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Tagawa K, Maruo Y. Dolutegravir metabolism: impact of genetic variations on uridine diphosphate glucuronosyltransferase subfamilies. Xenobiotica 2025:1-8. [PMID: 39815789 DOI: 10.1080/00498254.2025.2453983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/09/2025] [Accepted: 01/12/2025] [Indexed: 01/18/2025]
Abstract
Dolutegravir (DTG) is a key drug used to treat human immunodeficiency virus type-1 (HIV-1) infections. Adverse events (AEs) of DTG treatment, including headache, anxiety, depression, insomnia, and abnormal dreams, are influenced by sex, body weight, age, and serum bilirubin levels. DTG is mainly metabolised by members of the uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As), especially UGT1A1.Some studies suggest a relationship between UGT1A1 variants and AEs. The aim of this study was to identify UGT1A isoforms that exhibit DTG glucuronidation activity and determine the relationship between UGT1A variants and DTG glucuronidation in vitro.UGT1A1, UGT1A3, UGT1A9, and UGT1A10 exhibited DTG glucuronidation activity, of which UGT1A1 was the most active. Furthermore, variants of these isoforms showed decreased DTG glucuronidation activity. The different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.35, UGT1A1.63, UGT1A3.5, UGT1A9.2, UGT1A10M59I, and UGT1A10T202I, showed reduced glucuronidation activity towards DTG in comparison with the wild-type UGT1As.This study elucidates the relationship between UGT1A variants and the levels of glucuronidation associated with each variant.Checking for UGT1As may be helpful in predicting potential toxicities and adverse effects related to DTG treatment.
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Affiliation(s)
- Kouji Tagawa
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
- Department of Pediatrics, Sapporo Tokushukai Hospital, Hokkaido, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
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Tagawa K, Maruo Y, Mimura Y, Ikushiro S. Effects of common genetic variants of human uridine diphosphate glucuronosyltransferase subfamilies on irinotecan glucuronidation. Toxicol Mech Methods 2023; 33:197-205. [PMID: 35930428 DOI: 10.1080/15376516.2022.2109229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
The adverse effects (diarrhea and neutropenia) of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) are associated with genetic variants of uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As). UGT1As are enzymes that metabolize the active form of irinotecan, 7-ethyl-10 hydroxycamptothecin (SN-38), by glucuronidation in the liver. They are widely known as predictive factors of severe adverse effects, such as neutropenia and diarrhea. Some studies have suggested that variants of UGT1As affect SN-38 glucuronidation activities, thus exerting severe adverse effects. We aimed to identify UGT1A isoforms that show SN-38 glucuronidation activity and determine the relationship between UGT1A variants and SN-38 glucuronidation in vitro. We found that UGT1A1 and UGT1A6-UGT1A10 displayed SN-38 glucuronidation activity. Among these, UGT1A1 was the most active. Furthermore, the variants of these isoforms showed decreased SN-38 glucuronidation activity. In our study, we compared the different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.27, UGT1A1.35, UGT1A7.3, UGT1A8.4, UGT1A10M59I, and UGT1A10T202I, to determine the differences in the reduction of glucuronidation. Our study elucidates the relationship between UGT1A variants and the level of glucuronidation associated with each variant. Therefore, testing can be done before the initiation of irinotecan treatment to predict potential toxicities and adverse effects.
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Affiliation(s)
- Kouji Tagawa
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yu Mimura
- Department of Pediatrics, Toyosato Hospital, Shiga, Japan
| | - Shinichi Ikushiro
- Department of Biotechnology, Toyama Prefectural University, Toyama, Japan
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Huang MJ, Chen PL, Huang CS. Bilirubin metabolism and UDP-glucuronosyltransferase 1A1 variants in Asians: Pathogenic implications and therapeutic response. Kaohsiung J Med Sci 2022; 38:729-738. [PMID: 35942604 DOI: 10.1002/kjm2.12579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/04/2022] [Accepted: 07/12/2022] [Indexed: 11/09/2022] Open
Abstract
In the Asian general population, at least six single-nucleotide variants (SNVs) in the UDP-glucuronosyltransferase (UGT) 1A1 gene have been identified: -3279T>G, -53A(TA)6 TAA>A(TA)7 TAA, 211G>A, 686C>A, 1091C>T, and 1456T>G. Each of these six SNVs was observed in at least four ethnic groups of the 12 Asian populations studied. In East Asian populations, the descending frequency of these six SNVs was as follows: -3279G>[-53A(TA)7 TAA, 211A]>(686A, 1091T)>1456G. Because of the presence of linkage disequilibrium and the expulsion phenomenon, when the SNVs -3279G, -53A(TA)7 TAA, 211A, and 686A were simultaneously involved, 15 instead of the estimated 81 genotypes were observed. Those carrying 686AA or 1456GG developed Gilbert's syndrome or Crigler-Najjar syndrome type 2. Both -53A(TA)7 TAA/A(TA)7 TAA and 211AA are the main causes of Gilbert's syndrome in East Asian populations. In East Asian populations, the 211AA genotype is the main cause of neonatal hyperbilirubinemia, whereas -53A(TA)7 TAA/A(TA)7 TAA exerts a protective effect on hyperbilirubinemia development in neonates fed with breast milk. Both 211A and -53A(TA)7 TAA are significantly associated with adverse drug reactions induced by irinotecan (one of the most widely used anticancer agents) in Asians. However, at least three common SNVs (-3279G, -53A(TA)7 TAA, and 211A) should be comprehensively analyzed. This study investigated the clinical significance of these six SNVs and demonstrated that examining UGT1A1 variants in Asian populations is considerably challenging.
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Affiliation(s)
- May-Jen Huang
- Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan
| | - Pei-Lain Chen
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Ching-Shan Huang
- Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan
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Tsai HL, Chen PJ, Chen YC, Li CC, Chang TK, Su WC, Yin TC, Huang CW, Wang JY. Irinotecan dose reduction in metastatic colorectal cancer patients with homozygous UGT1A1*28 polymorphism: a single-center case series. J Int Med Res 2022; 50:3000605221110697. [PMID: 35822291 PMCID: PMC9284221 DOI: 10.1177/03000605221110697] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy. METHODS We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m2. RESULTS Six of the seven patients tolerated 120 mg/m2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed. CONCLUSIONS mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.
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Affiliation(s)
- Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
| | - Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Yen-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
| | - Ching-Chun Li
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Tsung-Kun Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
| | - Tzu-Chieh Yin
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung.,Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung.,Center for Cancer Research, Kaohsiung Medical University, Kaohsiung.,Ministry of Health and Welfare Pingtung Hospital, Pingtung
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Cozzi L, Nuti F, Degrassi I, Civeriati D, Paolella G, Nebbia G. Gilbert or Crigler–Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity. Ital J Pediatr 2022; 48:59. [PMID: 35436954 PMCID: PMC9014633 DOI: 10.1186/s13052-022-01251-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 03/29/2022] [Indexed: 11/10/2022] Open
Abstract
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.
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Gu L, Han Y, Zhang D, Gong Q, Zhang X. Genetic testing of UGT1A1 in the diagnosis of Gilbert syndrome: The discovery of seven novel variants in the Chinese population. Mol Genet Genomic Med 2022; 10:e1958. [PMID: 35426266 PMCID: PMC9266601 DOI: 10.1002/mgg3.1958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Genetic testing of UGT1A1 was used to facilitate the diagnosis of Gilbert syndrome, and analyze the distribution features of pathogenic variants in the Chinese population. METHODS DNA was extracted from whole blood samples of patients with unconjugated hyperbilirubinemia, and sequencing of the UGT1A1 gene was performed after PCR amplification. After alignment with reference sequences, the known pathogenic variants were identified, the variant spectrum was analyzed, and the pathogenicity of novel variants was predicted using online mutation prediction tools. RESULTS A total of 117 patients were confirmed with Gilbert syndrome by UGT1A1 genetic diagnosis, where the most common pathogenic variants included promoter A(TA)7 TAA insertion and p.Gly71Arg missense variant. Following novel variants were also identified: p.Ala61Gly, p.Tyr67Phe, p.Leu166Alafs*16, p.Arg240Lys, p.Ser306Phe, p.Arg341Gln, and p.Glu424* variants. CONCLUSIONS Genetic testing of UGT1A1 in clinical practices could facilitate confirming Gilbert syndrome and performing differential diagnosis. The pathogenic variant spectrum in the Chinese population was similar to other Asian populations. The novel pathogenic variants identified in this study require further investigation.
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Affiliation(s)
- Leilei Gu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Han
- Research Laboratory of Clinical Virology, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Donghua Zhang
- Research Laboratory of Clinical Virology, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiming Gong
- Research Laboratory of Clinical Virology, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinxin Zhang
- Research Laboratory of Clinical Virology, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yang H, Lin F, Chen ZK, Zhang L, Xu JX, Wu YH, Gu JY, Ma YB, Li JD, Yang LY. UGT1A1 mutation association with increased bilirubin levels and severity of unconjugated hyperbilirubinemia in ABO incompatible newborns of China. BMC Pediatr 2021; 21:259. [PMID: 34074250 PMCID: PMC8167307 DOI: 10.1186/s12887-021-02726-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 05/20/2021] [Indexed: 11/10/2022] Open
Abstract
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.
