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González-Padilla D, Camara MD, Lauschke VM, Zhou Y. Population-scale variability of the human UDP-glycosyltransferase gene family. J Genet Genomics 2024; 51:1228-1236. [PMID: 38969258 DOI: 10.1016/j.jgg.2024.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/10/2024] [Accepted: 06/26/2024] [Indexed: 07/07/2024]
Abstract
Human UDP-glycosyltransferases (UGTs) are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed. We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across 7 major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family. Overall, 9666 exonic variants were observed, of which 98.9% were rare. To interpret the functional impact of UGT missense variants, we developed a gene family-specific variant effect predictor. This algorithm identified a total of 1208 deleterious variants, most of which were found in African and South Asian populations. Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites. Combined, our analyses provide a systematic overview of UGT variability, which can yield insights into interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.
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Affiliation(s)
| | - Mahamadou D Camara
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
| | - Yitian Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
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2
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Hulshof EC, Deenen MJ, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, Houwink EJF, Risselada A, Rongen GAPJM, van Schaik RHN, Touw DJ, van der Weide J, van Westrhenen R, Deneer VHM, Guchelaar HJ, Swen JJ. Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. Eur J Hum Genet 2023; 31:982-987. [PMID: 36443464 PMCID: PMC10474017 DOI: 10.1038/s41431-022-01243-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 10/05/2022] [Accepted: 11/10/2022] [Indexed: 11/29/2022] Open
Abstract
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.
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Affiliation(s)
- Emma C Hulshof
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marga Nijenhuis
- Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands.
| | - Bianca Soree
- Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands
| | | | | | - Elisa J F Houwink
- Department of Public Health and Primary Care (PHEG), Leiden University Medical Centre, Leiden, The Netherlands
- National eHealth Living Lab (NELL), Leiden, The Netherlands
| | - Arne Risselada
- Department of Clinical Pharmacy, Wilhelmina Hospital, Assen, The Netherlands
| | - Gerard A P J M Rongen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Jan van der Weide
- Department of Clinical Chemistry, St. Jansdal Hospital, Harderwijk, The Netherlands
| | - Roos van Westrhenen
- Department of Psychiatry, Parnassia Group, Amsterdam, The Netherlands
- Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
- Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK
| | - Vera H M Deneer
- Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jesse J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
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Itoh S, Okada H, Koyano K, Nakamura S, Konishi Y, Iwase T, Kusaka T. Fetal and neonatal bilirubin metabolism. Front Pediatr 2023; 10:1002408. [PMID: 36824297 PMCID: PMC9941200 DOI: 10.3389/fped.2022.1002408] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/30/2022] [Indexed: 02/10/2023] Open
Abstract
Human fetal and neonatal bilirubin metabolism is centered on 4Z,15Z-bilirubin IXα (BR) due to the extremely low BR conjugating capacity of the liver. BR is a unique, highly lipophilic substance with physiological and toxic effects in the cell membranes of organs and body tissues. The fetus excretes BR through the placenta to the maternal circulation. After birth, BR is thought to act as an antioxidant against the increase in reactive oxygen species caused by the rapid increase in oxygen concentration during the adaptation process from in amniotic fluid to in air. However, bilirubin encephalopathy is a toxic effect of bilirubin. Due to the lipophilic nature of BR, it must be bound to a carrier to be distributed to various parts of the body by hydrophilic blood. This carrier of BR is human serum albumin (HSA). In humans, BR can be excreted efficiently after undergoing photochemical reactions upon high affinity binding to HSA. HSA also plays an important role in the prevention of bilirubin encephalopathy. This review focuses on the developmental and physiological role of bilirubin metabolism during the fetal and neonatal periods.
