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.
Asians/genetics* ; China ; Exons ; Glucuronosyltransferase/genetics* ; Humans ; Hyperbilirubinemia, Neonatal/genetics* ; Infant, Newborn ; Mutation

OBJECTIVENeonatal unconjugated hyperbilirubinemia is one of the most common conditions encountered by the practicing pediatricians. Although it is usually self-limited and benign, the condition is of importance because of the rare instances in which severe hyperbilirubinemia can lead to bilirubin encephalopathy or kernicterus. The uridine diphosphate-glucuronosyl transferase 1A1 (UGT 1A1) gene controls bilirubin conjugation by determining the structure of the enzyme glucuronosyltransferase, which is synthesized in the hepatocyte. In the recent years much has been learned about the relationship between UGT 1A1 gene mutation and neonatal hyperbilirubinemia. This study aimed to investigate the roles of UGT 1A1 gene mutation in the development of neonatal hyperbilirubinemia in Guangxi.

METHODSA total of 73 cases with hyperbilirubinemia and 31 healthy neonates were enrolled. UGT 1A1 G71R genotypes were identified by the (amplification refractory mutation system, ARMS) and direct sequencing method in all the neonates. To analyze the incidence of bilirubin encephalopathy, the peak (total serum bilirubin, TSB) concentration after 72 hours of age, and the possibility of TSB > 20 mg/dl of each group.

RESULTS(1) The frequencies of allele G71R were 0.1915 in this study, 0.2329 in hyperbilirubinemia group vs. 0.097 in healthy groups. The allele gene frequency of G71R in neonatal hyperbilirubinemia was higher than that in the normal group (P < 0.05). (2) Homozygous neonates had higher possibility to develop bilirubin encephalopathy and higher TSB concentration 72 hours after birth (28.57%, 23.12 ± 4.58) than the normal group (0%, 17.68 ± 2.69). The difference between the former two was significant (P < 0.001). (3) The TSB of the 5 neonates was > 20 mg/dl in G71R homozygous type, the odds ratio and 95%CI were 7.955 (1.349, 46.899).

CONCLUSION(1) G71R mutation gene was associated with neonatal jaundice in Guangxi region. (2) The possibility of TSB > 20 mg/dl in G71R homozygous was higher than those of the wild-type. (3) The incidence of bilirubin encephalopathy and TSB concentration after 72 hours of age for neonates who were homozygous to G71R gene were higher than the wild-type.

Case-Control Studies ; China ; epidemiology ; Genotype ; Glucuronosyltransferase ; genetics ; Humans ; Hyperbilirubinemia, Neonatal ; epidemiology ; genetics ; Infant, Newborn ; Mutation

OBJECTIVETo study association of uridine-diphosphate-glucuronosyltransferase1A1 (UGT1A1) Gly71Arg, UGT1A1 promoter TATA-box and glucose-6-phosphate dehydrogenase (G6PD) gene mutations with the occurrence of neonatal unconjugated hyperbilirubinemia.

METHODSThe TATA-box, exon 1 and exon 5 of the UGT1A1 gene and the exon 12 of G6PD gene were amplified by PCR. The products of PCR were analyzed by direct DNA sequencing. Clones for the mutations of the UGT1A1 gene and the G6PD gene were constructed in order to identify the results of the products of PCR. Seventy-two neonates with unconjugated hyperbilirubinemia (case group) and 65 healthy neonates (control group) were enrolled. The genotypes and allele frequencies of the polymorphisms of UGT1A1 Gly71Arg and UGT1A1 TATA-box were compared between the two groups. The effects of UGT1A1 Gly71Arg, UGT1A1 promoter TATA-box and G6PD gene mutations on the development of neonatal unconjugated hyperbilirubinemia were estimated using logistic regression models.

RESULTSThere were significant differences in the genotype distribution of Gly71Arg polymorphism of UGT1A1 gene between the case and control groups (P<0.01). The Arg allele frequency of the polymorphisms of UGT1A1 gene in the case group was significantly higher than in the control group (P<0.01). There were no significant differences in the genotype distribution of the UGT1A1 promoter TATA-box between the two groups (P>0.05). The OR and 95%CI values of UGT1A1 Gly71Arg, UGT1A1 TATA-box and G6PD gene mutations associated with the development of neonatal unconjugated hyperbilirubinemia were 5.468 (2.274, 12.818), 0.688 (0.266, 1.778) and 5.081 (1.070, 24.133) respectively.

CONCLUSIONSUGT1A1 Gly71Arg and G6PD gene mutations may be involved in the development of neonatal unconjugated hyperbilirubinemia.

Glucosephosphate Dehydrogenase ; genetics ; Glucuronosyltransferase ; genetics ; Humans ; Hyperbilirubinemia, Neonatal ; etiology ; genetics ; Infant, Newborn ; Mutation ; Polymerase Chain Reaction ; TATA Box

OBJECTIVETo study the distribution of mutations of UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship with hyperbilirubinemia among neonates with hyperbilirubinemia of Guangxi Heiyi Zhuang nationality.

METHODSTotal genomic DNA was extracted from the blood of 100 neonates with hyperbilirubinemia (case group) and 100 neonates without hyperbilirubinemia (control group), all of whom were selected from Guangxi Heiyi Zhuang population. TATA box and all exons of UGT1A1 gene were amplified by PCR and directly sequenced.