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Affiliation(s)
- Hui Yang
- Department of Laboratory Medicine, School of Medicine, Yangtze University, Jingzhou, Hubei Province, 434023, People's Republic of China
| | - Fen Lin
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Zi-Kai Chen
- School of Food Engineering and Biotechnology, Hanshan Normal University, Chaozhou, Guangdong Province, People's Republic of China
| | - Lin Zhang
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Jia-Xin Xu
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Yong-Hao Wu
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Jing-Ying Gu
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Yu-Bin Ma
- Department of Pediatrics, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Jian-Dong Li
- Department of Pediatrics, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, People's Republic of China
| | - Li-Ye Yang
- Lab for Respiratory Disease, People's Hospital of Yangjiang, No. 42 Dongshan Road, Yangjiang, 529500, Guangdong Province, People's Republic of China.
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Lai NH, Shen WC, Lee CN, Chang JC, Hsu MC, Kuo LN, Yu MC, Chen HY. Comparison of the predictive outcomes for anti-tuberculosis drug-induced hepatotoxicity by different machine learning techniques. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2020; 188:105307. [PMID: 31911332 DOI: 10.1016/j.cmpb.2019.105307] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 12/02/2019] [Accepted: 12/27/2019] [Indexed: 05/03/2023]
Abstract
BACKGROUND The study compared the predictive outcomes of artificial neural network, support vector machine and random forest on the occurrence of anti-tuberculosis drug-induced hepatotoxicity. METHODS The clinical and genomic data of patients treated with anti-tuberculosis drugs at Taipei Medical University-Wanfang Hospital were used as training sets, and those at Taipei Medical University-Shuang Ho Hospital served as test sets. Features were selected through a univariate risk factor analysis and literature evaluation. The accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve were calculated to compare the traditional, genomic, and combined models of the three techniques. RESULTS Nine models were created with 7 clinical factors and 4 genotypes. Artificial neural network with clinical and genomic factors exhibited the best performance, with an accuracy of 88.67%, a sensitivity of 80%, and a specificity of 90.4% for the test set. The area under the receiver operating characteristic curve of this best model reached 0.894 for training set and 0.898 for test set, which was significantly better than 0.801 for training set and 0.728 for test set by support vector machine and 0.724 for training set and 0.718 for test set by random forest. CONCLUSIONS Artificial neural network with clinical and genomic data can become a clinical useful tool in predicting anti-tuberculosis drug-induced hepatotoxicity. The machine learning technique can be an innovation to predict and prevent adverse drug reaction.
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Affiliation(s)
- Nai-Hua Lai
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Wan-Chen Shen
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chun-Nin Lee
- Department of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pulmonary Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Jui-Chia Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Man-Ching Hsu
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Li-Na Kuo
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ming-Chih Yu
- Department of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pulmonary Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Hsiang-Yin Chen
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave’s disease: a metabolomic approach. Arch Toxicol 2019; 94:231-244. [DOI: 10.1007/s00204-019-02618-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/06/2019] [Indexed: 12/11/2022]
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Huang MJ, Chen YC, Huang YY, Yang SS, Chen PL, Huang CS. Effect of UDP-glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome. Kaohsiung J Med Sci 2019; 35:432-439. [PMID: 31017737 DOI: 10.1002/kjm2.12077] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 04/08/2019] [Indexed: 12/19/2022] Open
Abstract
Variations at the six nucleotides -3279 (T > G), -53 (A[TA]6 TAA > A[TA]7 TAA), 211 (G > A), 686 (C > A), 1091 (C > T), and 1456 (T > G) in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene were determined in 178 Taiwanese patients with Gilbert's syndrome and in 200 healthy adults. Every subject was classified as a genotype depending on variation status of the six nucleotides in the UGT1A1 gene. The UGT1A1 activity for each genotype was calculated and then those genotypes were divided into 10 subgroups (Q1~Q10) according to their UGT1A1 activities, by using 10% as an interval. There were 24 genotypes observed, with UGT1A1 activity ranged 9%~100% of normal. There were two and six subjects with Gilbert's syndrome and none of healthy controls carrying genotypes in the Q1 and Q2 subgroups, respectively. The odds of developing Gilbert's syndrome were significantly higher for subjects carrying genotypes in the Q3, Q4, and Q5 subgroups than for those with genotype in the Q10 subgroup (odds ratios: 240.22, 59.80, and 14.67, respectively, P < .001 for each). Among the 178 patients of Gilbert's syndrome, serum bilirubin value was inversely correlated with UGT1A1 activity (r = -.306, P < .001). The sensitivity was 72.0% and the specificity was 90.5% by using UGT1A1 activity ≦40% of normal as the cut-off point to distinguish between healthy subjects and patients of Gilbert's syndrome. Our results demonstrate that UGT1A1 activity is certainly a determinate for serum bilirubin value and UGT1A1 activity ≦40% of normal is a proper risk factor for the development of Gilbert's syndrome.
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Affiliation(s)
- May-Jen Huang
- Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan
| | - Yi-Chun Chen
- Department of Internal Medicine, Changhua Christian Medical Foundation Changhua Christian Hospital, Changhua, Taiwan
| | - Yang-Yang Huang
- Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan
| | | | - Pei-Lain Chen
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Ching-Shan Huang
- Department of Clinical Pathology, Cathay General Hospital, Taipei, Taiwan
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Abuduxikuer K, Fang LJ, Li LT, Gong JY, Wang JS. UGT1A1 genotypes and unconjugated hyperbilirubinemia phenotypes in post-neonatal Chinese children: A retrospective analysis and quantitative correlation. Medicine (Baltimore) 2018; 97:e13576. [PMID: 30544479 PMCID: PMC6310575 DOI: 10.1097/md.0000000000013576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
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.
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Affiliation(s)
| | - Ling-Juan Fang
- Department of Hepatology, Children's Hospital of Fudan University
| | - Li-Ting Li
- Department of Hepatology, Children's Hospital of Fudan University
| | - Jing-Yu Gong
- Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jian-She Wang
- Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
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Risk assessment of prolonged jaundice in infants at one month of age: A prospective cohort study. Sci Rep 2018; 8:14824. [PMID: 30287871 PMCID: PMC6172203 DOI: 10.1038/s41598-018-33249-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 09/25/2018] [Indexed: 12/05/2022] Open
Abstract
Prolonged jaundice is a commonly evaluated condition. The aim of this study was to assess the risk factors of jaundice in healthy infants at one month of age. This prospective cohort study enrolled 509 healthy infants from 2013 to 2018. Those with gestational age (GA) less than 35 weeks, birth weight less than 2000 grams, and illness were not enrolled. Jaundice was defined as a transcutaneous bilirubin value ≥5 mg/dL at 25–45 days of age. Umbilical cord blood samples were obtained to examine seven common gene variants. The incidence of prolonged jaundice was 32.2%. Prolonged jaundice was more common in infants with exclusive breastfeeding (p < 0.001), GA 35~37 w (p = 0.001), stool passage >4 times/d (p < 0.001), previous phototherapy (p < 0.001), and gene variant of G to A at nt 211 of UGT1A1 (p = 0.004). A multivariate logistic regression analysis demonstrated the greatest risk for prolonged jaundice was exclusive breastfeeding (OR = 2.818, 95% CI = 1.851–4.292), followed by previous phototherapy (OR = 2.593, 95% CI = 1.716–3.919), GA 35~37 w (OR = 2.468, 95% CI = 1.350–4.512), and G to A at nt 211 of UGT1A1 (OR = 1.645, 95% CI = 1.070–2.528). In conclusion, infants with exclusive breastfeeding, GA 35~37 w, previous phototherapy, or G to A at nt 211 of UGT1A1 are at greater risk of prolonged jaundice. Healthcare professionals should consider these risk factors in their assessment of prolonged jaundice.
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Hawkins DS, Chi YY, Anderson JR, Tian J, Arndt CAS, Bomgaars L, Donaldson SS, Hayes-Jordan A, Mascarenhas L, McCarville MB, McCune JS, McCowage G, Million L, Morris CD, Parham DM, Rodeberg DA, Rudzinski ER, Shnorhavorian M, Spunt SL, Skapek SX, Teot LA, Wolden S, Yock TI, Meyer WH. Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol 2018; 36:2770-2777. [PMID: 30091945 DOI: 10.1200/jco.2018.77.9694] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m2) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m2) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.
