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Chu X, Liu L, Ye J, Wen Y, Li P, Cheng B, Cheng S, Zhang L, Qi X, Ma M, Liang C, Kafle OP, Wu C, Wang S, Wang X, Ning Y, Zhang F. Insomnia affects the levels of plasma bilirubin and protein metabolism: an observational study and GWGEIS in UK Biobank cohort. Sleep Med 2021; 85:184-190. [PMID: 34343768 DOI: 10.1016/j.sleep.2021.05.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/11/2021] [Accepted: 05/31/2021] [Indexed: 10/21/2022]
Abstract
STUDY OBJECTIVES We aim to explore the mechanism of relationship between insomnia and liver metabolism by examining the gene × insomnia interactions. METHODS Individual level genotypic and phenotypic data were obtained from the UK Biobank cohort. Regression analysis was first conducted to test the association of insomnia with plasma total bilirubin (TBil; n = 186,793), direct bilirubin (DBil; n = 159,854) and total protein (TP; n = 171,574) in UK Biobank cohort. Second, genome-wide gene-environment interaction study (GWGEIS) was conducted by PLINK 2.0, and FUMA platform was used to identify enriched pathway terms. RESULTS In UK Biobank cohort, we found that TP (P < 2.00 × 10-16), DBil (P = 1.72 × 10-3) and TBil (P = 3.38 × 10-5) were significantly associated with insomnia. GWGEIS of both DBil and TBil observed significant G × INSOMNIA effects between insomnia and UDP Glucuronosyltransferase Family 1 (rs6431558, P = 6.26 × 10-11) gene. GWGEIS of TP also detected several significant genes interacting with insomnia, such as KLF15, (rs70940816, P = 6.77 × 10-10) and DOK7, (rs2344205, P = 1.37 × 10-9). Multiple gene ontology (GO) terms were identified for bilirubin, such as GO_URONIC_ACID_METABOLIC_PROCESS (adjusted P = 4.15 × 10-26). CONCLUSION Our study results suggested negative associations between insomnia and DBil and TBil; and a positive association between insomnia and TP.
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Affiliation(s)
- Xiaomeng Chu
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Li Liu
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jing Ye
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yan Wen
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Ping Li
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Bolun Cheng
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Shiqiang Cheng
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Lu Zhang
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Xin Qi
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Mei Ma
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Chujun Liang
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Om Prakash Kafle
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Cuiyan Wu
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Sen Wang
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Xi Wang
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yujie Ning
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Feng Zhang
- Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China.
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Breithaupt-Groegler K, Coch C, Coenen M, Donath F, Erb-Zohar K, Francke K, Goehler K, Iovino M, Kammerer KP, Mikus G, Rengelshausen J, Sourgens H, Schinzel R, Sudhop T, Wensing G. Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials. Eur J Clin Pharmacol 2017; 73:409-416. [PMID: 28064353 PMCID: PMC5350217 DOI: 10.1007/s00228-016-2189-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 12/20/2016] [Indexed: 11/22/2022]
Abstract
Introduction/Methods A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. Results Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity. Consequences The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.
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Affiliation(s)
| | - Christoph Coch
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany
| | - Martin Coenen
- Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
| | - Frank Donath
- SocraTec Research and Development GmbH, D-99084, Erfurt, Germany
| | | | - Klaus Francke
- National Association of Statutory Health Insurance Funds, Medicinal Product Department, 10117, Berlin, Germany
| | - Karin Goehler
- Gruenenthal GmbH, Gruenenthal Innovation-Development-Clinical Development-Clinical Pharmacology, D-52099, Aachen, Germany
| | - Mario Iovino
- Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine and Clinical Pharmacology, D-88397, Biberach/Riss, Germany
| | - Klaus Peter Kammerer
- Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine and Clinical Pharmacology, D-88397, Biberach/Riss, Germany
| | - Gerd Mikus
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, D-69120, Heidelberg, Germany
| | - Jens Rengelshausen
- Gruenenthal GmbH, Gruenenthal Innovation-Research-Translational Science & Strategy-Early Clinical Science, D-52078, Aachen, Germany
| | | | | | - Thomas Sudhop
- Federal Institute for Drugs and Medical Devices (BfArM), D-53175, Bonn, Germany
| | - Georg Wensing
- Bayer Pharma AG, Pharmaceutical Division Clinical Pharmacology Cardiovascular/Hematology (Primary Care), D-42096, Wuppertal, Germany
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Pu D, Mao C, Cui L, Shi Z, Xiao P. Pyrosequencing with di-base addition for single nucleotide polymorphism genotyping. Anal Bioanal Chem 2016; 408:3113-23. [PMID: 26935928 DOI: 10.1007/s00216-016-9359-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 01/16/2016] [Accepted: 01/22/2016] [Indexed: 12/13/2022]
Abstract
We develop color code-based pyrosequencing with di-base addition for analysis of single nucleotide polymorphisms (SNPs). When a di-base is added into the polymerization, one or several two-color code(s) containing the type and the number of incorporated nucleotides will be produced. The code information obtained in a single run is useful to genotype SNPs as each allelic variant will give a specific pattern compared to the two other variants. Special care has to be taken while designing the di-base dispensation order. Here, we present a detailed protocol for establishing sequence-specific di-base addition to avoid nonsynchronous extension at the SNP sites. By using this technology, as few as 50 copies of DNA templates were accurately sequenced. Higher signals were produced and thus a relatively lower sample amount was required. Furthermore, the read length of per flow was increased, making simultaneous identification of multiple SNPs in a single sequencing run possible. Validation of the method was performed by using templates with two SNPs covering 37 bp and with three SNPs covering 58 bp as well as 82 bp. These SNPs were successfully genotyped by using only a sequencing primer in a single PCR/sequencing run. Our results demonstrated that this technology could be potentially developed into a powerful methodology to accurately determine SNPs so as to diagnose clinical settings.