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Affiliation(s)
- Susumu Itoh
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hitoshi Okada
- Division of Analytical Technology, Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa, Japan
| | - Kosuke Koyano
- Maternal Perinatal Center, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Shinji Nakamura
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yukihiko Konishi
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Takashi Iwase
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Takashi Kusaka
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Hanafusa H, Abe S, Ohyama S, Kyono Y, Kido T, Nakasone R, Ashina M, Tanimura K, Nozu K, Fujioka K. Influence of UGT1A1 Genetic Variants on Free Bilirubin Levels in Japanese Newborns: A Preliminary Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:13090. [PMID: 36293671 PMCID: PMC9603041 DOI: 10.3390/ijerph192013090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/03/2022] [Accepted: 10/09/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Free bilirubin (Bf) is a better marker than total serum bilirubin (TSB) for predicting bilirubin encephalopathy (BE). To date, two UGT1A1 genetic variants (rs4148323 and rs3064744) have been associated with neonatal hyperbilirubinemia; however, the direct association between UGT1A1 variants and Bf levels in newborns has not been elucidated. METHODS We retrospectively analyzed the clinical data of 484 infants, including the genotype data of two UGT1A1 genetic variants. We divided the infants into a high Bf group (Bf ≥ 1.0 µg/dL, n = 77) and a non-high Bf group (Bf < 1.0 µg/dL, n = 407), based on the peak Bf values. Logistic regression analysis was performed to calculate the odds ratios (ORs) for each variant allele compared to wild-type alleles. RESULTS The frequencies of the A allele in rs4148323 and (TA)7 allele in rs3064744 in the high Bf group (29% and 4%, respectively) were significantly different from those in the non-high Bf group (16% and 12%, respectively). In logistic regression analysis, for rs4148323, the A allele was significantly associated with an increased risk of hyper-free bilirubinemia over the G allele (adjusted OR: 1.80, 95% confidence interval [CI]: 1.19-2.72, p < 0.01). However, for rs3064744, the (TA)7 allele was significantly associated with a decreased risk of hyper-free bilirubinemia over the (TA)6 allele (adjusted OR: 0.42, 95% CI: 0.18-0.95, p = 0.04). CONCLUSIONS This study is the first to show that the A allele in rs4148323 is a risk factor and that the (TA)7 allele in rs3064744 is a protective factor for developing hyper-free bilirubinemia in Japanese newborns.
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Affiliation(s)
- Hiroaki Hanafusa
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Shinya Abe
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Shohei Ohyama
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yuki Kyono
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Takumi Kido
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Ruka Nakasone
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Mariko Ashina
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Kenji Tanimura
- Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Han K, Wannamaker P, Lu H, Zhu B, Wang M, Paff M, Spreen WR, Ford SL. Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men. Antimicrob Agents Chemother 2022; 66:e0205721. [PMID: 35129374 PMCID: PMC8923182 DOI: 10.1128/aac.02057-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/20/2022] [Indexed: 11/20/2022] Open
Abstract
Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 μg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 μg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).
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Affiliation(s)
- Kelong Han
- GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | - Paul Wannamaker
- ViiV Healthcare, Research Triangle Park, North Carolina, USA
| | - Hongzhou Lu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Biao Zhu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Meixia Wang
- State Drug Clinical Trial Institution, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Melanie Paff
- GlaxoSmithKline, Collegeville, Pennsylvania, USA
| | | | - Susan L. Ford
- GlaxoSmithKline, Research Triangle Park, North Carolina, USA
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Xu JX, Lin F, Chen ZK, Luo ZY, Zhan XF, Wu JR, Ma YB, Li JD, Yang LY. Co-inheritance of G6PD deficiency and 211 G to a variation of UGT1A1 in neonates with hyperbilirubinemia in eastern Guangdong. BMC Pediatr 2021; 21:564. [PMID: 34895177 PMCID: PMC8665559 DOI: 10.1186/s12887-021-03010-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 11/10/2021] [Indexed: 11/25/2022] Open
Abstract
Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world. Objective To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia. Method The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal bilirubin was collected and analyzed retrospectively. Results Seventy four cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubinin of the G6PD-deficient group of hyperbilirubinemia neonates was 334.43 ± 79.27 μmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30 ± 68.62 μmol/L). The most common genotypes of G6PD deficiency were c.1376G > T and c.1388G > A, and the peak bilirubin of neonates with these two variants were 312.60 ± 71.81 μmol/L and 367.88 ± 75.79 μmol/L, respectively. The bilirubin level of c.1388G > A was significantly higher than that of c.1376G > T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55 ± 84.51 μmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50 ± 63.21 μmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63 ± 57.52 μmol/L). Conclusion The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.
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Affiliation(s)
- Jia-Xin Xu
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Fen Lin
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Zi-Kai Chen
- School of Food Engineering and Biotechnology, Hanshan Normal University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Zhao-Yun Luo
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Xiao-Fen Zhan
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Jiao-Ren Wu
- Central Laboratory, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Yu-Bin Ma
- Department of Pediatrics, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Jian-Dong Li
- Department of Pediatrics, Chaozhou Central Hospital Affiliated to Southern Medical University, Chaozhou, 521021, Guangdong Province, People's Republic of China
| | - Li-Ye Yang
- Precision Medical Center, People's Hospital of Yangjiang Affiliated to Guangdong Medical University, No. 42 Dongshan Road, Yangjiang, 529500, Guangdong Province, People's Republic of China.