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Affiliation(s)
- Douglas S Hawkins
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Yueh-Yun Chi
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - James R Anderson
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Jing Tian
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Carola A S Arndt
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lisa Bomgaars
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Sarah S Donaldson
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Andrea Hayes-Jordan
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Leo Mascarenhas
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Mary Beth McCarville
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Jeannine S McCune
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Geoff McCowage
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lynn Million
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Carol D Morris
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - David M Parham
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - David A Rodeberg
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Erin R Rudzinski
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Margarett Shnorhavorian
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Sheri L Spunt
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Stephen X Skapek
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lisa A Teot
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Suzanne Wolden
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Torunn I Yock
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - William H Meyer
- Douglas S. Hawkins, Erin R. Rudzinski, and Margarett Shnorhavorian, Seattle Children's Hospital, Seattle, WA; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Carola A.S. Arndt, Mayo Clinic, Rochester, MN; Lisa Bomgaars, Texas Children's Hospital; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston; Stephen X. Skapek, University of Texas Southwestern, Dallas, TX; Sarah S. Donaldson, Lynn Million, and Sheri L. Spunt, Stanford University School of Medicine, Stanford; Leo Mascarenhas and David M. Parham, Children's Hospital of Los Angeles, Los Angeles; Jeannine S. McCune, City of Hope, Duarte, CA; Mary Beth McCarville, St Jude Children's Research Hospital, Memphis, TN; Geoff McCowage, Children's Hospital at Westmead, Westmead, New South Wales, Australia; Carol D. Morris, Johns Hopkins University, Baltimore, MD, David A. Rodeberg, East Carolina University, Greenville, NC; Lisa A. Teot, Boston Children's Hospital; Torunn I. Yock, Massachusetts General Hospital, Boston, MA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York, NY; and William H. Meyer, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Heydari MR, Fardaei M, Kadivar MR, Rezaianzadeh A, Panjehshahin MR, Gholami Bardeji Z, Miri MR, Saberzadeh J. Prevalence of 2 UGT1A1 Gene Variations Related to Gilbert’s Syndrome in South of Iran: An Epidemiological, Clinical, and Genetic Study. IRANIAN RED CRESCENT MEDICAL JOURNAL 2017; 19. [DOI: 10.5812/ircmj.44363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Yang H, Wang Q, Zheng L, Zheng XB, Lin M, Zhan XF, Yang LY. Clinical Significance of UGT1A1 Genetic Analysis in Chinese Neonates with Severe Hyperbilirubinemia. Pediatr Neonatol 2016; 57:310-7. [PMID: 26727668 DOI: 10.1016/j.pedneo.2015.08.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 08/12/2015] [Accepted: 08/14/2015] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Neonatal hyperbilirubinemia is common in Asia, and the importance of genetically determined conditions has been recently recognized. The aim of this study was to assess the clinical utility of genetic testing in Chinese neonates with severe hyperbilirubinemia. METHODS Fifty-eight term infants with bilirubin level ≥ 20 mg/dL (342 μmol/L), and 65 controls were enrolled in the study. Variation status of UGT1A1, G6PD, and thalassemia genes in our study cohort was determined by direct sequencing or genotype assays. RESULTS Among these case infants, seven were confirmed with G6PD deficiency, four were heterozygous for α- or β-thalassemia, and forty-four were detected with at least one heterozygous UGT1A1 functional variant, including nine homozygous for UGT1A1 variation. As well as the predominant c.211G>A (Gly71Arg) variant, three UGT1A1 coding variants [c.1091C>T (Pro364Leu), c.1352C>T (pro451leu), and c.1456C>T (Tyr486Asp)] were observed in our case neonates. The results of multivariate logistic regressions, adjusted for covariates, revealed odds ratios for neonates who carried heterozygous, homozygous variation at nucleotide 211 of UGT1A1, and G6PD deficiency of 3.47 (1.26-9.55), 12.46 (1.09-142.7) ,and 12.87 (1.32-135.87) compared with those having the wild genotype and normal G6PD activity, respectively. CONCLUSION Besides G6PD-deficiency screening, UGT1A1 genetic analysis, and especially the UGT1A1*6(c.211G>A, p.Arg71Gly) polymorphism detection, may be taken into consideration for early diagnosis and treatment of severe hyperbilirubinemic newborns in southern China.
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Affiliation(s)
- Hui Yang
- Laboratory Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China; Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, PR China
| | - Qian Wang
- Laboratory Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China.
| | - Lei Zheng
- Laboratory Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, PR China
| | - Xiang-Bin Zheng
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, PR China
| | - Min Lin
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, PR China
| | - Xiao-Fen Zhan
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, PR China
| | - Li-Ye Yang
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, Guangdong Province, PR China.
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16
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Chen SC, Chang PMH, Yang MH. Cisplatin/Tegafur/Uracil/Irinotecan Triple Combination Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: A Phase I/II Clinical Study. Oncologist 2016; 21:537-8. [PMID: 27091418 PMCID: PMC4861372 DOI: 10.1634/theoncologist.2015-0515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 03/10/2016] [Indexed: 11/17/2022] Open
Abstract
LESSONS LEARNED Cisplatin/tegafur/uracil/irinotecan triple combination therapy shows moderate response, especially in patients without previous chemoradiotherapy within the 6 months before this combination therapy.Toxicity is tolerable, and quality of life is improved in responders. BACKGROUND The prognosis is poor in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Triple combination therapy may increase tumor response. METHODS This phase I/II prospective trial first determined the dose-limiting toxicity and recommended dose of irinotecan with cisplatin and tegafur/uracil (UFUR) in phase I. Irinotecan was supplied at doses of 40, 50, 60, and 70 mg/m(2) by using a standard 3+3 design. Doses of cisplatin and UFUR were held stable. In phase II, the recommended dose of irinotecan was administered intravenously (i.v.) over 90 min on day 1, with cisplatin 50 mg/m(2) i.v. over 60 min also on day 1, and oral UFUR 200 mg twice a day for 5 days every 2 weeks a cycle. RESULTS In the phase I portion, 14 patients were enrolled, and the dose level of irinotecan at 60 mg/m(2) was defined as the recommended dose for the phase II portion of the study. Among 43 patients enrolled in the phase II portion, complete response was seen in 2 patients (4.7%) and partial response in 10 patients (23.3%), and the disease control rate was 39.5%. In a subgroup analysis of patients whose prior chemoradiotherapy was more than 6 months earlier, a response rate of 40.7% and disease control rate of 59.3% were observed. CONCLUSION Cisplatin/UFUR/irinotecan triple combination therapy is tolerated and effective for selected patients. Individualized choice of treatment will influence prognosis and quality of life in R/M HNSCC patients.
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Affiliation(s)
- San-Chi Chen
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Faculty of Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China
| | - Peter Mu-Hsin Chang
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Faculty of Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China
| | - Muh-Hwa Yang
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Faculty of Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, Republic of China
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17
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Mu SC, Chen YL, Tsai LY, Shih YL, Chen ES, Huang CS. Prolonged Hyperbilirubinemia in a Neonate with a Novel Mutation in the UDP-glucuronosyltransferase 1A1 Gene. Neonatology 2016; 109:235-8. [PMID: 26859599 DOI: 10.1159/000443365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 12/14/2015] [Indexed: 11/19/2022]
Abstract
The total bilirubin value of a male infant was 385 μmol/l on day 5. Liver function test results were normal and there was no evidence of sepsis and no hemolysis reaction. Phototherapy was administered and on day 8 the patient's total bilirubin level was 255 μmol/l. Intermittent episodes of hyperbilirubinemia occurred without phototherapy, with the total bilirubin level reaching 335 μmol/l on day 19. A 3-day regimen of phenobarbital was administered and on day 24 his total bilirubin level was 180 μmol/l. The patient was discharged. At the age of 2 months, the total bilirubin value was 27 μmol/l. His direct bilirubin value was <15% of total bilirubin in every determination. A family study of the UDP-glucuronosyltransferase(UGT)1A1 gene showed that the infant carries a homozygous mutation at nucleotide -3279 plus compound heterozygous mutations at nucleotides 782 and 1091. The mutation at nucleotide 782 is a novel finding. Gilbert's syndrome was diagnosed.
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Affiliation(s)
- Shu-Chi Mu
- Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital and School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan, ROC
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Rodrigues C, Santos-Silva A, Costa E, Bronze-da-Rocha E. Performance of In Silico Tools for the Evaluation of UGT1A1 Missense Variants. Hum Mutat 2015; 36:1215-25. [PMID: 26377032 DOI: 10.1002/humu.22903] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 08/31/2015] [Indexed: 01/17/2023]
Abstract
Variations in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) are particularly important because they have been associated with hyperbilirubinemia in Gilbert's and Crigler-Najjar syndromes as well as with changes in drug metabolism. Several variants associated with these phenotypes are nonsynonymous single-nucleotide polymorphisms (nsSNPs). Bioinformatics approaches have gained increasing importance in predicting the functional significance of these variants. This study was focused on the predictive ability of bioinformatics approaches to determine the pathogenicity of human UGT1A1 nsSNPs, which were previously characterized at the protein level by in vivo and in vitro studies. Using 16 Web algorithms, we evaluated 48 nsSNPs described in the literature and databases. Eight of these algorithms reached or exceeded 90% sensitivity and six presented a Matthews correlation coefficient above 0.46. The best-performing method was MutPred, followed by Sorting Intolerant from Tolerant (SIFT). The prediction measures varied significantly when predictors such us SIFT, polyphen-2, and Prediction of Pathological Mutations on Proteins were run with their native alignment generated by the tool, or with an input alignment that was strictly built with UGT1A1 orthologs and manually curated. Our results showed that the prediction performance of some methods based on sequence conservation analysis can be negatively affected when nsSNPs are positioned at the hypervariable or constant regions of UGT1A1 ortholog sequences.