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Affiliation(s)
- Dan Pu
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China
| | - Chengguang Mao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China
| | - Lunbiao Cui
- Key Laboratory of Enteric Pathogenic Microbiology (NHFPC), Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, 210009, China
| | - Zhiyang Shi
- Key Laboratory of Enteric Pathogenic Microbiology (NHFPC), Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, 210009, China
| | - Pengfeng Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, 210096, China.
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Huangfu H, Pan H, Wang B, Wen S, Han R, Li L. Association between UGT1A1 Polymorphism and Risk of Laryngeal Squamous Cell Carcinoma. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:ijerph13010112. [PMID: 26751466 PMCID: PMC4730503 DOI: 10.3390/ijerph13010112] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/21/2015] [Indexed: 01/14/2023]
Abstract
Laryngeal cancer is one of the largest subgroups of head and neck cancers. In addition to smoking and alcohol consumption, genetic polymorphisms are also risk factors for the development of laryngeal cancer. However, the exact relation between genetic variants and pathogenesis of laryngeal cancer has remained elusive. The aim of this study was to examine UGT1A1*6 (rs4148323 A/G) polymorphisms in 103 patients with laryngeal cancer and 220 controls using the high resolution melting curve (HRM) technique and to explore the association between UGT1A1*6 (rs4148323 A/G) polymorphisms and laryngeal cancer. The results showed an association between the rs4148323 G allele and increased risk of laryngeal cancer. While there was no statistically significant difference between rs4148323 genotype frequencies and different histological grades or different clinical stages of laryngeal cancer, stratification analysis indicated smoking or alcohol consumption and rs4148323 G allele combined to increase the risk of laryngeal cancer. In conclusion, the rs4148323 G allele is associated with the high UGT1A1 enzyme activity, and might increase the risk of laryngeal cancer. Furthermore, smoking or alcohol consumption and the rs4148323 G allele act synergistically to increase the risk of laryngeal cancer.
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Affiliation(s)
- Hui Huangfu
- Department of ear-nose-throat (ENT), the First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001 Shanxi, China.
| | - Hong Pan
- Department of ear-nose-throat (ENT), the First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001 Shanxi, China.
| | - Binquan Wang
- Department of ear-nose-throat (ENT), the First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001 Shanxi, China.
| | - Shuxin Wen
- Department of ear-nose-throat (ENT), the First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001 Shanxi, China.
| | - Rui Han
- Department of ear-nose-throat (ENT), the First Hospital of Shanxi Medical University, 85 Jiefangnan Road, Taiyuan, 030001 Shanxi, China.
| | - Li Li
- Department of biology, the Basic Medical School of Shanxi Medical University, 56 Xinjiannan Road, Taiyuan, 030001 Shanxi, China.