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The importance of the UGT1A1 variants in the development of osteopenia and osteoporosis in postmenopausal women. Sci Rep 2021; 11:17385. [PMID: 34462452 PMCID: PMC8405802 DOI: 10.1038/s41598-021-96429-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/03/2021] [Indexed: 11/08/2022] Open
Abstract
The UDP-glucuronosyltransferase 1A1 (UGT1A1) is involved in the process of estrogen conjugation and elimination. The aim of the study was to analyze whether the UGT1A1 genetic variants are associated with the development of osteopenia and osteoporosis in postmenopausal women. The analysis of the rs4148323 (UGT1A1*6) and rs3064744 (UGT1A1*28) variants in the UGT1A1 gene was conducted using real-time PCR. A significant correlation was observed between the genotypes of the rs3064744 (UGT1A1*28) sequence variant and body mass in women with osteoporosis. The analysis of the Z-score values revealed that women with osteoporosis and carrying the 6/6 variant had the lowest Z-score values as compared to women with the 6/7 and the 7/7 variants (− 1.966 ± 0.242 vs. − 1.577 ± 0.125 and − 1.839 ± 0.233). In addition, the odds ratio for the investigated genotypes (6/6, 6/7, 7/7) indicated an increased risk for osteopenia and osteoporosis in women with the 7/7 homozygous genotype. The analysis of the frequencies of the GG, GA and AA genotypes of the rs4148323 UGT1A1 gene showed no statistically significant differences between the groups. Our analysis revealed that the UGT1A1 rs3064744 variant may affect the risk of developing osteoporosis in postmenopausal Polish women. The UGT1A1 rs4148323 variant is not directly associated with the development of osteopenia and osteoporosis.
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Patel P, Xue Z, King KS, Parham L, Ford S, Lou Y, Bakshi KK, Sutton K, Margolis D, Hughes AR, Spreen WR. Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir. J Antimicrob Chemother 2021; 75:2240-2248. [PMID: 32361755 PMCID: PMC7366207 DOI: 10.1093/jac/dkaa147] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/28/2020] [Accepted: 03/18/2020] [Indexed: 12/31/2022] Open
Abstract
Background Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. Objectives To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). Methods Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). Results Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. Conclusions This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.
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Affiliation(s)
- Parul Patel
- ViiV Healthcare, Research Triangle Park, NC, USA
| | | | | | | | - Susan Ford
- GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Yu Lou
- GlaxoSmithKline, Research Triangle Park, NC, USA
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9
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Lei HP, Qin M, Cai LY, Wu H, Tang L, Liu JE, Deng CY, Liu YB, Zhu Q, Li HP, Hu W, Yang M, Zhu YZ, Zhong SL. UGT1A1 rs4148323 A Allele is Associated With Increased 2-Hydroxy Atorvastatin Formation and Higher Death Risk in Chinese Patients With Coronary Artery Disease. Front Pharmacol 2021; 12:586973. [PMID: 33762934 PMCID: PMC7982952 DOI: 10.3389/fphar.2021.586973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 01/21/2021] [Indexed: 12/17/2022] Open
Abstract
It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism (UGT1A1) showed an increase in 2-hydroxy ATV/ATV ratio (p = 1.69E−07, false discovery rate [FDR] = 8.66E−03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients (p = 1.08E−07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio [HR] 1.774; 95% confidence interval [CI], 1.031–3.052; p = 0.0198). In conclusion, our results suggested that the UGT1A1 rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.
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Affiliation(s)
- He-Ping Lei
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.,School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Min Qin
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Li-Yun Cai
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.,School of Pharmacy, Southern Medical University, Guangzhou, China
| | - Hong Wu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lan Tang
- School of Pharmacy, Southern Medical University, Guangzhou, China
| | - Ju-E Liu
- Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chun-Yu Deng
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China
| | - Yi-Bin Liu
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China
| | - Qian Zhu
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China
| | - Han-Ping Li
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China
| | - Wei Hu
- School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Min Yang
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Shi-Long Zhong
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China.,Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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10
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Zeng N, Erwin E, Wen W, Corsi DJ, Wen SW, Guo Y. Comparison of adverse perinatal outcomes between Asians and Caucasians: a population-based retrospective cohort study in Ontario. BMC Pregnancy Childbirth 2021; 21:9. [PMID: 33402112 PMCID: PMC7786932 DOI: 10.1186/s12884-020-03467-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Racial disparities in adverse perinatal outcomes have been studied in other countries, but little has been done for the Canadian population. In this study, we sought to examine the disparities in adverse perinatal outcomes between Asians and Caucasians in Ontario, Canada. METHODS We conducted a population-based retrospective cohort study that included all Asian and Caucasian women who attended a prenatal screening and resulted in a singleton birth in an Ontario hospital (April 1st, 2015-March 31st, 2017). Generalized estimating equation models were used to estimate the independent adjusted relative risks and adjusted risk difference of adverse perinatal outcomes for Asians compared with Caucasians. RESULTS Among 237,293 eligible women, 31% were Asian and 69% were Caucasian. Asians were at an increased risk of gestational diabetes mellitus, placental previa, early preterm birth (< 32 weeks), preterm birth, emergency cesarean section, 3rd and 4th degree perineal tears, low birth weight (< 2500 g, < 1500 g), small-for-gestational-age (<10th percentile, <3rd percentile), neonatal intensive care unit admission, and hyperbilirubinemia requiring treatment, but had lower risks of preeclampsia, macrosomia (birth weight > 4000 g), large-for-gestational-age neonates, 5-min Apgar score < 7, and arterial cord pH ≤7.1, as compared with Caucasians. No difference in risk of elective cesarean section was observed between Asians and Caucasians. CONCLUSION There are significant differences in several adverse perinatal outcomes between Asians and Caucasians. These differences should be taken into consideration for clinical practices due to the large Asian population in Canada.