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Affiliation(s)
- Carina Rodrigues
- UCIBIO/REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Escola Superior de Saúde, Instituto Politécnico de Bragança, Bragança, Portugal
| | - Alice Santos-Silva
- UCIBIO/REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Elísio Costa
- UCIBIO/REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Elsa Bronze-da-Rocha
- UCIBIO/REQUIMTE, Laboratório de Bioquímica, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
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Shiu TY, Huang HH, Lin HH, Shih YL, Chu HC, Chang WK, Hsieh TY. Restriction fragment length polymorphism effectively identifies exon 1 mutation of UGT1A1 gene in patients with Gilbert's Syndrome. Liver Int 2015; 35:2050-6. [PMID: 25611851 DOI: 10.1111/liv.12785] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 01/14/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Gilbert's syndrome causes pharmacological variation in drug glucuronidation and unexpected toxicity from therapeutic agents. The two common genotypes of Gilbert's syndrome are a dinucleotide polymorphism (TA)7 in TATA-Box as well as the 211G>A mutation in the coding exon 1, particularly in Asians, of human UGT1A1 gene. In this study, we aimed to establish an effective method to detect the 211G>A mutation. METHODS The coding exon 1 sequence of human UGT1A1 gene was analysed by Vector NTI software. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by restriction fragment length polymorphism (RFLP) method. Serum total bilirubin level was measured as well. RESULTS A newly identified BsmBI site was located in the coding exon 1 of UGT1A1 gene. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by DNA RFLP. Furthermore, we reported our present work on genetic analysis of mutations of UGT1A1 gene, and the correlation of UGT1A1 mutations with serum total bilirubin levels in Taiwanese population. The results showed that 15 subjects carried 211G>A mutation in 23 subjects related with Gilbert's syndrome. The homozygous 211G>A mutant as well as simultaneously heterozygous mutants both in TATA-Box and 211G>A significantly increased the risk of Gilbert's syndrome similar to subjects carrying homozygous TATA-Box mutant. CONCLUSIONS BsmBI RFLP is an effective method to detect 211G>A mutation in the coding exon 1 of UGT1A1 gene. The common 211G>A mutation is one of the causes of Gilbert's syndrome in Taiwanese population.
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Affiliation(s)
- Tzu-Yue Shiu
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsin-Hung Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsuan-Hwai Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Heng-Cheng Chu
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Kuo Chang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Hu RT, Wang NY, Huang MJ, Huang CS, Chen DS, Yang SS. Multiple variants in UGT1A1 gene are factors to develop indirect hyper-bilirubinemia. Hepatobiliary Surg Nutr 2014; 3:194-8. [PMID: 25202696 DOI: 10.3978/j.issn.2304-3881.2014.08.04] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 08/08/2014] [Indexed: 01/17/2023]
Abstract
Most Taiwanese patients with hyper-bilirubinemia have genetic abnormalities in the uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene beyond the variants in the TATA box upstream of UGT1A1 associated with Gilbert's syndrome. To investigate the role of UGT1A1 in the pathogenesis of indirect hyper-bilirubinemia, we prospectively studied 97 consecutive patients with indirect hyper-bilirubinemia for genotypes of promoter [(TA)6TAA6, (TA)7TAA7] and coding region [nucleotide (nt)-211, nt-686, nt-1,091 and nt-1,456] of UGT1A1. Thirty-six of the patients (45.6%) were found to have Gilbert's syndrome with 7/7 genotype; among them, 14 also carried variants at nt-686. Forty-two patients (43.3%) had the 6/7 genotype; among them, 36 patients were found to have one or more variants in the coding region. Patients with higher serum total bilirubin are associated with higher likelihood of carrying Gilbert's syndrome genotype: 60.0% (P=0.007) patients with serum total bilirubin level ≥2.5 mg/dL carried the Gilbert's syndrome genotype, while only 23.9% of patients with serum total bilirubin level <2.5 mg/dL carry the same genotype (P=0.0006). Forty-one of the 61 non-Gilbert's patients had one homogenous variants or two or more heterozygous variants in UGT1A1. Further studies are necessary to confirm the role of one homo-zygous variant or two or more hetero-zygous variants in UGT1A1 gene as factors for indirect hyper-bilirubinemia.
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Affiliation(s)
- Rei-Ting Hu
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
| | - Nai-Yuan Wang
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
| | - May-Jen Huang
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
| | - Ching-Shan Huang
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
| | - Ding-Shinn Chen
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
| | - Sien-Sing Yang
- 1 Liver Unit, 2 Department of Surgery, 3 Department of Laboratory Medicine, Cathay General Hospital, Taipei, Taiwan ; 4 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan ; 5 Medical Faculty, Fujen Catholic University, Taipei, Taiwan
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Ishii Y, Koba H, Kinoshita K, Oizaki T, Iwamoto Y, Takeda S, Miyauchi Y, Nishimura Y, Egoshi N, Taura F, Morimoto S, Ikushiro S, Nagata K, Yamazoe Y, Mackenzie PI, Yamada H. Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants. Drug Metab Dispos 2014; 42:229-38. [PMID: 24255116 DOI: 10.1124/dmd.113.054833] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.
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Affiliation(s)
- Yuji Ishii
- Laboratory of Molecular Life Sciences (Y.Is., H.K., K.K., T.O., Y.Iw., S.T., Y.M., Y.N., N.E., H.Y.) and Laboratory of Medicinal Resource Regulation (F.T., S.M.), Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, Japan (S.I.); Tohoku Pharmaceutical University, Sendai, Japan (K.N.); Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (Y.Y.); and Department of Clinical Pharmacology, Flinders Medical Centre and Flinders University, Adelaide, Australia (P.I.M.)
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22
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Kim DY, Paek TY, Oh SY, Kim YB, Lee JH, Lee MY, Choi ZS, Suh KW. Pretreatment selection of regimen according to genetic analysis improves the efficacy of chemotherapy in the first line treatment of metastatic colorectal cancer. J Surg Oncol 2013; 109:250-4. [PMID: 24318863 DOI: 10.1002/jso.23500] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 10/17/2013] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES Metastatic colon cancer patients are treated with the chemotherapy regimens, FOLFOX and FOLFIRI, in either order. So far, we cannot predict the response of chemotherapeutic agent, so it is necessary to find which regimen is adequate before starting chemotherapy. METHODS Enrolled patients are randomized into either conventional treatment or planned treatment preceded by pretreatment genetic analysis. Blood samples of patients in planned treatment group (N = 53) were analyzed for the genetic polymorphism before selection of chemotherapeutic agents. Target genes were XPD-751, GSTP-1-105, XRCC1-399 for oxaliplatin, UGT1A1 for irinotecan. The response was measured by computed tomographic scan after completion of three cycles of chemotherapy. RESULTS Overall response rate was significantly higher in planned group (67.9% vs. 46.3%, P = 0.020). In FOLFOX group, response rate was significantly improved in the planned patients(77.1% vs. 50%, P = 0.018). In FOLFIRI group, the difference didn't reach statistical significance (50% vs. 42.5%, P = 0.776). CONCLUSIONS We found significantly improved response rates in the chemotherapy of metastatic colon cancer by pretreatment genetic analysis, especially in FOLFOX group.
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Affiliation(s)
- Do Yoon Kim
- Department of Surgery, Ajou University School of Medicine, Suwon, Korea
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Alkharfy KM, Alghamdi AM, Bagulb KM, Al-Jenoobi FI, Al-Mohizea AM, Al-Muhsen S, Halwani R, Parvez MK, Al-Dosari MS. Distribution of selected gene polymorphisms of UGT1A1 in a Saudi population. Arch Med Sci 2013; 9:731-8. [PMID: 24049537 PMCID: PMC3776187 DOI: 10.5114/aoms.2013.37012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 04/26/2012] [Accepted: 07/16/2012] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Glucuronidation is an important phase II pathway responsible for the metabolism of many endogenous substances and drugs to less toxic metabolites, which undergo renal excretion. The aim of the current work was to evaluate genotype and allele frequencies of certain UDP-glucuronosyltransferase 1A1 (UGT1A1) variants in an Arab population. MATERIAL AND METHODS Genomic DNA was isolated from 192 healthy unrelated Saudi males of various geographic regions and genotyping of UGT1A1*6, *27, *36, *28, *37, and *60 was carried out using polymerase chain reaction (PCR) amplification followed by direct sequencing. RESULTS The most common allele for (TA) repeats was the wild type (TA)6 with a frequency of 74.3% followed by the mutant (TA)7 (i.e., UGT1A1*28) with a frequency of 25.7%. The distribution of UGT1A1*60 allele was 62.4% among subjects with the homozygous mutant genotype of 35.4%, while the wild type variant represents 10.6% only. Both UGT1A1*6 and *27 were not detected as all screened subjects showed a homozygous wild type pattern. Similarly, UGT1A1*36* and *37 were either not present or rarely found, respectively. In comparison to other populations, the frequency of UGT1A1*60 and *28 in the studied population was less than that of African Americans but higher than Asians. The geographical origin of the study subjects also implied some differences in genotype distribution of (TA) repeats and UGT1A1*60. CONCLUSIONS Our data indicate that Saudis harbor some important UGT1A1 mutations known to affect enzyme activity. Additional studies are warranted to assess the clinical implications of these gene polymorphisms in this ethnic group.
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Affiliation(s)
- Khalid M. Alkharfy
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Biomarkers Research Program, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Amal M. Alghamdi
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Khawla M. Bagulb
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Fahad I. Al-Jenoobi
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah M. Al-Mohizea
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saleh Al-Muhsen
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Rabih Halwani
- Department of Pediatrics, Asthma Research Chair and Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad K. Parvez
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed S. Al-Dosari
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Skierka JM, Kotzer KE, Lagerstedt SA, O'Kane DJ, Baudhuin LM. UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia. J Pediatr 2013; 162:1146-52, 1152.e1-2. [PMID: 23290513 DOI: 10.1016/j.jpeds.2012.11.042] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 10/01/2012] [Accepted: 11/14/2012] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To assess the clinical utility of UGT1A1 genetic testing and describe the spectrum and prevalence of UGT1A1 variations identified in pediatric unconjugated hyperbilirubinemia (UCH), and to characterize specific genotype-phenotype relationships in suspected Gilbert and Crigler-Najjar syndromes. STUDY DESIGN A retrospective study was conducted to review clinical information and UGT1A1 genotyping data from 181 pediatric patients referred for UCH. In silico analyses were performed to aid in the assessment of novel UGT1A1 variants. RESULTS Overall, 146/181 pediatric patients had at least one heterozygous UGT1A1 functional variant. Identified UGT1A1 variants included 17 novel variants, 7 rare star alleles, and 1 rare variant. There were 129 individuals who possessed the TA7 (*28) promoter repeat and 15 individuals who possessed the *6 (c.211G > A) variation. Out of the 104 individuals with accompanying bilirubin levels, 41 individuals did not have identifiable UGT1A1 variants that explained their UCH, although glucose-6-phosphate dehydrogenase deficiency and other causes of UCH could not be ruled out. CONCLUSION Much of the observed UCH could be attributed to variation at the UGT1A1 locus, and UGT1A1 testing helped to substantiate a genetic diagnosis, thereby aiding in individual and family disease management. Although UGT1A1 variation plays a large role in UCH, genetic assessment of UGT1A1 alone may not be comprehensive. Assessment of additional genes may also be useful to evaluate genetic causes for UCH.