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Etienne-Grimaldi MC, Boyer JC, Thomas F, Quaranta S, Picard N, Loriot MA, Narjoz C, Poncet D, Gagnieu MC, Ged C, Broly F, Le Morvan V, Bouquié R, Gaub MP, Philibert L, Ghiringhelli F, Le Guellec C. UGT1A1genotype and irinotecan therapy: general review and implementation in routine practice. Fundam Clin Pharmacol 2015; 29:219-37. [DOI: 10.1111/fcp.12117] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 02/05/2015] [Accepted: 02/24/2015] [Indexed: 12/19/2022]
Affiliation(s)
| | - Jean-Christophe Boyer
- Unité de Toxicologie; Laboratoire de Biochimie; CHU Carémeau, Place du Pr Debré; 30029 Nîmes Cedex France
| | - Fabienne Thomas
- Institut Claudius Regaud; 1, avenue Irène Joliot-Curie 31059 Toulouse France
| | - Sylvie Quaranta
- Service de Pharmacocinétique et Toxicologie; Laboratoire de Biologie Médicale; Hôpital de la Timone; Bât F; 264 rue Saint Pierre 13385 Marseille Cedex 05 France
| | - Nicolas Picard
- Service Pharmacologie; Toxicologie et Pharmacovigilance; CHU Limoges, Bâtiment CBRS; 2 avenue Martin Luther King 87042 Limoges France
| | - Marie-Anne Loriot
- Hôpital Européen Georges Pompidou; SERVICE BIOCHIMIE; 20 Rue Leblanc 75015 Paris France
| | - Céline Narjoz
- Hôpital Européen Georges Pompidou; SERVICE BIOCHIMIE; 20 Rue Leblanc 75015 Paris France
| | - Delphine Poncet
- Equipe Signalisation Métabolisme et Progression Tumorale; UMR 1052-5286; Centre Léon Bérard; 28 rue Laennec 69373 Lyon Cedex 08 69008 Lyon France
| | - Marie-Claude Gagnieu
- Fédération de Biochimie; UF Pharmacologie Spécialisée; Hôpital E. Herriot; 5 place d'Arsonval 69437 Lyon Cedex 03 France
| | - Cécile Ged
- Plateau Technique de Biologie Moléculaire; Pôle de Biologie et Pathologie; CHU de Bordeaux; 1, place A Raba Leon 33 000 Bordeaux France
| | - Franck Broly
- Service de Toxicologie et Génopathies; Centre de Biologie Pathologie Génétique; Centre Hospitalier Régional et Universitaire de Lille; 59037 Lille Cedex France
| | - Valérie Le Morvan
- Institut Bergonié; Unité Inserm VINCO; 229 cours de l'Argonne 33076 Bordeaux Cedex France
| | - Régis Bouquié
- Laboratoire de Pharmacologie clinique; Institut de Biologie - CHU Nantes; 9, quai Moncousu 44093 Nantes Cedex 1 France
| | - Marie-Pierre Gaub
- EA3430; FMTS Université de Strasbourg; Laboratoire de Biochimie- Biologie Moléculaire; Hôpital de hautepierre; Avenue Molière 67098 Strasbourg France
| | - Laurent Philibert
- Unité de Biopathologie et pharmacogénétique; Laboratoire d'oncopharmacologie; Institut régional du Cancer Montpellier - Val d'Aurelle; 208 Avenue des Apothicaires 34298 Montpellier Cedex 5 France
| | - François Ghiringhelli
- Département de biopathologie; Centre Georges Francois Leclerc; 1 rue du professeur Marion 21000 Dijon France
| | - Chantal Le Guellec
- Unité de pharmacogénétique; Laboratoire de biochimie et biologie moléculaire; CHU Bretonneau; 2 bis boulevard Tonnellé 37044 Tours France
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Simon TW, Simons SS, Preston RJ, Boobis AR, Cohen SM, Doerrer NG, Fenner-Crisp PA, McMullin TS, McQueen CA, Rowlands JC. The use of mode of action information in risk assessment: Quantitative key events/dose-response framework for modeling the dose-response for key events. Crit Rev Toxicol 2014; 44 Suppl 3:17-43. [DOI: 10.3109/10408444.2014.931925] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Liu W, Kulkarni K, Hu M. Gender-dependent differences in uridine 5'-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics. Expert Opin Drug Metab Toxicol 2013; 9:1555-69. [DOI: 10.1517/17425255.2013.829040] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Biason P, Masier S, Toffoli G. UGT1A1*28 and Other UGT1A Polymorphisms as Determinants of Irinotecan Toxicity. J Chemother 2013; 20:158-65. [DOI: 10.1179/joc.2008.20.2.158] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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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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Liu F, Wen B, Kayser M. Colorful DNA polymorphisms in humans. Semin Cell Dev Biol 2013; 24:562-75. [PMID: 23587773 DOI: 10.1016/j.semcdb.2013.03.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/26/2013] [Indexed: 10/26/2022]
Abstract
In this review article we summarize current knowledge on how variation on the DNA level influences human pigmentation including color variation of iris, hair, and skin. We review recent progress in the field of human pigmentation genetics by focusing on the genes and DNA polymorphisms discovered to be involved in determining human pigmentation traits, their association with diseases particularly skin cancers, and their power to predict human eye, hair, and skin colors with potential utilization in forensic investigations.
