Glucuronosyltransferase ; genetics ; Humans ; Infant, Newborn ; Jaundice, Neonatal ; genetics

PURPOSE: Irinotecan (CPT-11) is hydrolyzed to an active SN-38, which is further detoxicated to SN-38G through conjugation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzymes. There are many reports that UGT1A1 polymorphisms are associated with irinotecan related dose-limiting toxicity. The aim of the present study is to determine whether UGT1A1 polymorphisms affect individual variations of the toxicity due to and the tumor response to irinotecan via the alteration of bioavailability of SN-38 in Korean patients with locally advanced rectal cancer. METHODS: Twenty patients with locally advanced rectal cancer, who had received surgery after irinotecan-containing chemoradiation from 2003 to 2006, were enrolled. We analyzed the association of UGT1A1 genotypes with toxicity and tumor response to chemoradiation therapy. A tumor response was assumed when a tumor regression grade I or II was obtained. Toxicity was graded in accordance with the NCI common toxicity criteria. RESULTS: The frequence of square53(TA)6>7 (UGT1A1*28), 211G>A (UGT1A1*6), 686C>A (UGT1A1*27), square3279T>G (UGT1A1*60), and square3156G>A were 25% (5/20), 25% (5/20), 0% (0/20), 55% (11/20), and 20% (4/20), respectively. There were five grade III neutropenia and one severe diarrhea. Patients with UGT1A1*28 and square3156G>A showed higher complete tumor response rates (40% vs. 6.7%, P=0.07; 50% vs. 6.3%, P=0.08), but there was no differences in toxicity and tumor response between responders and non-responders. Patients with square3279T>G (UGT1A1*60) showed a tendency for lower tumor response in tumor responders, but there was no statistically significant difference (P=0.07). CONCLUSIONS: This study suggested that square3279T>G (UGT1A1*60) may be useful in predicting tumor response of irinotecan. In the future, further study is warranted using large numbers of cases to reach statistical significance.
Biological Availability ; Colorectal Neoplasms ; Diarrhea ; Genotype ; Glucuronosyltransferase ; Humans ; Neutropenia ; Rectal Neoplasms* ; Uridine Diphosphate

A case of Gilbert syndrome (GS) with a heterozygous mutation in the gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood. Laboratory examinations revealed an elevated unconjugated bilirubin. Biliary obstruction, hemolysis and other diseases that might cause jaundice were excluded. *28 and c.211G>A heterozygous mutations in gene were found, which may be another type of mutation causing GS in Chinese population.
Asian Continental Ancestry Group ; Bilirubin ; Gilbert Disease ; genetics ; Glucuronosyltransferase ; genetics ; Heterozygote ; Humans ; Mutation

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

OBJECTIVE: To study the expression of hyaluronan synthasel-3 (HAS1-3) in nasal polyps, and discuss their clinical significance. METHOD: The expression of HA, HAS1, HAS2 and HAS3 in nasal polyps group (25 cases) and inferior turbinate group (15 cases) was detected by immunohistochemistry and semi-quantitative RT-PCR. RESULT: Compared with the control, the expression of HA, HAS1 and HAS3 was higher in nasal polyps (P<0. 05), while there was no significant difference in HAS2 expression (P>0. 05). CONCLUSION The increase of HASI and HAS3 expression may be the main cause of the excessive deposition of HA in nasal polyps, which may play an important role in the pathogenic process of nasal polyps, and become a potential target for therapy of nasal polyps.
Glucuronosyltransferase ; metabolism ; Humans ; Hyaluronan Synthases ; Hyaluronic Acid ; Immunohistochemistry ; Nasal Polyps ; enzymology

Congenital hemolytic anemia is mainly developed due to intrinsic defects of erythrocytes, but in some cases the cause of hemolytic anemia is unclear. Gilbert's syndrome shows mild, chronic unconjugated hyperbilirubinemia that is due to reduced UDP glucuronosyltransferase (UGT-1A1) activity and this develops because of UGT-1A1 gene mutation. We report here on a case of severe hyperbilirubinemia in a 17-year-old male who was diagnosed with congenital hemolytic anemia of an unknown cause combined with Gilbert's syndrome.
Adolescent ; Anemia, Hemolytic ; Anemia, Hemolytic, Congenital ; Erythrocytes ; Gilbert Disease ; Glucuronosyltransferase ; Humans ; Hyperbilirubinemia ; Male

BACKGROUND: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. METHODS: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. RESULTS: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not. CONCLUSIONS In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.
Camptothecin/therapeutic use* ; Glucuronosyltransferase/genetics* ; Humans ; Lung Neoplasms/drug therapy* ; Mutation ; Polymorphism, Genetic ; Retrospective Studies

OBJECTIVETo detect potential mutation of the UGT1A1 gene in a child affected with Crigler-Najjar syndrome type II.

METHODSBlood samples were collected from the patient and his parents for the extraction of genomic DNA. Potential mutation of the UGT1A1 gene was detected with polymerase chain reaction (PCR) and direct sequencing. The child was followed up until the age of 3 years and 6 months.

RESULTSThe patient showed persistent unconjugated hyperbilirubinemia. Sequencing of the UGT1A1 gene has detected a rare heterozygous c.610 A>G (p.Met204Val) mutation in the exon 1, in addition with a heterozygous c.1091 C>T (p.Pro364Leu) mutation in exon 4. The two mutations were inherited from his father and mother, respectively. The patient was diagnosed with Crigler-Najjar syndrome type II and received oral phenobarbital treatment.

CONCLUSIONThe compound UGT1A1 gene mutation probably accounts for the disease in the patient manifesting persistent mild unconjugated hyperbilirubinemia. Genetic counseling and prenatal diagnosis should be provided for his family.

Crigler-Najjar Syndrome ; genetics ; Glucuronosyltransferase ; genetics ; Humans ; Infant ; Male ; Mutation ; Sequence Analysis, DNA

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

A two-year-old girl was admitted due to repeated yellowing of the skin and sclera for 2 years and had no other specific symptoms or signs. The use of phenobarbital could relieve the symptoms of jaundice. Multiple examinations showed increased indirect bilirubin levels, and the results of aminotransferases and liver imaging were normal. There was no evidence of hemolysis. The analysis of UGT1A1 gene in her family found that this child had double homozygous mutation of c.211G>A(G71R) and c.1456T>G(Y486D), which had been reported as the pathogenic mutation for Gilbert syndrome. Her parents carried double heterozygous mutation of G71R and Y486D and had no symptom of jaundice. The child was diagnosed as having Gilbert syndrome. It is concluded that as for patients with unconjugated hyperbilirubinemia which cannot be explained by liver damage and hemolysis, their family history should be investigated in detail and gene analysis should be performed as early as possible, in order to identify congenital bilirubin metabolic disorders.
Child, Preschool ; Female ; Gilbert Disease ; diagnosis ; Glucuronosyltransferase ; genetics ; Humans ; Mutation ; Sclera ; pathology ; Skin ; pathology