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Affiliation(s)
- Jennifer M Skierka
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
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25
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Moriya H, Saito K, Helsby N, Sugino S, Yamakage M, Takasaki M, Kato H, Kurosawa N. The Association Between Heterozygosity forUGT1A1*6,UGT1A1*28, and Variation in the Serum Total-Bilirubin Level in Healthy Young Japanese Adults. Genet Test Mol Biomarkers 2013; 17:464-9. [DOI: 10.1089/gtmb.2012.0402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Hiroyuki Moriya
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
| | - Katsuhiko Saito
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
- Department of Anesthesiology, School of Medicine, Sapporo Medical University, Sapporo, Japan
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Nuala Helsby
- Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Shigekazu Sugino
- Department of Anesthesiology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Michiaki Yamakage
- Department of Anesthesiology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Masahiko Takasaki
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Hidenori Kato
- Department of Gynecology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Nahoko Kurosawa
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
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Chaouch L, Talbi E, Moumni I, Ben Chaabene A, Kalai M, Chaouachi D, Mallouli F, Ghanem A, Abbes S. Early complication in Sickle Cell Anemia children due to A(TA)<formula>_n</formula> TAA polymorphism at the promoter of UGT1A1 gene. DISEASE MARKERS 2013; 35:M781724278TK288P. [PMID: 23619273 PMCID: PMC3774959 DOI: 10.1155/2013/173474] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 04/13/2013] [Indexed: 11/18/2022]
Abstract
AIM: To determine the implication of the polymorphism namely A(TA)nTAA of UGT1A1 in lithogenesis for the first time in Tunisia among sickle cell anemia (SCA) children patients. MATERIAL AND METHODS: Our study was performed in 2010 and it involved 76 subjects chosen as control group characterized with normal hemoglobin status and presence of cholelithiasis and 102 SCA pediatric patients among whom 52 have cholelithiasis. We analyzed the polymorphism A(TA)_{n} TAA at the UGT1A1 promoter and the relationships between the various A(TA)_{n} TAA genotypes and alleles and bilirubin levels and occurrence of cholelithiasis. RESULTS AND DISCUSSION: The repartition of genotypes found according to serum bilirubin level shows a significant association between genotypes carried variant (TA)_{7} and hyperbilirubinemia (p< 0.05). We demonstrated the association of two genotypes with gallstones formation among SCA children patients: (TA)_{7}/(TA)_{7} and (TA)_{7}/(TA)_{8} with p=8.1 × 10^{ - 8} and p=0.01 respectively. (TA)_{7} and (TA)_{8} allele variants act as a risk factor for early gallstones formation in SCA patients with p=5.8 × 10^{ -9} and p=0.01 respectively. As for the control group only the genotype (TA)_{7}/(TA)_{7} presented a risk factor for gallstones formation. CONCLUSION: The novelty of this report is that it is the first time that a similar study was made on the Tunisian children sickle cell population and that the results show a clear association of (TA)_{7} variant in early gallstones formation in Tunisian SCA children. Interestingly our findings highlighted the association of (TA)_{8} variant as well, which was not found in previous studies.
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Affiliation(s)
- Leila Chaouch
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
| | - Emna Talbi
- Université de Tunis El Manar, Tunis, Tunisia
| | - Imen Moumni
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
| | - Arij Ben Chaabene
- Département de Biologie Clinique, Institut Salah Azaiez de Cancer, Université de Tunis El Manar, Tunis, Tunisia
| | - Miniar Kalai
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
| | - Dorra Chaouachi
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
| | - Fethi Mallouli
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
| | - Abderraouf Ghanem
- Département de Biochimie, Hôpital de Traumatologie et des Grands Brulés, Université de Tunis El Manar, Ben Arous, Tunisia
| | - Salem Abbes
- Laboratoire d'Hématologie Moléculaire et Cellulaire, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia
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Soo RA, Yong WP, Innocenti F. Systemic therapies for pancreatic cancer--the role of pharmacogenetics. Curr Drug Targets 2012; 13:811-28. [PMID: 22458528 DOI: 10.2174/138945012800564068] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Revised: 02/23/2012] [Accepted: 03/27/2012] [Indexed: 12/17/2022]
Abstract
Effective systemic treatment of pancreatic cancer remains a major challenge, with progress hampered by drug resistance and treatment related toxicities. Currently available cytotoxic agents as monotherapy or in combination have provided only a modest survival benefit for patients with advanced disease. Disappointing phase III results with gemcitabine-based combinations in patients with advanced pancreatic cancer might be related to poor efficacy of systemic therapies in unselected patients. Future research strategies should prioritize identification of predictive markers through pharmacogenetic investigations. The individualization of patient treatment through pharmacogenetics may help to improve outcome by maximizing efficacy whilst lowering toxicity. This review provides an update on the pharmacogenetics of pancreatic cancer treatment and its influence on treatment benefits and toxicity.
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Affiliation(s)
- Ross A Soo
- Department of Hematology-Oncology, National University Health System, Singapore
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28
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Soo RA, Yong WP, Innocenti F. Systemic therapies for pancreatic cancer--the role of pharmacogenetics. Curr Drug Targets 2012. [PMID: 22458528 DOI: 10.1016/j.pestbp.2011.02.012.investigations] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Effective systemic treatment of pancreatic cancer remains a major challenge, with progress hampered by drug resistance and treatment related toxicities. Currently available cytotoxic agents as monotherapy or in combination have provided only a modest survival benefit for patients with advanced disease. Disappointing phase III results with gemcitabine-based combinations in patients with advanced pancreatic cancer might be related to poor efficacy of systemic therapies in unselected patients. Future research strategies should prioritize identification of predictive markers through pharmacogenetic investigations. The individualization of patient treatment through pharmacogenetics may help to improve outcome by maximizing efficacy whilst lowering toxicity. This review provides an update on the pharmacogenetics of pancreatic cancer treatment and its influence on treatment benefits and toxicity.
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Affiliation(s)
- Ross A Soo
- Department of Hematology-Oncology, National University Health System, Singapore
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29
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Bosch TM, Doodeman VD, Smits PHM, Meijerman I, Schellens JHM, Beijnen JH. Pharmacogenetic Screening for Polymorphisms in Drug-Metabolizing Enzymes and Drug Transporters in a Dutch Population. Mol Diagn Ther 2012; 10:175-85. [PMID: 16771603 DOI: 10.1007/bf03256456] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. METHODS Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. RESULTS In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. CONCLUSION In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.
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Affiliation(s)
- T M Bosch
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands
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30
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Kobayashi M, Hazama S, Takahashi K, Oba K, Okayama N, Nishioka M, Hinoda Y, Oka M, Okamoto K, Maeda H, Nakamura D, Sakamoto J, Mishima H. Is there diversity among UGT1A1 polymorphism in Japan. World J Gastrointest Oncol 2012; 4:170-5. [PMID: 22848786 PMCID: PMC3406281 DOI: 10.4251/wjgo.v4.i7.170] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 05/22/2012] [Accepted: 05/27/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate into the diversity of UGT1A1 polymorphism across three different districts in Japan and highlight genetic differences among the population in Japan.
METHODS: We enrolled 50 healthy volunteers from each of the Yamaguchi (western part of Japan), Kochi (southern part of Japan) and Akita (northern part of Japan) prefectures. Blood samples (7 mL) were collected from each participant and stored in EDTA for subsequent genotyping by fragment size analysis, direct sequencing and TaqMan assay of UGT1A1*28, UGT1A7*3/UGT1A9*22 and UGT1A1*93/UGT1A1*6/UGT1A1*27/UGT1A1*60/UGT1A7 (-57), respectively.
RESULTS: The only statistically significant differences in allele polymorphisms among the group examined were for UGT1A1*6. The Akita population showed more UGT1A1*6 heterozygosity (P = 0.0496).
CONCLUSION: Our study revealed no regional diversity among UGT1A1, UGT1A7 or UGT1A9 polymorphisms in Japan.