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Affiliation(s)
- Fan Liu
- Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans. Hum Genet 2012; 132:147-58. [PMID: 23052946 DOI: 10.1007/s00439-012-1232-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 09/18/2012] [Indexed: 01/09/2023]
Abstract
Natural variation in human skin pigmentation is primarily due to genetic causes rooted in recent evolutionary history. Genetic variants associated with human skin pigmentation confer risk of skin cancer and may provide useful information in forensic investigations. Almost all previous gene-mapping studies of human skin pigmentation were based on categorical skin color information known to oversimplify the continuous nature of human skin coloration. We digitally quantified skin color into hue and saturation dimensions for 5,860 Dutch Europeans based on high-resolution skin photographs. We then tested an extensive list of 14,185 single nucleotide polymorphisms in 281 candidate genes potentially involved in human skin pigmentation for association with quantitative skin color phenotypes. Confirmatory association was revealed for several known skin color genes including HERC2, MC1R, IRF4, TYR, OCA2, and ASIP. We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. Overall, digital quantification of human skin color allowed detecting new skin color genes. The variants identified in this study may also contribute to the risk of skin cancer. Our findings are also important for predicting skin color in forensic investigations.
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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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Rawa K, Adamowicz-Salach A, Matysiak M, Trzemecka A, Burzynska B. Coexistence of Gilbert syndrome with hereditary haemolytic anaemias. J Clin Pathol 2012; 65:663-5. [DOI: 10.1136/jclinpath-2011-200580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BackgroundGilbert syndrome is an inherited disease characterised by mild unconjugated hyperbilirubinaemia caused by mutations in UGT1A1 gene which lead to decreased activity of UDP-glucuronosyltransferase 1A1. The most frequent genetic defect is a homozygous TA dinucleotide insertion in the regulatory TATA box in the UGT1A1 gene promoter.Methods and results182 Polish healthy individuals and 256 patients with different types of hereditary haemolytic anaemias were examined for the A(TA)nTAA motif. PCR was performed using sense primer labelled by 6-Fam and capillary electrophoresis was carried out in an ABI 3730 DNA analyser. The frequency of the (TA)7/(TA)7 genotype in the control group was estimated at 18.13%, (TA)6/(TA)7 at 45.05% and (TA)6/(TA)6 at 36.26%. There was a statistically significant difference in the (TA)6/(TA)6 genotype distribution between healthy individuals and patients with glucose-6-phosphate dehydrogenase deficiency (p=0.041). Additionally, uncommon genotypes, (TA)5/(TA)6, (TA)5/(TA)7 and (TA)7/(TA)8 of the promoter polymorphism, were discovered.ConclusionGenotyping of the UGT1A1 gene showed distinct distribution of the common A(TA)nTAA polymorphism relative to other European populations. Because of a greater risk of hyperbilirubinaemia due to hereditary haemolytic anaemia, the diagnosis of Gilbert syndrome in this group of patients is very important.
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Amacher DE. The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol 2012; 8:335-47. [DOI: 10.1517/17425255.2012.658041] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet 2011; 27:9-54. [PMID: 22123129 DOI: 10.2133/dmpk.dmpk-11-rv-111] [Citation(s) in RCA: 184] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Drug lag, recently discussed extensively in Japan, can be divided into two phases: clinical development time and application review time. The former factor is still an important problem that might be improved by promoting multi-regional clinical trials and considering the results from other similar populations with Japanese, such as Koreans and Chinese. In this review, we compare the allelic or genotype frequencies of 30 relatively common functional alleles mainly between Eastern Asians and Europeans as well as among 3 major populations in Eastern Asian countries, Japan, Korea, and China, in 12 pharmacokinetics (PK)/pharmacodynamics (PD)-related genes; CYP2C9 (*2 and *3), CYP2C19 (*2, *3 and *17), 13 CYP2D6 haplotypes including *4, *5 and *10, CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5, *6 and *7), GSTM1 and GSTT1 null genotypes, SLCO1B1 521T>C, ABCG2 421C>A, and HLA-A*31:01 and HLA-B*58:01. In this review, differences in allele frequencies (AFs) or genotype frequencies (GFs) less than 0.1 (in the cases of highest AF (GF) ≥0.1) or less than 0.05 (in the cases of lowest AF (GF) <0.1) were regarded as similar. Between Eastern Asians and Europeans, AFs (or GFs) are regarded as being different for many alleles such as CYP2C9 (*2), CYP2C19 (*2, *3 and *17), CYP2D6 (*4 and *10), CYP3A5 (*3), UGT1A1 (*28 and *6), NAT2 (*5*7), GSTT1 null and ABCG2 421C>A. Among the 3 Eastern Asian populations, however, only AFs of CYP2C19*3, CYP2D6*10, HLA-A*31:01 and HLA-B*58:01 are regarded as dissimilar. For CYP2C19*3, the total functional impact on CYP2C19 could be small if the frequencies of the two null alleles CYP2C19*2 and *3 are combined. Regarding CYP2D6*10, frequency difference over 0.1 is observed only between Japanese and Chinese (0.147). Although environmental factors should be considered for PK/PD differences, we could propose that among Japan, Korea, and China, genetic differences are very small for the analyzed common PK-related gene polymorphisms. On the other hand, AFs of the two HLA alleles important for cutaneous adverse drug reactions are diverse even among Eastern Asians and thus should be taken into account.
