in the HMOX1 gene promoter may have a higher risk of neonatal hyperbilirubinemia.
Assuntos
Heme Oxigenase-1 , Hiperbilirrubinemia Neonatal , China , Predisposição Genética para Doença , Genótipo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Polimorfismo Genético , Regiões Promotoras GenéticasRESUMO
BACKGROUND: This study aimed to evaluate the relationship between UGT1A1*28 gene polymorphism and the risk of neonatal hyperbilirubinemia (NHBI). METHODS: The studies meet certain selection condition which was obtained from databases such as PubMed, Embase, and Cochrane Library. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed according to criteria such as country. Hardy-Weinberg's equilibrium (HWE) tests were performed on the control group using chi-square test, while the evaluation index was represented by odds ratio (OR) and 95% confidence interval (CI). Egger's test and sensitivity analysis were used to evaluate the publication bias and reliability, repetitively. RESULTS: Totally, four studies with high overall quality were enrolled in this study. No association was observed between UGT1A1*28 gene polymorphisms and NHBI in allele model (TA7 versus TA6, OR (95% CI) = 2.13 (0.81-5.62), p = .13), codominance models (TA7/6 versus TA6/6, OR (95% CI) = 2.94 (0.90-9.57), p = .07; TA7/7 versus TA6/6, OR (95% CI) = 2.08 (0.37-11.52), p = .40), recessive model (TA7/7 versus TA6/6 + TA7/6, OR (95% CI) = 1.44 (0.41-5.14), p = .57), and dominant model (TA7/7 + TA7/6 versus TA6/6, OR (95% CI) = 2.92 (0.84-10.12), p = .09). Furthermore, there was no publication bias found in current meta-analysis. CONCLUSIONS: Gene polymorphism of UGT1A1*28 might not be associated with the risk of NHBI.
Assuntos
Glucuronosiltransferase , Hiperbilirrubinemia Neonatal , Predisposição Genética para Doença , Glucuronosiltransferase/genética , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Razão de Chances , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Reprodutibilidade dos TestesRESUMO
Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl-tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis-like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole-exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.
Assuntos
Doenças do Prematuro/genética , Leucina-tRNA Ligase/genética , Falência Hepática/genética , Anormalidades Musculoesqueléticas/genética , Mutação de Sentido Incorreto , Mutação Puntual , Sítios de Splice de RNA/genética , Substituição de Aminoácidos , Anemia Neonatal/genética , Éxons/genética , Evolução Fatal , Retardo do Crescimento Fetal/genética , Genes Recessivos , Heterozigoto , Humanos , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/patologia , Íntrons/genética , Leucina-tRNA Ligase/deficiência , Cirrose Hepática/etiologia , Falência Hepática/patologia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/patologia , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Músculo Esquelético/patologia , Anormalidades Musculoesqueléticas/patologia , Alinhamento de Sequência , Síndrome , Sequenciamento do ExomaRESUMO
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.