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Affiliation(s)
- Michiya Kobayashi
- Michiya Kobayashi, Ken Okamoto, Hiromichi Maeda, Department of Human Health and Medical Sciences, Kochi Medical School, Nankoku 783-8505, Japan
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31
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Zhang X, Ao G, Wang Y, Yan W, Wang M, Chen E, Yang F, Yang J. Genetic variants and haplotypes of the UGT1A9, 1A7 and 1A1 genes in Chinese Han. Genet Mol Biol 2012; 35:428-34. [PMID: 22888291 PMCID: PMC3389530 DOI: 10.1590/s1415-47572012005000036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 03/26/2012] [Indexed: 11/22/2022] Open
Abstract
In this report, we describe combined polymorphisms of the UGT1A9, UGT1A7 and UGT1A1 genes in 100 unrelated, healthy Chinese Han subjects. The functional regions of these genes were sequenced and comprehensively analyzed for genetic polymorphisms. Thirty variants were detected, including five novel forms. Tentative functional predictions indicated that a Cys → Arg substitution at position 277 in the UGT1A7 gene could alter the protein conformation and that 12460T > G in the 3′UTR might influence protein translation through specifically expressed miRNAs. UGT1A9*1b was a major functional variant in the subjects examined whereas the *1f allele had a frequency of only 0.5%. A special functional haplotype (GAGAAC) was identified for UGT1A9, 1A7 and 1A1. These findings provide fundamental genetic information that may serve as a basis for larger studies designed to assess the metabolic phenotypes associated with UGT1A polymorphisms. They also provide important data for the implementation of personalized medicine in Chinese Han.
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Affiliation(s)
- Xiaoqing Zhang
- National Engineering Research Center for Miniaturized Detection System, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China
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32
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Yang J, Cai L, Huang H, Liu B, Wu Q. Genetic variations and haplotype diversity of the UGT1 gene cluster in the Chinese population. PLoS One 2012; 7:e33988. [PMID: 22514612 PMCID: PMC3325998 DOI: 10.1371/journal.pone.0033988] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 02/24/2012] [Indexed: 12/22/2022] Open
Abstract
Vertebrates require tremendous molecular diversity to defend against numerous small hydrophobic chemicals. UDP-glucuronosyltransferases (UGTs) are a large family of detoxification enzymes that glucuronidate xenobiotics and endobiotics, facilitating their excretion from the body. The UGT1 gene cluster contains a tandem array of variable first exons, each preceded by a specific promoter, and a common set of downstream constant exons, similar to the genomic organization of the protocadherin (Pcdh), immunoglobulin, and T-cell receptor gene clusters. To assist pharmacogenomics studies in Chinese, we sequenced nine first exons, promoter and intronic regions, and five common exons of the UGT1 gene cluster in a population sample of 253 unrelated Chinese individuals. We identified 101 polymorphisms and found 15 novel SNPs. We then computed allele frequencies for each polymorphism and reconstructed their linkage disequilibrium (LD) map. The UGT1 cluster can be divided into five linkage blocks: Block 9 (UGT1A9), Block 9/7/6 (UGT1A9, UGT1A7, and UGT1A6), Block 5 (UGT1A5), Block 4/3 (UGT1A4 and UGT1A3), and Block 3′ UTR. Furthermore, we inferred haplotypes and selected their tagSNPs. Finally, comparing our data with those of three other populations of the HapMap project revealed ethnic specificity of the UGT1 genetic diversity in Chinese. These findings have important implications for future molecular genetic studies of the UGT1 gene cluster as well as for personalized medical therapies in Chinese.
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Affiliation(s)
- Jing Yang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Cai
- Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haiyan Huang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bingya Liu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Wu
- Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- * E-mail:
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Paz PF, Michalik DE. Newborn infant with prolonged jaundice. Clin Pediatr (Phila) 2011; 50:981-2. [PMID: 21357205 DOI: 10.1177/0009922811398965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Pedro F Paz
- University of California, Irvine School of Medicine, Orange, CA, USA
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Long J, Zhang S, Fang X, Luo Y, Liu J. Association of neonatal hyperbilirubinemia with uridine diphosphate-glucuronosyltransferase 1A1 gene polymorphisms: meta-analysis. Pediatr Int 2011; 53:530-40. [PMID: 21342357 DOI: 10.1111/j.1442-200x.2011.03337.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Recent reports have suggested that genetic factors, including mutations in the coding region or promoter of uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) may increase the risk of development of neonatal hyperbilirubinemia, but the relationship has not been evaluated on systematic review or meta-analysis. METHODS A meta-analysis of observational studies reporting effect estimates and 95% confidence intervals (95%CI) was conducted on the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. RESULTS A total of 27 eligible studies were identified. In total, 17 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, which indicated that these polymorphisms were associated with an increased risk of neonatal hyperbilirubinemia (A/A+G/A vs G/G: odds ratio [OR], 2.70; P= 0.00; 95%CI: 2.22-3.29; I(2) = 0.0%; P(heterogeneity) = 0.55). Subgroup analyses by ethnicity validated this correlation in Asian, but not in Caucasian, populations (OR, 1.74; P= 0.10; 95%CI: 0.90-3.35; I(2) = 0.00%; P(heterogeneity) = 0.67). Furthermore, 18 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphisms. These studies concluded that TATA promoter variants were not associated with an increased risk of neonatal hyperbilirubinemia (7/7 + 6/7 vs 6/6: OR, 1.13; P= 0.23; 95%CI: 0.93-1.37; I(2) = 80.0%; P(heterogeneity) = 0.00). CONCLUSION UGT1A1 Gly71Arg polymorphisms are a risk factor for developing neonatal hyperbilirubinemia in Asian, but not Caucasian, subjects. UGT1A1 TATA promoter polymorphisms were not associated with an increased risk of neonatal hyperbilirubinemia in Asian subjects, but results from the Caucasian population were conflicting and require further epidemiological investigation.
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Affiliation(s)
- Jun Long
- Department of Pediatrics, Fifth People's Hospital of Shenzhen, Shenzhen, China
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Huang YY, Huang MJ, Wang HL, Chan CC, Huang CS. Bilirubin concentrations in thalassemia heterozygotes in university students. Eur J Haematol 2011; 86:317-23. [DOI: 10.1111/j.1600-0609.2011.01578.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Fujiwara Y, Minami H. An overview of the recent progress in irinotecan pharmacogenetics. Pharmacogenomics 2010; 11:391-406. [PMID: 20235794 DOI: 10.2217/pgs.10.19] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Recent developments in a number of molecular profiling technologies, including genomic/genetic testing, proteomic profiling and metabolomic analysis have allowed the development of 'personalized medicine'. Irinotecan is one of the models for personalized medicine based on pharmacogenetics, and a number of clinical studies have revealed significant associations between UGT1A1*28 and irinotecan toxicity. Based on this cumulative evidence, the US FDA and pharmaceutical companies revised the irinotecan label in June 2005. However, a recommended strategy for irinotecan-dose adjustments based on individual genetic factors has not yet been fully established. This article provides an overview of recent progress in irinotecan pharmacogenetics and discusses the clinical significance of the UGT1A1 genotype/haplotype with regard to severe irinotecan toxicity.
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Affiliation(s)
- Yutaka Fujiwara
- Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital & Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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Abstract
The potential for genetic variation to modulate neonatal hyperbilirubinemia risk is increasingly being recognized. In particular, polymorphisms across three genes involved in bilirubin production and metabolism [glucose-6-phosphate dehydrogenase (G6PD), uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and solute carrier organic anion transporter polypeptide 1B1 (SLCO1B1)] may interact with each other and/or environmental contributors to produce significant hyperbilirubinemia. Variant gene co-expression including compound and synergistic heterozygosity enhances hyperbilirubinemia risk, contributing to the etiologic heterogeneity and complex nature of neonatal jaundice.
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Affiliation(s)
- Jon F Watchko
- Division of Newborn Medicine, Department of Pediatrics, Magee-Women's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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Shimoyama S. Pharmacogenetics of irinotecan: An ethnicity-based prediction of irinotecan adverse events. World J Gastrointest Surg 2010; 2:14-21. [PMID: 21160829 PMCID: PMC2999195 DOI: 10.4240/wjgs.v2.i1.14] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 12/16/2009] [Accepted: 12/23/2009] [Indexed: 02/06/2023] Open
Abstract
Irinotecan is now regarded as the most active drug for the treatment of colorectal cancer. However, one of the most difficult issues oncologists face is deciding the optimal dose for an individual patient, as each individual shows different outcomes even at the same dose with regard to treatment related adverse events, ranging from no toxicity to a lethal event. Inherited genetic polymorphism of a single gene or multiple genes (haplotype or linkage disequilibrium) involved in SN-38 glucuronidation, a predominant route of irinotecan detoxification, is now recognized as a significant factor that can alter the incidence of side effects. Attempts to explore such inherited genetic variability have been focused on elucidating interindividual as well as interethnic differences. Genotyping studies in relation to adverse events in an individual or in a group of similar ethnicity should contribute to establishing individual-oriented or ethnicity-oriented irinotecan treatment regimens. This review highlights current single- or multi-tired approaches for the elucidation of genetic predispositions of patients to severe toxicities, especially among Asians. The purpose of this is to contribute to minimizing toxicity by dose modifications, with the consequent aim of maximizing dose intensity and efficacy, an ultimate goal of irinotecan-individualized therapy.