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Affiliation(s)
- Kouichi Kurose
- Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan
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Fukui T, Mitsufuji H, Kubota M, Inaoka H, Hirose M, Iwabuchi K, Masuda N, Kobayashi H. Prevalence of topoisomerase I genetic mutations and UGT1A1 polymorphisms associated with irinotecan in individuals of Asian descent. Oncol Lett 2011; 2:923-928. [PMID: 22866151 DOI: 10.3892/ol.2011.346] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 06/17/2011] [Indexed: 12/31/2022] Open
Abstract
Topoisomerase I (TOP-I) mutations have been shown to be correlated to irinotecan resistance in vitro. However, the prevalence of TOP-I germline mutations has yet to be systematically elucidated. On the other hand, polymorphisms of UGT1A1 have been shown to be associated with CPT-11 toxicity in clinical situations. The primary aim of this study was to investigate the prevalence of mutations in the TOP-I exons associated with CPT-11 resistance, including untreated cancer tissue. A secondary aim was to confirm the less frequent UGT1A1*28 and more frequent UGT1A1*6 in individuals of Asian descent compared to Caucasians and individuals of African descent. The prevalence of 5 reported TOP-I mutations in exons was investigated in volunteers (n=236) using DNA sequencing of the PCR products. The prevalence of TOP-I mutations in untreated lung cancer tissues (n=16) was also investigated. Additionally, 3 UGT1A1 polymorphisms, UGT1A1*6, *27 and *28, were investigated in volunteers (n=126). There were no mutations of TOP-I in any of the 236 subjects or in the untreated lung tissues. Among 128 subjects, the distribution of homozygous polymorphisms of UGT1A1 was: UGT1A1*28 in 3 (2.4%) and UGT1A1*6 in 4 (3.2%) subjects, and co-occurrence of heterozygous polymorphisms for both UGT1A1*6 and UGT1A1*28 in 4 (3.2%) subjects, and for UGT1A1*27 and UGT1A1*28 in 1 subject (0.8%). The Hardy-Weinberg deviation test showed there was no significant deviation from the equilibrium, and the association analysis indicated no significant linkage between UGT1A1*6 and UGT1A1*28. In conclusion, TOP-I genetic mutations correlated to CPT-11 resistance were not detected in any of the subjects and untreated lung cancer tissues. Less frequent UGT1A1*28 and more frequent UGT1A1*6 were confirmed in East Asian individuals compared to Caucasians and individuals of African descent. Linkage disequilibrium was not detected between UGT1A1*6 and UGT1A1*28.
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Affiliation(s)
- Tomoya Fukui
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa 252-0373, Japan
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Horsfall LJ, Zeitlyn D, Tarekegn A, Bekele E, Thomas MG, Bradman N, Swallow DM. Prevalence of clinically relevant UGT1A alleles and haplotypes in African populations. Ann Hum Genet 2011; 75:236-46. [PMID: 21309756 DOI: 10.1111/j.1469-1809.2010.00638.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8) )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n) . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.
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Affiliation(s)
- Laura J Horsfall
- Department of Genetics, Evolution and Environment, University College London, Wolfson House, UK
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18
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Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, Park D, Zhu G, Larsson M, Duffy DL, Montgomery GW, Mackey DA, Walsh S, Lao O, Hofman A, Rivadeneira F, Vingerling JR, Uitterlinden AG, Martin NG, Hammond CJ, Kayser M. Digital quantification of human eye color highlights genetic association of three new loci. PLoS Genet 2010; 6:e1000934. [PMID: 20463881 PMCID: PMC2865509 DOI: 10.1371/journal.pgen.1000934] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 04/01/2010] [Indexed: 01/23/2023] Open
Abstract
Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.