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Affiliation(s)
- Na Zeng
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Erica Erwin
- OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Better Outcomes Registry & Network Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Wendy Wen
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Daniel J Corsi
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Better Outcomes Registry & Network Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Department of Obstetrics and Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Shi Wu Wen
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Obstetrics and Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
| | - Yanfang Guo
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.
- OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
- Better Outcomes Registry & Network Ontario, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
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11
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Carvalho Henriques B, Yang EH, Lapetina D, Carr MS, Yavorskyy V, Hague J, Aitchison KJ. How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing? Front Genet 2020; 11:491895. [PMID: 33363564 PMCID: PMC7753050 DOI: 10.3389/fgene.2020.491895] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/25/2020] [Indexed: 12/11/2022] Open
Abstract
Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug-drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.
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Affiliation(s)
| | - Esther H. Yang
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Diego Lapetina
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Michael S. Carr
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Vasyl Yavorskyy
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Joshua Hague
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Katherine J. Aitchison
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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12
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Hansen TWR, Wong RJ, Stevenson DK. Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn. Physiol Rev 2020; 100:1291-1346. [PMID: 32401177 DOI: 10.1152/physrev.00004.2019] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.
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Affiliation(s)
- Thor W R Hansen
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Ronald J Wong
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - David K Stevenson
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
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13
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de Man FM, Goey AKL, van Schaik RHN, Mathijssen RHJ, Bins S. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet 2019. [PMID: 29520731 PMCID: PMC6132501 DOI: 10.1007/s40262-018-0644-7] [Citation(s) in RCA: 259] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.
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Affiliation(s)
- Femke M de Man
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands
| | - Andrew K L Goey
- Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands.
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14
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Mossé YP, Fox E, Teachey DT, Reid JM, Safgren SL, Carol H, Lock RB, Houghton PJ, Smith MA, Hall D, Barkauskas DA, Krailo M, Voss SD, Berg SL, Blaney SM, Weigel BJ. A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921). Clin Cancer Res 2019; 25:3229-3238. [PMID: 30777875 PMCID: PMC6897379 DOI: 10.1158/1078-0432.ccr-18-2675] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/20/2018] [Accepted: 02/14/2019] [Indexed: 02/01/2023]
Abstract
PURPOSE Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). PATIENTS AND METHODS Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. RESULTS A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. CONCLUSIONS Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
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Affiliation(s)
- Yael P Mossé
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Pennsylvania.
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Elizabeth Fox
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Pennsylvania
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - David T Teachey
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Pennsylvania
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | - Hernan Carol
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia
| | - Richard B Lock
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia
| | - Peter J Houghton
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas
| | | | - David Hall
- Children's Oncology Group, Monrovia, California
| | | | - Mark Krailo
- Department of Preventive Medicine, University of Southern California, Los Angeles, California
| | - Stephan D Voss
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Stacey L Berg
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Susan M Blaney
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Brenda J Weigel
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
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15
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Phototherapy for neonatal hyperbilirubinemia and childhood eczema, rhinitis and wheeze. Pediatr Neonatol 2019; 60:28-34. [PMID: 29678409 PMCID: PMC6129174 DOI: 10.1016/j.pedneo.2018.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 08/24/2017] [Accepted: 03/20/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The pathogenesis of allergic diseases in childhood may be attributed to influences of early environmental stimuli on fetal and neonatal immune regulation. Neonatal hyperbilirubinemia is common in the Asian population and up to 20% of infants require phototherapy. We examined the hypothesis that phototherapy for neonatal hyperbilirubinemia modulates the infant's risk of developing eczema, rhinitis and wheeze in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort. METHOD Interviewers collected information on demographics, lifestyle, birth data and allergic outcomes. Atopic sensitization was assessed through skin prick testing (SPT) to aeroallergens and food allergens. RESULTS A total of 135 (12.8%) children underwent phototherapy for neonatal hyperbilirubinemia. Infants who underwent phototherapy were of a significantly lower mean (SD) gestational age [37.5 (2.5) weeks] compared to those who did not [38.5 (1.2) weeks p < 0.01]. A higher proportion of infants born by Caesarean section underwent phototherapy compared to those who were born vaginally (17.5% vs 10.7%, p < 0.01). There were no differences in prevalence of allergen sensitization, eczema, rhinitis and early onset wheeze with use of nebulizer in the first 5 years of life between subjects that underwent phototherapy and those that did not. There were also no associations between mean bilirubin peak levels within the phototherapy group with development of eczema, rhinitis and early onset wheeze in the first 5 years of life. CONCLUSION We found no evidence for a link between phototherapy for neonatal hyperbilirubinemia and childhood allergic outcomes in this prospective mother-offspring cohort. TRIAL REGISTRATION NCT01174875 Registered 1 July 2010, retrospectively registered.