Assuntos
Predisposição Genética para Doença , Glucuronosiltransferase/genética , Hiperbilirrubinemia Neonatal/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático , População Negra , Estudos de Casos e Controles , Expressão Gênica , Humanos , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/etnologia , Hiperbilirrubinemia Neonatal/patologia , Recém-Nascido , Razão de Chances , População BrancaRESUMO
OBJECTIVES: This study aimed to determine whether maternal-fetal blood group isoimmunization, breastfeeding, birth trauma, age when first total serum bilirubin (TSB) was measured, age of admission, and genetic predispositions to hemolysis [due to genetic variants of glucose-6-phosphate dehydrogenase (G6PD) enzyme], and reduced hepatic uptake and/or conjugation of serum bilirubin [due to genetic variants of solute carrier organic anion transporter protein family member 1B1 (SLCO1B1) and uridine diphosphate glucuronosyltransferase family 1 member A1 (UGT1A1)] were significant risk factors associated with severe neonatal hyperbilirubinemia (SNH, TSB ≥ 342µmol/l) in jaundiced term neonates admitted for phototherapy. METHODS: The inclusion criteria were normal term neonates (gestation ≥ 37 weeks). Parents/care-givers were interviewed to obtain data on demography, clinical problems, feeding practice and age when first TSB was measured. Polymerase chain reaction-restriction fragment length polymorphism method was used to detect common G6PD, UGT1A1 and SLCO1B1 variants on each neonate's dry blood specimens. RESULTS: Of 1121 jaundiced neonates recruited, 232 had SNH. Logistic regression analysis showed that age (in days) when first TSB was measured [adjusted odds ratio (aOR) = 1.395; 95% confidence interval (CI) 1.094-1.779], age (in days) of admission (aOR = 1.127; 95% CI 1.007-1.260) and genetic mutant UGT1A1 promoter A(TA)7TAA (aOR = 4.900; 95% CI 3.103-7.739), UGT1A1 c.686C>A (aOR = 6.095; 95% CI 1.549-23.985), SLCO1B1 c.388G>A (aOR = 1.807; 95% CI 1.242-2.629) and G6PD variants and/or abnormal G6PD screening test (aOR = 2.077; 95% CI 1.025-4.209) were significantly associated with SNH. CONCLUSION: Genetic predisposition, and delayed measuring first TSB and commencing phototherapy increased risk of SNH.
Assuntos
Bilirrubina/sangue , Glucosefosfato Desidrogenase/genética , Glucuronosiltransferase/genética , Hiperbilirrubinemia Neonatal/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Fígado/metabolismo , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Glucosefosfato Desidrogenase/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/terapia , Recém-Nascido , Icterícia , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , FototerapiaRESUMO
BACKGROUND: We found that Taiwanese adults carrying genotypes of UDP-glucuronosyltransferase (UGT) 1A1 with enzyme activity ≤40% of normal were at high risk for developing Gilbert's syndrome. However, the relationship between UGT1A1 activity and neonatal hyperbilirubinemia has never been evaluated for Taiwanese. METHODS: We enrolled 141 hyperbilirubinemic neonates partially fed supplementary infant formula and 432 controls; and 112 hyperbilirubinemic neonates exclusively breastfed and 493 controls. The five single nucleotide polymorphisms (SNPs) at nucleotides -53, 211, 686, 1091 and 1456 in the UGT1A1 gene were determined and UGT1A1 activity was estimated. Odds ratios (ORs) of variation status in the UGT1A1 gene and enzyme activity for the development of neonatal hyperbilirubinemia were calculated, respectively. RESULTS: For neonates partially fed supplementary infant formula, the adjusted OR (AOR) for the development of hyperbilirubinemia was significantly higher in the neonates carrying the homozygous variation (211AA) in the UGT1A1 gene than for those carrying the wild type (AOR = 6.00, p < 0.001). Only the AOR of those carrying UGT1A1 activity ranked 31-40% of normal was statistically significant (AOR = 3.16, p < 0.001). For the hyperbilirubinemic neonates exclusively breastfed, AOR for the development of hyperbilirubinemia is positively correlated to degree of variation (AOR = 1.95, 2.19 and 4.53; with p = 0.003, 0.05 and < 0.001, respectively), while the effect of UGT1A1 enzyme activity was varied (AOR = 1.02-3.72, with p = 0.95â¼<0.001). CONCLUSION: The estimated enzyme activity depending on combination of SNPs (genotypes) in the UGT1A1 gene could not be utilized to explain the development of neonatal hyperbilirubinemia. We reconfirm that the -53 A(TA)7TAA/A(TA)7TAA is not, while the 211AA is a risk factor for the development of neonatal hyperbilirubinemia in Taiwanese.