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Affiliation(s)
- Fan Liu
- Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Andreas Wollstein
- Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Pirro G. Hysi
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Georgina A. Ankra-Badu
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Timothy D. Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Daniel Park
- Queensland Institute of Medical Research, Brisbane, Australia
| | - Gu Zhu
- Queensland Institute of Medical Research, Brisbane, Australia
| | - Mats Larsson
- Queensland Institute of Medical Research, Brisbane, Australia
| | - David L. Duffy
- Queensland Institute of Medical Research, Brisbane, Australia
| | | | - David A. Mackey
- Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia
| | - Susan Walsh
- Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Oscar Lao
- Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Fernando Rivadeneira
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Johannes R. Vingerling
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - André G. Uitterlinden
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Christopher J. Hammond
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Manfred Kayser
- Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Lacko M, Roelofs HM, te Morsche RH, Voogd AC, Ophuis MBO, Peters WH, Manni JJ. Genetic polymorphism in the conjugating enzyme UGT1A1 and the risk of head and neck cancer. Int J Cancer 2010; 127:2815-21. [DOI: 10.1002/ijc.25296] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Glimelius B, Garmo H, Berglund A, Fredriksson LA, Berglund M, Kohnke H, Byström P, Sørbye H, Wadelius M. Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. THE PHARMACOGENOMICS JOURNAL 2010; 11:61-71. [PMID: 20177420 PMCID: PMC3036798 DOI: 10.1038/tpj.2010.10] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09–13.2), and in patients carrying the UGT1A1*28/*28 genotype, OR=4.43 (95% CI=1.30–15.2). Patients with UGT1A1*28/*28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70–27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01–2.45).
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Affiliation(s)
- B Glimelius
- Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden
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Pacheco PR, Brilhante MJ, Ballart C, Sigalat F, Polena H, Cabral R, Branco CC, Mota-Vieira L. UGT1A1, UGT1A6 and UGT1A7 genetic analysis: repercussion for irinotecan pharmacogenetics in the São Miguel Island Population (Azores, Portugal). Mol Diagn Ther 2010; 13:261-8. [PMID: 19712005 DOI: 10.2165/11317170-000000000-00000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
BACKGROUND Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects. METHODS Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes. RESULTS Allelic analysis disclosed the presence of rare alleles - UGT1A1*36 and UGT1A1*37--only found in individuals of African descent, and UGT1A7*4. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A1*28-UGT1A6*2-UGT1A7*3), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity. CONCLUSIONS In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.
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Affiliation(s)
- Paula R Pacheco
- Molecular Genetics and Pathology Unit, Hospital of Divino Espirito Santo of Ponta Delgada, São Miguel Island, Azores, Portugal
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22
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Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J Gastroenterol 2009; 15:5058-66. [PMID: 19859999 PMCID: PMC2768885 DOI: 10.3748/wjg.15.5058] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a low-dose weekly irinotecan chemotherapeutic regimen.
METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC.
RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) (6/6) 39.0%, heterozygous genotype (6/7) 49.5%, and homozygous genotype (7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the (6/7, 7/7) or the WT genotype (6/6) (44.3% vs 43.2%, P = 0.75). Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the (6/6) when compared to the (6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [(6/7, 7/7) vs (6/6); 13.0% vs 6.2%, P = 0.08], treatment delays [(6/7, 7/7) vs (6/6); 25.1% vs 19.3%, P =0.24] or dose reductions [(6/7, 7/7) vs (6/6); 21.5% vs 27.2%, P = 0.07].
CONCLUSION: This analysis demonstrates the non-significant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.
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Argiris A, Buchanan A, Brockstein B, Kolesar J, Ghebremichael M, Pins M, Hahn K, Axelrod R, Forastiere A. Docetaxel and irinotecan in recurrent or metastatic head and neck cancer: a phase 2 trial of the Eastern Cooperative Oncology Group. Cancer 2009; 115:4504-13. [PMID: 19634157 PMCID: PMC2749918 DOI: 10.1002/cncr.24528] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Docetaxel and irinotecan have single-agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN. METHODS Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m(2) and irinotecan 60 mg/m(2), intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase-2 and VEGF in baseline tumor tissue. RESULTS Fifty-two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel-exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression-free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085). CONCLUSIONS Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum-based regimens.