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16
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DuBois SG, Mosse YP, Fox E, Kudgus RA, Reid JM, McGovern R, Groshen S, Bagatell R, Maris JM, Twist CJ, Goldsmith K, Granger MM, Weiss B, Park JR, Macy ME, Cohn SL, Yanik G, Wagner LM, Hawkins R, Courtier J, Lai H, Goodarzian F, Shimada H, Boucher N, Czarnecki S, Luo C, Tsao-Wei D, Matthay KK, Marachelian A. Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 2018; 24:6142-6149. [PMID: 30093449 PMCID: PMC6295246 DOI: 10.1158/1078-0432.ccr-18-1381] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 06/30/2018] [Accepted: 08/06/2018] [Indexed: 01/26/2023]
Abstract
PURPOSE In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. PATIENTS AND METHODS We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. RESULTS Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. CONCLUSIONS This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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Affiliation(s)
- Steven G DuBois
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts.
| | - Yael P Mosse
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth Fox
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Rachel A Kudgus
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Joel M Reid
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Renee McGovern
- Department of Pharmacology, Mayo Clinic, Rochester, Minnesota
| | - Susan Groshen
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Rochelle Bagatell
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - John M Maris
- Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Clare J Twist
- Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York
| | - Kelly Goldsmith
- Department of Pediatrics, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia
| | - M Meaghan Granger
- Department of Pediatrics, Cook Children's Hospital, Fort Worth, Texas
| | - Brian Weiss
- Department of Pediatrics, Cincinnati Children's Medical Center, Cincinnati, Ohio
| | - Julie R Park
- Department of Pediatrics, Seattle Children's Hospital and University of Washington, Seattle, Washington
| | - Margaret E Macy
- Department of Pediatrics, Children's Hospital Colorado and University of Colorado, Aurora, Colorado
| | - Susan L Cohn
- Department of Pediatrics, Comer Children's Hospital and University of Chicago, Chicago, Illinois
| | - Greg Yanik
- Department of Pediatrics, CS Mott Children's Hospital and University of Michigan, Ann Arbor, Michigan
| | - Lars M Wagner
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Randall Hawkins
- Department of Radiology, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Jesse Courtier
- Department of Radiology, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Hollie Lai
- Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Fariba Goodarzian
- Department of Radiology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Hiroyuki Shimada
- Department of Pathology, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Najee Boucher
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Scarlett Czarnecki
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Chunqiao Luo
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Denice Tsao-Wei
- Department of Preventive Medicine, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
| | - Katherine K Matthay
- Department of Pediatrics, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, California
| | - Araz Marachelian
- Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California
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17
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Shirasu H, Todaka A, Omae K, Fujii H, Mizuno N, Ozaka M, Ueno H, Kobayashi S, Uesugi K, Kobayashi N, Hayashi H, Sudo K, Okano N, Horita Y, Kamei K, Yukisawa S, Kobayashi M, Fukutomi A. Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX. Cancer Sci 2018; 110:707-716. [PMID: 30447099 PMCID: PMC6361560 DOI: 10.1111/cas.13883] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/13/2018] [Accepted: 11/14/2018] [Indexed: 12/18/2022] Open
Abstract
Studies have indicated an association between UDP‐glucuronosyltransferase‐1A1 (UGT1A1) genetic polymorphisms and irinotecan‐induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 200 mg/m2, bolus 5‐fluorouracil [5‐FU] 400 mg/m2, and continuous 5‐FU 2400 mg/m2) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 200 mg/m2, and continuous 5‐FU 2400 mg/m2) as first‐line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.
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Affiliation(s)
- Hiromichi Shirasu
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akiko Todaka
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiro Omae
- Clinical Research Promotion Unit, Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hirofumi Fujii
- Department of Clinical Oncology, Jichi Medical University Hospital, Tochigi, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Masato Ozaka
- Department of Gastroenterology, The Cancer Institute Hospital of the Japanese Foundation For Cancer Research, Tokyo, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Kazuhiro Uesugi
- Departments of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | | | - Hideyuki Hayashi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kentaro Sudo
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan
| | - Yosuke Horita
- Department of Chemotherapy and Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Keiko Kamei
- Departments of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Seigo Yukisawa
- Departments of Medical Oncology, Tochigi Cancer Center, Tochigi, Japan
| | - Marina Kobayashi
- Clinical Trial Promotion Section, Shizuoka Industrial Foundation Pharma Valley Center, Shizuoka, Japan
| | - Akira Fukutomi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
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18
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Abstract
Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.