RESULTS(TA)7 insertion mutation in TATA box, G71R missense mutation in exon 1, and 4 single nucleotide polymorphisms (SNPs) (rs199539868, rs114982090, rs1042640 and rs8330) in exon 5 were observed. The allele frequency of G71R mutation in the case group was significantly higher than that in the control group (P<0.01). There were no significant differences in the genotype distribution and allele frequency of TATA box mutation and SNPs (rs1042640 and rs8330) between the two groups (P>0.05). The logistic regression analysis showed that the odds ratios (95% confidence intervals) of UGT1A1 TATA box mutation, G71R mutation, and SNPs (rs1042640 and rs8330) associated with the development of neonatal hyperbilirubinemia were 0.846 (0.440, 1.629), 3.932 (1.745, 8.858), 0.899 (0.364, 2.222), respectively.

CONCLUSIONS(TA)7 insertion mutation and G71R missense mutation of UGT1A1 gene are common mutation types in neonates with hyperbilirubinemia of Guangxi Heiyi Zhuang nationality. Four SNPs (rs199539868, rs114982090, rs1042640, and rs8330) was first reported in China. UGT1A1 G71R missense mutation is a risk factor for hyperbilirubinemia in neonates of Guangxi Heiyi Zhuang nationality.

China ; ethnology ; Glucuronosyltransferase ; genetics ; Humans ; Hyperbilirubinemia, Neonatal ; genetics ; Infant, Newborn ; Logistic Models ; Mutation ; Polymorphism, Single Nucleotide ; TATA Box

OBJECTIVEMultiple genetic and environmental factors contribute to the onset of many human diseases, such as neonatal hyperbilirubinemia. OATP 1B1 is an important polymorphism gene which transmembrane transports unconjugated bilirubin(UCB). Genetic polymorphisms that affect the functionality of the protein may potentially lead to altered transport characteristics. The T521C/A388G polymorphism of this gene has been reported to considerably reduce the transporting property of drugs like pravastatin, and may be involved in the membrane translocation of bilirubin. Some studies have shown that OATP 1B1 mediates bilirubin uptake from blood into the liver, and the OATP 1B1 polymorphism is a likely mechanism explaining the differences of bilirubin level in peripheral blood. The aim of this study was to evaluate the relationship between OATP 1B1 polymorphisms and neonatal hyperbilirubinemia.

METHODSA total of 220 newborn infants with hyperbilirubinemia were recruited from Hunan Children Hospital from November 2008 to December 2009 according to the diagnostic criteria. Age and sex matched control subjects comprised of 200 unrelated, hyperbilirubinemia-free newborns. Biochemical and clinical data were collected from the case history. One ml venous blood samples in EDTA vials were taken from each subject and DNA was isolated from peripheral leukocytes by standard methods, preserved in 4°C. 1 - 2 ml venous blood samples were also taken for detecting the serum total bilirubin and direct bilirubin level by chemical oxidation method. OATP 1B1 T521C/A388G polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allele and genotype frequencies were compared between patients and control. The gene polymorphism and risk of disease were also analyzed. Serum total bilirubin, conjugated bilirubin and unconjugated bilirubin levels were compared between different OATP 1B1 T521C/A388G genotypes.

RESULTSAllele frequencies in patients and control population were in Hardy-Weinberg equilibrium (P > 0.05). Allele and genotype frequencies of the OATP 1B1 T521C polymorphism in patients were significantly different from the controls. The OATP 1B1 521C allele frequency was only 8.2% in patients, while reached 14.0% in the control group which was very close to the frequency of common Chinese people. However, the proportion of wild type genotypes was significantly higher than those of the controls, reached 84.1%. The 521 C allele and genotypes carrying 521 C allele illustrated low risk for neonatal hyperbilirubinemia (OR = 0.530, 95%CI = 0.328 - 0.857; OR = 0.541, 95%CI = 0.344 - 0.851). However, the frequencies of alleles and genotypes of SLCO1B1 A388G did not differ significantly from those of the controls, and this polymorphism did not influence susceptibility to such disease. Among the three OATP 1B1 A388G genotypes, the level of total serum bilirubin (TSB), direct bilirubin (DB) and unconjugated bilirubin (UCB) were significantly different. Values of TSB, DB and UCB were the highest in wild type subjects, lower in heterozygotes, and the lowest in mutant homozygotes. TSB and UCB in patients with wild type genotypes reached 602.5 µmol/L and 585.0 µmol/L respectively, nearly twice the average value of homozygous patients. While the TSB and UCB in homozygotes were below the average value of all patients, only 351.7 µmol/L and 338.8 µmol/L respectively.

CONCLUSIONSOur findings indicated that OATP 1B1 A388G polymorphism has a notable influence on the serum bilirubin level in neonatal hyperbilirubinemia patients. The OATP 1B1 521T allele may be a potential risk factor of such disease. OATP 1B1 T521C/A388G was an important polymorphism gene which related with neonatal hyperbilirubinemia. Future study should involve other polymorphisms of OATP 1B1, more candidate genes and environmental risk factors. It is also necessary to investigate their association with the severity and prognosis of this disease in order to elucidate the genetic pathogenesis of neonatal hyperbilirubinemia as a complex disease. This study should be repeated in a larger population and different ethnic groups.

Bilirubin ; blood ; Case-Control Studies ; Female ; Humans ; Hyperbilirubinemia, Neonatal ; genetics ; Infant, Newborn ; Male ; Organic Anion Transporters ; genetics ; Polymorphism, Restriction Fragment Length ; Solute Carrier Organic Anion Transporter Family Member 1b1