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Affiliation(s)
- Athanassios Argiris
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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Xing Y, Yang L, Wang L, Shao L, Wei Z, Xuan J, Li J, Qin S, Shu A, He L, Xing Q. Systematic screening for polymorphisms within the UGT1A6 gene in three Chinese populations and function prediction through structural modeling. Pharmacogenomics 2009; 10:741-52. [PMID: 19450126 DOI: 10.2217/pgs.09.21] [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
AIMS To date, there have been relatively few studies on the UGT1A6 gene in the Chinese population. The present study was designed to determine the allele frequencies and haplotypes of this gene in the population and predict the candidate functional mutations. MATERIALS & METHODS We carried out the first systematic screening of polymorphisms of the gene in an SNP analysis involving 1074 Chinese subjects from three ethnic groups, namely Han, Dong and She, using direct sequencing. We identified the putative substrate binding pocket using a homology-modeled structure and produced a practical model for predicting the function of polymorphisms in UGT1A6. RESULTS A total of six SNPs and 10 mutations were detected including nine known and seven novel ones. The novel mutations were 73G>A (V25I), 89T>G (L30R), 222A>C, 657C>A, 773A>T (D258V), 1040A>G (N347S) and 1467C>T. In addition, we detected, for the first time in the Chinese population, SNPs 105C>T, 627G>T as well as mutations 308C>A (S103X), IVS2+15T>C and 1088C>T (P363L). Strong linkage disequilibrium was observed among 19T>G, 315A>G, 541A>G and 552A>C. There were seven haplotypes whose frequencies were more than 0.01 in one or more of the three ethnic groups. P363L in the C-terminal domain might weaken the binding of cofactor UDPGA to the domain and induce a poor metabolism genotype of UGT1A6. CONCLUSION Our study suggests that genetic polymorphisms in UGT1A6 may contribute to interindividual and intra-ethnic differences. The results should prove helpful in the development of pharmacogenomics in China.
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Affiliation(s)
- Yi Xing
- Bio-X Center, Shanghai Jiao Tong University, Shanghai, China
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Romanowski T, Sikorska K, Bielawski KP. UGT1A1 gene polymorphism as a potential factor inducing iron overload in the pathogenesis of type 1 hereditary hemochromatosis. Hepatol Res 2009; 39:469-78. [PMID: 19207584 DOI: 10.1111/j.1872-034x.2008.00487.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Aim Hereditary hemochromatosis is a common genetic disorder characterized by iron overload and subsequent organ damage. It is caused in most cases by HFE gene mutations which penetrance can be affected by many factors. The aim of this study was to establish the role of UGT1A1 gene polymorphism and serum bilirubin concentration in the pathogenesis of hereditary hemochromatosis. Methods Biochemical, histopathological and genetic data indicating iron excess and serum total bilirubin concentration were determined in 32 patients with the type 1 hereditary hemochromatosis. Fluorescent molecular probes assays were used for genotyping of UGT1A1*28 and UGT1A1*60 mutations in these individuals. Results High incidence and a significant correlation of UGT1A1 gene mutations with increased serum bilirubin level and lower grades of liver tissue inflammatory activity were observed in study participants. UGT1A1*28 and UGT1A1*60 mutations were strongly linked together. Two of the subjects presented very rare genotypes of UGT1A1 gene: (TA)(5/7) and c.-64G>C heterozygotes. Conclusions UGT1A1 gene polymorphism and as its consequence of high serum bilirubin level may promote iron accumulation in hemochromatosis patients by reducing the activity of inflammation. We proposed a possible mechanism of this interaction.
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Affiliation(s)
- Tomasz Romanowski
- Molecular Diagnostics Division, Department of Biotechnology, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Poland
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Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med 2009; 11:21-34. [PMID: 19125129 DOI: 10.1097/gim.0b013e31818efd77] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
This evidence-based review addresses the question of whether testing for UGT1A1 mutations in patients with metastatic colorectal cancer treated with irinotecan leads to improvement in outcomes (e.g., irinotecan toxicity, response to treatment, morbidity, and mortality), when compared with no testing. No studies were identified that addressed this question directly. The quality of evidence on the analytic validity of current UGT1A1 genetic testing methods is adequate (scale: convincing, adequate, inadequate), with available data indicating that both analytic sensitivity and specificity for the common genotypes are high. For clinical validity, the quality of evidence is adequate for studies reporting concentration of the active form of irinotecan (SN-38), presence of severe diarrhea, and presence of severe neutropenia stratified by UGT1A1 common genotypes. The strongest association for a clinical endpoint is for severe neutropenia. Patients homozygous for the *28 allele are 3.5 times more likely to develop severe neutropenia compared with individuals with the wild genotype (risk ratio 3.51; 95% confidence interval 2.03-6.07). The proposed clinical utility of UGT1A1 genotyping would be derived from a reduction in drug-related adverse reactions (benefits) while at the same time avoiding declines in tumor response rate and increases in morbidity/mortality (harms). At least three treatment options for reducing this increased risk have been suggested: modification of the irinotecan regime (e.g., reduce initial dose), use of other drugs, and/or pretreatment with colony-stimulating factors. However, we found no prospective studies that examined these options, particularly whether a reduced dose of irinotecan results in a reduced rate of adverse drug events. This is a major gap in knowledge. Although the quality of evidence on clinical utility is inadequate, two of three reviewed studies (and one published since our initial selection of studies for review) found that individuals homozygous for the *28 allele had improved survival. Three reviewed studies found statistically significant higher tumor response rates among individuals homozygous for the *28 allele. We found little or no direct evidence to assess the benefits and harms of modifying irinotecan regimens for patients with colorectal cancer based on their UGT1A1 genotype; however, results of our preliminary modeling of prevalence, acceptance, and effectiveness indicate that reducing the dose would need to be highly effective to have benefits outweigh harms. An alternative is to increase irinotecan dose among wild-type individuals to improve tumor response with minimal increases in adverse drug events. Given the large number of colorectal cancer cases diagnosed each year, a randomized controlled trial of the effects of irinotecan dose modifications in patients with colorectal cancer based on their UGT1A1 genotype is feasible and could clarify the tradeoffs between possible reductions in severe neutropenia and improved tumor response and/or survival in patients with various UGT1A1 genotypes.