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Affiliation(s)
| | | | - André B P van Kuilenburg
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, F0-220, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Goey AK, Sissung TM, Peer CJ, Figg WD. Pharmacogenomics and histone deacetylase inhibitors. Pharmacogenomics 2016; 17:1807-1815. [PMID: 27767376 DOI: 10.2217/pgs-2016-0113] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.
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Affiliation(s)
- Andrew Kl Goey
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tristan M Sissung
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cody J Peer
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - William D Figg
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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20
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Fukuda M, Suetsugu T, Shimada M, Kitazaki T, Hashiguchi K, Kishimoto J, Harada T, Seto T, Ebi N, Takayama K, Sugio K, Semba H, Nakanishi Y, Ichinose Y. Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: Results of Lung Oncology Group in Kyusyu (LOGIK1004B). Thorac Cancer 2016; 7:467-72. [PMID: 27385990 PMCID: PMC4930967 DOI: 10.1111/1759-7714.12360] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 04/05/2016] [Indexed: 11/27/2022] Open
Abstract
Background Uridine 5′‐diphospho‐glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m2; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0–2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/−, *6/−, −/− observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients.
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Affiliation(s)
- Minoru Fukuda
- Clinical Oncology Center, Nagasaki University Hospital Nagasaki Japan
| | - Takayuki Suetsugu
- Department of Respiratory Medicine Sendai Medical Association Hospital Kagoshima Japan
| | - Midori Shimada
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Takeshi Kitazaki
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Kohji Hashiguchi
- Division of Respiratory Diseases, Department of Internal Medicine Japanese Red Cross Nagasaki Genbaku Hospital Nagasaki Japan
| | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine Kyusyu University Fukuoka Japan
| | - Taishi Harada
- Graduate School of Medical Sciences, Research Institute for Disease of the Chest Kyusyu University Fukuoka Japan
| | - Takashi Seto
- Department of Thoracic Oncology National Kyusyu Cancer Center Fukuoka Japan
| | - Noriyuki Ebi
- Department of Respiratory Oncology Medicine Iizuka Hospital Fukuoka Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine Kyoto Prefectual University of Medicine Kyoto Japan
| | - Kenji Sugio
- Department of Thoracic and Breast Surgery Oita University Faculty of Medicine Oita Japan
| | - Hiroshi Semba
- Department of Respiratory Medicine Kumamoto Regional Medical Center Kumamoto Japan
| | - Yoichi Nakanishi
- Graduate School of Medical Sciences, Research Institute for Disease of the Chest Kyusyu University Fukuoka Japan
| | - Yukito Ichinose
- Clinical Research Institute, National Kyusyu Cancer Center Fukuoka Japan
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21
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DuBois SG, Marachelian A, Fox E, Kudgus RA, Reid JM, Groshen S, Malvar J, Bagatell R, Wagner L, Maris JM, Hawkins R, Courtier J, Lai H, Goodarzian F, Shimada H, Czarnecki S, Tsao-Wei D, Matthay KK, Mosse YP. Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial. J Clin Oncol 2016; 34:1368-75. [PMID: 26884555 DOI: 10.1200/jco.2015.65.4889] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population. PATIENTS AND METHODS Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained. RESULTS Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib. CONCLUSION Alisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.
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Affiliation(s)
- Steven G DuBois
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY.
| | - Araz Marachelian
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Elizabeth Fox
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Rachel A Kudgus
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Joel M Reid
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Susan Groshen
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Jemily Malvar
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Rochelle Bagatell
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Lars Wagner
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - John M Maris
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Randall Hawkins
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Jesse Courtier
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Hollie Lai
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Fariba Goodarzian
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Hiroyuki Shimada
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Scarlett Czarnecki
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Denice Tsao-Wei
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Katherine K Matthay
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
| | - Yael P Mosse
- Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY
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22
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Abstract
Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy.