Assuntos
Glucuronosiltransferase/genética , Hiperbilirrubinemia Neonatal/genética , Polimorfismo de Nucleotídeo Único , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Recém-Nascido , Masculino , Razão de ChancesRESUMO
INTRODUCTION: There are many studies on the relationship between serum levels of hyperbilirubinemia and hearing impairment. However, the mechanism of hyperbilirubinemia on auditory impairment is not clear. METHODS AND ANALYSIS: A total of 1000 children with hyperbilirubinemia who are mainly indirectly elevated bilirubin in the full-term neonatal ward of Xiamen Children's Hospital from March 2020 to September 2020 will be enrolled. Using second-generation high-throughput sequencing technology, 127 deaf-related genes were sequenced from the collected samples. At the same time, physical audiometry was performed on the selected persons and audiometry data were recorded. DISCUSSION: In this study, we will combine gene sequencing with clinical indications of hyperbilirubinemia to find the loci suitable for high-frequency pathogenic deafness related to hyperbilirubinemia, so as to provide early guidance for deafness gene screening in children with hyperbilirubinemia. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2000030075.
Assuntos
Protocolos Clínicos , Surdez/genética , Hiperbilirrubinemia Neonatal/genética , Distribuição de Qui-Quadrado , Correlação de Dados , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Recém-Nascido , Masculino , Estudos ProspectivosRESUMO
Hyperbilirubinemia is a prevalent disease in neonates and is also a main reason for hospitalization within the first week after birth, and this disease is mainly caused by the imbalance between production and elimination of bilirubin. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), organic anion transporter polypeptide 2 (OATP2), heme oxygenase 1 (HO-1), and biliverdin reductase A (BLVRA) play crucial roles in the metabolism of bilirubin. More and more studies have revealed the association between the variation of the encoding genes for these enzymes and hyperbilirubinemia. This article reviews the research advances in the association between the gene polymorphisms of bilirubin metabolic enzymes and hyperbilirubinemia.
Assuntos
Hiperbilirrubinemia Neonatal , Polimorfismo Genético , Bilirrubina , Glucuronosiltransferase , Heme Oxigenase-1 , Humanos , Hiperbilirrubinemia , Hiperbilirrubinemia Neonatal/genética , Recém-Nascido , Transportador 1 de Ânion Orgânico Específico do FígadoRESUMO
BACKGROUND: To investigate the relationship between unexplained indirect hyperbilirubinemia of Vietnamese newborns and the polymorphism of the promoter TATA box and exon 1 of bilirubin uridine diphosphate glucuronosyltransferase (UGT1A1) gene. METHODS: A total of 149 neonates were divided into the hyperbilirubinemia group (n = 99) and control group (n = 50). The gene polymorphisms of UGT1A1 gene in the two groups were detected by PCR and direct sequencing, which revealed the relationship between UGT1A1 polymorphism with neonatal hyperbilirubinemia of neonates. The types of UGT1A1 polymorphism in the hyperbilirubinemia group and the peak total serum bilirubin (PSB) levels with different genotypes were observed. RESULTS: (1) (TA)7 insertion mutation, 211G>A, 189C>T, 190G>A, 378C>T and 686C>A were detected. (2) The allele frequency of 211G>A allele mutation was significantly different between the two groups (p < 0.05). (3) Logistic regression analysis showed that homozygosity and heterozygosity of 211G>A were both significantly associated with neonatal hyperbilirubinemia. (4) In the hyperbilirubinemia group, the peak total serum bilirubin level of 211G>A homozygous neonates was higher than that of the wild-type neonates (p < 0.05). CONCLUSIONS: We noted that there was an association between neonates with unexplained indirect hyperbilirubinemia in Vietnam and the polymorphism of UGT1A1c.211G>A. In addition, the homozygous 211G>A polymorphism was related to the degree of hyperbilirubinemia. IMPACT: Our article provided data on UGT1A1 polymorphism distribution in the Vietnamese population, which have not been reported yet. Our findings revealed that mutations in UGT1A1 gene are risk factors for unexplained hyperbilirubinemia in Vietnamese neonates. Our article will strengthen the cognition of neonatal jaundice at the genetic level in the pediatric field in Vietnam.