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Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1. Pharmacogenet Genomics 2008; 18:559-68. [PMID: 18551036 DOI: 10.1097/fpc.0b013e3282fe9a2c] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES Genetic variability in hepatic uptake was recently shown to influence the disposition and cholesterol-lowering effects of statins. Ezetimibe, an inhibitor of the intestinal cholesterol uptake protein Niemann-Pick C 1 like 1, is another drug for which genetic polymorphisms of hepatic organic anion transporting polypeptides (OATPs) are expected to be of clinical relevance because ezetimibe undergoes intensive enterohepatic circulation for which hepatic uptake transporters may be rate-limiting determinants. METHODS Using OATP1B3-, OATP2B1-, and OATP1B1-transfected HEK cells, including the OATP1B1 variants OATP1B1*1b and OATP1B1*5, we measured the uptake of ezetimibe and its glucuronide and we analyzed the competition with the common OATP-substrate bromosulfophthalein. Disposition and sterol-lowering effects of 20-mg ezetimibe were measured in 35 healthy participants genotyped for OATP1B1, ABCB1, ABCC2, and UGT1A1. RESULTS Ezetimibe glucuronide inhibited bromosulfophthalein uptake in all OATP-transfected cells (50% inhibitory concentration (IC50): 0.14-0.26 mumol/l) whereas ezetimibe was 30-100 times less potent. Only the glucuronide was accumulated significantly in cells expressing OATP1B1 and OATP2B1. Its uptake in cells expressing OATP1B1*1b and *5 was reduced. In-vivo studies showed there was a gene-dose-dependent decrease in the area under the curve of ezetimibe in participants with the OATP1B1*1b protein (*1a/*1a, N=12, 112+/-66 ngxh/ml vs. *1a/*1b, N=8, 88+/-39 ngxh/ml vs. *1b/*1b, N=5, 55+/-18 ngxh/ml; Jonkheere-Terpstra, P=0.041) and a tendency for increased glucuronide exposure (704+/-296 vs. 878+/-369 vs. 1059+/-363 ngxh/ml; P=0.092). Fecal ezetimibe excretion was significantly decreased whereas renal glucuronide excretion was increased in carriers of *1b/*1b. Fecal excretion was also diminished in carriers of OATP1B1*5 and *15. The sterol-lowering effect of ezetimibe was not influenced by OATP1B1 polymorphisms. CONCLUSION Pharmacokinetics of ezetimibe is influenced by OATP1B1 polymorphisms in healthy participants after single dose administration.
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Saracino MR, Lampe JW. Phytochemical regulation of UDP-glucuronosyltransferases: implications for cancer prevention. Nutr Cancer 2008; 59:121-41. [PMID: 18001207 DOI: 10.1080/01635580701458178] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are Phase II biotransformation enzymes that metabolize endogenous and exogenous compounds, some of which have been associated with cancer risk. Many phytochemicals have been shown to induce UGTs in humans, rodents, and cell culture systems. Because UGTs maintain hormone balance and facilitate excretion of potentially carcinogenic compounds, regulation of their expression and activity may affect cancer risk. Phytochemicals regulate transcription factors such as the nuclear factor-erythroid 2-related factor 2 (Nrf2), aryl hydrocarbon, and pregnane X receptors as well as proteins in several signal transduction cascades that converge on Nrf2 to stimulate UGT expression. This induction can be modified by several factors, including phytochemical dose and bioavailability and interindividual variation in enzyme expression. In this review, we summarize the knowledge of dietary modulation of UGTs, particularly by phytochemicals, and discuss the potential mechanisms by which phytochemicals regulate UGT transcription.
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Singer JB, Shou Y, Giles F, Kantarjian HM, Hsu Y, Robeva AS, Rae P, Weitzman A, Meyer JM, Dugan M, Ottmann OG. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia 2007; 21:2311-5. [PMID: 17611564 DOI: 10.1038/sj.leu.2404827] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.
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Affiliation(s)
- J B Singer
- Clinical Pharmacogenetics, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
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