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Affiliation(s)
- Andrew K L Goey
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - William D Figg
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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23
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Yu Z, Zhu K, Wang L, Liu Y, Sun J. Association of Neonatal Hyperbilirubinemia with UGT1A1 Gene Polymorphisms: A Meta-Analysis. Med Sci Monit 2015; 21:3104-14. [PMID: 26467199 PMCID: PMC4612146 DOI: 10.12659/msm.894043] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Background The results of studies on association between the polymorphisms in the coding region and the promoter of uridine diphosphateglucuronosyl transferase 1A1 (UGT1A1) and neonatal hyperbilirubinemia are controversial. This study aimed to determine whether the UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter were significant risk factors associated with neonatal hyperbilirubinemia. Material/Methods The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. Results A total of 32 eligible studies and 6520 participants were identified. Among them, 24 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, and a significant difference was found for the comparison of AA vs. AG+GG (OR=3.47, 95% CI=2.29–5.28, P<0.0001). We included 19 studies on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphism, which also found a statistically significant difference between 7/7 and 6/7 + 6/6 (OR=2.24, 95% CI=1.29–3.92, P=0.004). Conclusions This meta-analysis demonstrated that UGT1A1 polymorphisms (Gly71Arg and TATA promoter) significantly increase the risk of neonatal hyperbilirubinemia.
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Affiliation(s)
- Zibi Yu
- Songjiang Branch of The Affiliated Shuguang Hospital of Shanghai University of TCM, Shanghai, China (mainland)
| | - Kaichang Zhu
- Department of Urology, Fengxian District Central Hospital, Shanghai, China (mainland)
| | - Li Wang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Dalian City, Dalian, Liaoning, China (mainland)
| | - Ying Liu
- Department of Neonatology, Obstetrics and Gynecology Hospital of Dalian City, Dalian, Liaoning, China (mainland)
| | - Jianmei Sun
- Department of Neonatology, Affiliated Tongji Hospital of Tongji University, Shanghai, China (mainland)
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Han JH, Kim S, Jang H, Kim SW, Lee MG, Koh H, Lee JH. Identification of a novel p.Q1772X ANK1 mutation in a Korean family with hereditary spherocytosis. PLoS One 2015; 10:e0131251. [PMID: 26107955 PMCID: PMC4480973 DOI: 10.1371/journal.pone.0131251] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 05/31/2015] [Indexed: 12/13/2022] Open
Abstract
Hereditary spherocytosis (HS), a common form of inherited hemolytic anemia, is a heterogeneous group of disorders with regard to clinical severity, protein defects, and mode of inheritance. Causal mutations in at least five genes have been reported so far. Because multiple genes have been associated with HS, clinical genetic testing that relies on direct sequencing will be a challenge. In this study, we used whole exome sequencing to identify a novel nonsense mutation in ANK1 (p.Q1772X, NM_020476) that resulted in a truncated protein in a Korean patient with HS. Sanger sequencing confirmed the two affected individuals in the patient's family were heterozygous for the mutation. This is the first report of a Korean family that carries an ANK1 mutation responsible for HS. Our results demonstrate that next generation sequencing is a powerful approach for rapidly determining the genetic etiology of HS.
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Affiliation(s)
| | - Seung Kim
- Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hoon Jang
- Department of Chemistry, Yonsei University, Seoul, Korea
| | - So Won Kim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea
- Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, Korea
| | - Min Goo Lee
- Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hong Koh
- Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea
- * E-mail: (JHL); (HK)
| | - Ji Hyun Lee
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea
- * E-mail: (JHL); (HK)
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Sato H, Uchida T, Toyota K, Nakamura T, Tamiya G, Kanno M, Hashimoto T, Watanabe M, Aoki K, Hayasaka K. Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms. J Hum Genet 2014; 60:35-40. [PMID: 25391605 DOI: 10.1038/jhg.2014.98] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 09/12/2014] [Accepted: 10/16/2014] [Indexed: 01/08/2023]
Abstract
Neonates have physiologically increased bilirubin production and immature bilirubin metabolism, and present hyperbilirubinemia in association with genetic and or epigenetic factors. We previously reported that maximal body weight loss (inadequate feeding) is an independent risk factor for the development of hyperbilirubinemia in breast-fed Japanese neonates, and the UGT1A1 211G>A genotype becomes a risk factor under conditions of inadequate feeding. We extended the study to the association of other genetic factors, the UGT1A1 (TA)7 and solute-carrier organic anion transporters (SLCOs) polymorphisms with neonatal hyperbilirubinemia. We enrolled 401 full-term Japanese infants who were exclusively breastfeeding and classified them into two groups based on the degree of maximal body weight loss. We analyzed the clinical characteristics and UGT1A1 and SLCOs genotypes. Statistical analysis revealed that maximal body weight loss is the only independent risk factor for the development of neonatal hyperbilirubinemia. UGT1A1, SLCO1B1 and SLCO1B3 polymorphisms become risk factors in neonates showing 10% or greater body weight loss during the neonatal period. Inadequate feeding may increase the bilirubin burden and cause apparent hyperbilirubinemia in neonates, who have a polymorphic change in the genes involved in the transport and/or metabolism of bilirubin.