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Affiliation(s)
- Shouji Shimoyama
- Shouji Shimoyama, Gastrointestinal Unit, Settlement Clinic, 4-20-7, Towa, Adachi-ku, Tokyo 120-0003, Japan
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Chang PF, Lin YC, Liu K, Yeh SJ, Ni YH. Prolonged unconjugated hyperbiliriubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase. J Pediatr 2009; 155:860-3. [PMID: 19683255 DOI: 10.1016/j.jpeds.2009.05.034] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2009] [Revised: 04/17/2009] [Accepted: 05/26/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To test the hypothesis that a mutation in uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) gene of breast-fed infants is a contributory factor to prolonged unconjugated hyperbilirubinemia. STUDY DESIGN Of 125 breast-fed term infants, 35 infants had prolonged unconjugated hyperbilirubinemia; another 90 breast-fed neonates without prolonged jaundice were control infants. The polymerase chain reaction-restriction fragment length polymorphism method was used to detect the known variant sites (promoter area, nucleotides 211, 686, 1091, and 1456) of the UGT1A1 gene. RESULTS Of 35 breast-fed infants with prolonged unconjugated hyperbilirubinemia, 29 had at least 1 mutation of the UGT1A1 gene. Variation at nucleotide 211 was most common. The percentages of the neonates carrying the variant nucleotide 211 were significantly different between the prolonged hyperbilirubinemia group and control neonates. Male breast-fed infants had a higher risk than female infants for prolonged hyperbilirubinemia. CONCLUSIONS Male breast-fed neonates with a variant nucleotide 211 in UGT1A1 have a high risk for developing prolonged hyperbilirubinemia.
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Affiliation(s)
- Pi-Feng Chang
- Department of Pediatrics, Far Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan
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Lin YC, Chang PF, Hu FC, Chang MH, Ni YH. Variants in the UGT1A1 gene and the risk of pediatric nonalcoholic fatty liver disease. Pediatrics 2009; 124:e1221-7. [PMID: 19948621 DOI: 10.1542/peds.2008-3087] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Oxidative stress is increased in nonalcoholic fatty liver disease (NAFLD). Variants in the UGT1A1 gene contribute to increased bilirubin levels, and bilirubin can act as an antioxidant. We hypothesize that variant UGT1A1 genotypes reduce the risk for NAFLD development. METHODS Two hundred thirty-four obese children 6 to 13 years of age were recruited. NAFLD was determined through liver ultrasonography. The UGT1A1 genotypes UGT1A1*6 and UGT1A1*28 were detected. We assessed the effects of UGT1A1 genotypes on pediatric NAFLD. RESULTS In total, 12% of the obese children had NAFLD. The subjects with NAFLD had lower serum total bilirubin levels (0.25 +/- 0.30 mg/dL) than did those without NAFLD (0.36 +/- 0.38 mg/dL; P = .021). With conditioning on the effects of age- and gender-adjusted BMI, waist/hip ratio, and adiponectin levels, variant UGT1A1*6 genotypes were a protecting factor for NAFLD, with an estimated adjusted odds ratio of 0.31 (95% confidence interval: 0.11-0.91; P = .033), but variant UGT1A1*28 genotypes were not significantly associated with the occurrence of NAFLD. CONCLUSIONS Variant UGT1A1*6 genotypes are associated with a lower risk of NAFLD in obese Taiwanese children. The UGT1A1 genotype is a new risk factor for pediatric NAFLD.
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Affiliation(s)
- Yu-Cheng Lin
- Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan
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Watchko JF, Lin Z, Clark RH, Kelleher AS, Walker MW, Spitzer AR. Complex multifactorial nature of significant hyperbilirubinemia in neonates. Pediatrics 2009; 124:e868-77. [PMID: 19858149 DOI: 10.1542/peds.2009-0460] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To determine whether glucose-6-phosphate dehydrogenase (G6PD), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1), and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene variants occur at greater frequency in neonates with significant hyperbilirubinemia. METHODS Infants with gestational ages of >or=37 weeks and ages of <7 days were studied. Case subjects had >or=1 bilirubin level above the 95th percentile (high-risk zone), whereas control subjects had bilirubin levels of <40th percentile (low-risk zone) at study entry. RESULTS A total of 153 case subjects (median bilirubin level: 15.7 mg/dL) and 299 control subjects (median bilirubin level: 4.6 mg/dL) were evaluated. There were no statistical differences in the frequencies of G6PD, UGT1A1, and SCLO1B1 gene variants between case and control subjects (G6PD: 5.2% vs 3.3%; UGT1A1: 14.4% vs 9.4%; SLCO1B1: 73.2% vs 73.6%). However, coexpression of the G6PD African A- mutation with UGT1A1 and/or SLCO1B1 variants was seen more frequently for case subjects. Case subjects more often demonstrated >or=2 factors contributing to hyperbilirubinemia, including ABO blood group heterospecificity in which the mother had blood group O (47.7% vs 11.4%), positive direct Coombs test results (33.3% vs 4%), sibling treated with phototherapy (16.3% vs 5.4%), maternal circulating blood group antibodies (10.5 vs 0.7%), maternal diabetes mellitus (13.1% vs 6.4%), and maternal East Asian ethnicity (6.5% vs 1.3%). CONCLUSIONS Clinical contributors to hyperbilirubinemia were identified more frequently for case subjects but individually G6PD, UGT1A1, and SLCO1B1 variants were not. Coexpression of the G6PD African A- mutation with UGT1A1 and SLCO1B1 variants was seen more often for case subjects.
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Affiliation(s)
- Jon F Watchko
- Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Boo NY, Wong FL, Wang MK, Othman A. Homozygous variant of UGT1A1 gene mutation and severe neonatal hyperbilirubinemia. Pediatr Int 2009; 51:488-93. [PMID: 19674361 DOI: 10.1111/j.1442-200x.2008.02798.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND The aim of the present study was to compare, in a case-control study, the prevalence of nucleotide 211 guanine to adenine (G-->A) mutation of uridine diphosphoglucuronosyl transferase (UGT1A1) gene in Malaysian Chinese newborns with and without severe hyperbilirubinemia (total serum bilirubin >250 micromol/L during first 48 h of life or > or =300 micromol/L thereafter), and to determine whether this mutation was a significant risk factor associated with severe hyperbilirubinemia. METHODS Seventy-four term infants of Chinese descent admitted with severe hyperbilirubinemia were recruited. Infants without severe hyperbilirubinemia (n = 125) were randomly selected from among healthy Chinese term infants. UGT1A1 nucleotide 211 polymorphism was assayed using the Taqman single nucleotide polymorphism genotyping method. Using gestational age, types of feeds, G6PD mutation, G6PD enzyme levels, and UGT1A1 gene mutation status as independent variables, logistic regression analysis was carried out to determine the significant risk factors associated with severe hyperbilirubinemia. RESULTS UGT1A1 gene mutation was significantly more common among hyperbilirubinemic infants (39.2%) than controls (25.6%; P = 0.04). Gestational age (adjusted odds ratio [OR], 0.7; 95% confidence intervals [CI]: 0.5-0.9; P = 0.01), G6PD mutation (adjusted OR, 7.2; 95%CI: 2.7-19.0; P < 0.0001), exclusive breast-feeding (adjusted OR, 11.7; 95%CI: 2.7-49.9; P = 0.001), and homozygous variant of UGT1A1 gene mutation (adjusted OR, 32.2; 95%CI: 3.8-273.2; P = 0.001) were significant risk factors. Heterozygous variant of UGT1A1 gene mutation, actual levels of G6PD enzyme, and mixed feeding were not. CONCLUSION Homozygous variant of nucleotide 211 G-->A mutation of UGT1A1 gene is a significant risk factor associated with severe hyperbilirubinemia among Malaysian Chinese newborns.
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Affiliation(s)
- Nem-Yun Boo
- Department of Paediatrics, Universiti Kebangsaan Malaysia, Jalan Yaacbo Latif, Kuala Lumpur, Malaysia.
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Di YM, Chan E, Wei MQ, Liu JP, Zhou SF. Prediction of deleterious non-synonymous single-nucleotide polymorphisms of human uridine diphosphate glucuronosyltransferase genes. AAPS JOURNAL 2009; 11:469-80. [PMID: 19572200 DOI: 10.1208/s12248-009-9126-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2009] [Accepted: 06/15/2009] [Indexed: 01/15/2023]
Abstract
UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.
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Affiliation(s)
- Yuan Ming Di
- Discipline of Chinese Medicine, School of Health Sciences, RMIT University, Bundoora, Melbourne, Victoria, Australia
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Watchko JF. Identification of neonates at risk for hazardous hyperbilirubinemia: emerging clinical insights. Pediatr Clin North Am 2009; 56:671-87, Table of Contents. [PMID: 19501698 DOI: 10.1016/j.pcl.2009.04.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Hyperbilirubinemia is the most common condition requiring evaluation and treatment in neonates. Identifying among all newborns those few at risk to develop marked hyperbilirubinemia is a clinical challenge. Clinical, epidemiologic, and genetic risk factors associated with severe hyperbilirubinemia include late preterm gestational age, exclusive breastfeeding, glucose-6-phosphate dehydrogenase deficiency, ABO hemolytic disease, East Asian ethnicity, jaundice observed in the first 24 hours of life, cephalohematoma or significant bruising, and history of a previous sibling treated with phototherapy. It is increasingly apparent that the etiopathogenesis of severe hyperbilirubinemia is often multifactorial, and emerging evidence suggests that combining risk factor assessment with measurement of predischarge total serum or transcutaneous bilirubin levels will improve hyperbilirubinemia risk prediction.
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Affiliation(s)
- Jon F Watchko
- Department of Pediatrics, Division of Newborn Medicine, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Magee-Womens Hospital, Pittsburgh, PA 15213, USA.
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Lin R, Wang X, Wang Y, Zhang F, Wang Y, Fu W, Yu T, Li S, Xiong M, Huang W, Jin L. Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations. Hum Mutat 2009; 30:609-15. [DOI: 10.1002/humu.20895] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Huang YY, Huang MJ, Yang SS, Teng HC, Huang CS. Variations in the UDP-glucuronosyltransferase 1A1 gene for the development of unconjugated hyperbilirubinemia in Taiwanese. Pharmacogenomics 2009; 9:1229-35. [PMID: 18781851 DOI: 10.2217/14622416.9.9.1229] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION Results of several studies have indicated that the variation of c.-3279T>G in the UDP-glucuronosyltransferase (UGT)1A1 gene could be a further factor for the development of hyperbilirubinemia. However, this variant has not been reported in the Taiwanese population. MATERIALS & METHODS PCR-restriction fragment length polymorphism was utilized to determine variants at nucleotides -3279 (*60), -53 (*28) and 211 (*6) in the UGT1A1 gene for 178 Taiwanese hyperbilirubinemic patients and 200 controls. RESULTS A total of ten and nine diplotypes were observed in the hyperbilirubinemic patients and controls, respectively. Subjects possessing diplotypes of compound haplotypes (*60/*28, *60/*6, *1/*60 plus *1/*28 plus *1/*6); *60/*60; *60/*60 plus 1/*28 and *6/*6 were significantly related to hyperbilirubinemia development, with an odds ratio of 7.83-188.00 (p = 0.012 approximately <0.001). A subgroup possessing diplotypes of *60/*60 plus *28/*28 were only found in hyperbilirubinemic patients, not in the controls. Bilirubin concentration amongst these patients carrying a diplotype of *60/*60 plus *28/*28 (mean [SD]: 39.2 [10.77] micromol/l) was significantly higher than that in the diplotype subgroups of *60/*60 plus *1/*28 (30.4 [4.10] micromol/l) and *6/*6 (30.3 [3.08] micromol/l) (p = 0.046 and 0.034, respectively). CONCLUSIONS The c.-3279T>G variant is a further factor for the development of hyperbilirubinemia. Our results also demonstrate that possessing the *60/*60 plus *28/*28 diplotype in the UGT1A1 gene is a determinant of relatively higher bilirubin values amongst hyperbilirubinemic patients.
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Affiliation(s)
- Yang-Yang Huang
- Department of Laboratory Medicine, Cathay General Hospital, No 280, Section 4, Jen-Ai Road, Taipei 106, Taiwan
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Chowbay B, Zhou S, Lee EJD. An Interethnic Comparison of Polymorphisms of the Genes Encoding Drug-Metabolizing Enzymes and Drug Transporters: Experience in Singapore. Drug Metab Rev 2008; 37:327-78. [PMID: 15931768 DOI: 10.1081/dmr-28805] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Much of the interindividual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes and drug transporters. In recent years, we have investigated the polymorphisms in a number of genes encoding phase I and II drug-metabolizing enzymes including CYPIA1, CYP3A4, CYP3A5, GSTM1, NAT2, UGT1A1, and TPMT and drug transporter (MDR1) in three distinct Asian populations in Singapore, namely the Chinese, Malays, and Indians. Significant differences in the frequencies of common alleles encoding these proteins have been observed among these three ethnic groups. For example, the frequency of the variant A2455G polymorphism of CYP1A1 was 28% in Chinese and 31% in Malays, but only 18% in Indians. CYP3A4*4 was detected in two of 110 Chinese subjects, but absent in Indians and Malays. Many Chinese and Malays (61-63%) were homozygous for the GSTM1*0 null genotype compared with 33% of Indians. The frequency of the UGTIA1*28 allele was highest in the Indian population (35%) compared to similar frequencies that were found in the Chinese (16%) and Malay (19%) populations. More importantly, our experience over the years has shown that the pharmacogenetics of these drug-metabolizing enzymes and MDR1 in the Asian populations are different from these in the Caucasian and African populations. For example, the CYP3A4*1B allele, which contains an A-290G substitution in the promoter region of CYP3A4, is absent in all three Asian populations of Singapore studied, but occurs in more than 54% of Africans and 5% of Caucasians. There were no difference in genotype and allelic variant frequencies in exon 12 of MDR1 between the Chinese, Malay, and Indian populations. When compared with other ethnic groups, the distribution of the wild-type C allele in exon 12 in the Malays (34.2%) and Indians (32.8%) was relatively high and similar to the Japanese (38.55%) and Caucasians (41%) but different from African-Americans (15%). The frequency of wild-type TT genotype in Asians (43.5% to 52.1%) and Japanese (61.5%) was much higher than those found in Caucasians (13.3%). All the proteins we studied represent the primary hepatic or extrahepatic enzymes, and their polymorphic expression may be implicated in disease risk and the disposition of drugs or endogenous substances. As such, dose requirements of certain drugs may not be optimal for Asian populations, and a second look at the factors responsible for this difference is necessary.
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Affiliation(s)
- Balram Chowbay
- Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore
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Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer 2008; 112:1932-40. [PMID: 18300238 DOI: 10.1002/cncr.23370] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND It is known that the uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC). METHODS In total, 128 patients with metastatic CRC who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed. RESULTS Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%; P < .01), neutropenic fever (38.5% vs 3.9%; P < .01), diarrhea (26.9% vs 5.9%; P < .01), and pretreatment bilirubin level (23.1% vs 8.8%; P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%; P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%; P = .80), and it did not significantly affect progression-free survival (10 months vs 11 months; P = .94) or overall survival (19 months vs 18 months; P = .84). CONCLUSIONS The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic CRC. Further prospective studies are warranted for using this polymorphism to optimize irinotecan-based chemotherapy.
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Affiliation(s)
- Chun-Yu Liu
- National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
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Hsieh CJ, Chen MJ, Liao YL, Liao TN. Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease. Cell Mol Biol Lett 2007; 13:1-10. [PMID: 17952380 PMCID: PMC6275749 DOI: 10.2478/s11658-007-0030-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2006] [Accepted: 01/05/2007] [Indexed: 01/12/2023] Open
Abstract
Bilirubin, an antioxidant in the blood, plays a role in protection from atherosclerosis. The level of bilirubin is highly correlated to the incidence of coronary artery disease (CAD). Unconjugated bilirubin is conjugated with glucuronic acid through the reaction of uridine 5'-diphosphate-glucuronosyl transferase 1A1 (UGT1A1). The interactions of CAD and the variations in the coding regions of the UGT1A1 gene have never been evaluated. The purpose of this study was to analyze the influence of the UGT1A1 variant on the incidence of CAD. There were 135 participants in this study: 61 in the experimental group, who had CAD, and 74 in the control group, who did not have CAD. The blood samples from all 135 participants were collected and assayed to clarify the relationship between bilirubin and CAD. The assay of the polymerase chain reaction and the sequence of the UGT1A1 gene were examined to find the gene's polymorphisms. The bilirubin levels for the participants in the control group were significantly higher than for the patients in the CAD group. Although the concentration of bilirubin in the UGT1A1 variant was higher than the wild type for the patients in the CAD group, there was no significant difference in the polymorphism of UGT1A1 between the patients in the CAD group and the participants in the control group.
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Affiliation(s)
- Chia-Jung Hsieh
- Chung-Hwa University of Medical Technology, 89, Wen-Hwa 1st Street, Tainan, Taiwan
| | - Meng-Jung Chen
- Chi-Mei Medical Center, 901, Chung-Hwa Road, Tainan, Taiwan
| | - Yung-Liang Liao
- Department of Pathology, Chi-Mei Medical Center, 901, Chung-Hwa Road, Tainan, Taiwan
| | - Tung-Nan Liao
- Chung-Hwa University of Medical Technology, 89, Wen-Hwa 1st Street, Tainan, Taiwan
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Teng HC, Huang MJ, Tang KS, Yang SS, Tseng CS, Huang CS. Combined UGT1A1 and UGT1A7 variant alleles are associated with increased risk of Gilbert’s syndrome in Taiwanese adults. Clin Genet 2007; 72:321-8. [PMID: 17850628 DOI: 10.1111/j.1399-0004.2007.00873.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Gilbert's syndrome (GS) is caused by a reduction in the activity of hepatic bilirubin UDP-glucuronosyltransferase (UGT). This reduction is associated with UGT1A1*28 and UGT1A1*6 polymorphisms. Recent research also showed that carriage of UGT1A1*6 allele were significantly related with UGT1A7*3. Polymerase chain reaction-restriction fragment length polymorphism were utilized to determine UGT1A7 and UGT1A1 genes for 207 patients with GS and 207 gender/age-matched healthy controls. For the 207 healthy controls, linkage disequilibrium was observed between -57UGT1A7 and 622UGT1A7 loci (D' = 1.00 and r(2) = 1.00), -57UGT1A7 and 211UGT1A1 loci (D' = 0.72 and r(2) = 0.36), respectively. A dose-response effect for number of at-risk allele of UGT1A1 and risk for GS was noted (odds ratio (OR) = 8.19 for heterozygous UGT1A1*28 genotype; OR = 124.96 for homozygous UGT1A1*28 genotype; and p for trend <0.05). Patients with combined genotypes carrying UGT1A7 variant alleles and UGT1A1 variant alleles (including UGT1A1*28 and UGT1A1*6) are associated with increased risk of GS (OR = 13.96 for patients with combined genotype carrying at least one variant allele of UGT1A1 and UGT1A7). In conclusion, the -57UGT1A7 (T>G) is highly associated with UGT1A7*3 and moderately associated with 211UGT1A1 (G>A). Certain UGT1A1/UGT1A7 combined genotypes are risk factors of GS.
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Affiliation(s)
- H-C Teng
- College of Medicine and Health, Fooyin University, 151 Chin-Hsueh Road, La-Tiao Hsiang, Kaohsiung Hsien 831, Taiwan.
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