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Affiliation(s)
- Hiroko Sato
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Toshihiko Uchida
- Department of Pediatrics, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Kentaro Toyota
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Tomohiro Nakamura
- Statistical genetics and genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Gen Tamiya
- Statistical genetics and genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Miyako Kanno
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Taeko Hashimoto
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Masashi Watanabe
- Department of Pediatrics, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Kuraaki Aoki
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
| | - Kiyoshi Hayasaka
- Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
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Zahedpasha Y, Ahmadpour M, Niaki HA, Alaee E. Relation between Neonatal Icter and Gilbert Syndrome in Gloucose-6-Phosphate Dehydrogenase Deficient Subjects. J Clin Diagn Res 2014; 8:63-5. [PMID: 24783083 DOI: 10.7860/jcdr/2014/6674.4108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Accepted: 11/28/2013] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND AIM The pathogenesis of neonatal hyperbilirubinemia hasn't been completely defined in Gloucose-6-Phosphate Dehydrogenase (G6PD) deficient newborns. The aim of this study was to detect the relationship between Gilbert's syndrome and hyperbilirubinemia in Gloucose-6-Phosphate Dehydrogenase (G6PD) deficient neonates. MATERIALS AND METHODS This case-control study was conducted in Amirkola pediatrics teaching hospital, Babol, Iran. A total number of one hundred four infants were included in the study (51 infants with neonatal jaundice and Gloucose-6-Phosphate Dehydrogenase (G6PD) deficiency admitted to phototherapy or transfusion were selected as the case group and 53 infants with Gloucose-6-Phosphate Dehydrogenase (G6PD) deficiency admitted for other reasons than jaundice were selected as the control group). Exclusion criteria were ABO or Rh incompatibility or other reasons that made Coombs test positive, sepsis, hepatosplenomegaly, metabolic diseases, medical treatment and phototherapy. The promoter and coding regions of Uridine diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) of genomic DNA were amplified by polymerase chain reaction (PCR) isolated from leukocytes. We used chi-square test and t-test to compare cases and controls. RESULTS Distribution of Gilbert genome was not significantly different between the two groups; among cases, 33.3% were homozygote, 35.3% heterozygote, and 31.4% normal. Among controls, 22.6% were homozygote, 34% heterozygote, and 43.4% normal (p-value=xxx). Hyperbilirubinemia family history didn't differ significantly between these two groups. CONCLUSIONS We showed that in Gloucose-6-Phosphate Dehydrogenase (G6PD) deficient neonates, there was no significant association between Gilbert's syndrome (promoter polymorphism) and hyperbilirubinemia.
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Affiliation(s)
- Yadollah Zahedpasha
- Faculty, Paediatric Research Center, Amirkola Children Hospital, Department of Paediatric, School of Medicine, Babol University of Medical Sciences , Babol, Iran
| | - Mousa Ahmadpour
- Faculty, Paediatric Research Center, Amirkola Pediatrics Hospital, Department of Paediatric, School of Medicine, Babol University of Medical Sciences Babol, Iran
| | - Haleh Akhavan Niaki
- Faculty, Cellular and Molecular Biology Research Center (CMBRC) of Babol University of Medical Sciences , Iran
| | - Ehsan Alaee
- Neonatologist, Neonatal and Children's Health Research Center, Golestan University of Medical Sciences , Gorgan, Iran
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Higher serum direct bilirubin levels were associated with a lower risk of incident chronic kidney disease in middle aged Korean men. PLoS One 2014; 9:e75178. [PMID: 24586219 PMCID: PMC3930500 DOI: 10.1371/journal.pone.0075178] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 08/12/2013] [Indexed: 11/23/2022] Open
Abstract
Background The association between serum bilirubin levels and incident chronic kidney disease (CKD) in the general population is unknown. We aimed to examine the association between serum bilirubin concentration (total, direct, and indirect) and the risk of incident CKD. Methods and Findings Longitudinal cohort study of 12,823 Korean male workers 30 to 59 years old without CKD or proteinuria at baseline participating in medical health checkup program in a large worksite. Study participants were followed for incident CKD from 2002 through 2011. Estimated glomerular filtration rate (eGFR) was estimated by using the CKD-EPI equation. CKD was defined as eGFR <60 mL/min per 1.73 m2. Parametric Cox models and pooled logistic regression models were used to estimate adjusted hazard ratios for incident CKD. We observed 238 incident cases of CKD during 70,515.8 person-years of follow-up. In age-adjusted models, the hazard ratios for CKD comparing quartiles 2–4 vs. quartile 1 of serum direct bilirubin were 0.93 (95% CI 0.67–1.28), 0.88 (0.60–1.27) and 0.60 (0.42–0.88), respectively. In multivariable models, the adjusted hazard ratio for CKD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.60 (95% CI 0.41–0.87; P trend = 0.01). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of CKD. Conclusions Higher serum direct bilirubin levels were significantly associated with a lower risk of developing CKD, even adjusting for a variety of cardiometabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for CKD risk.
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UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine. Invest New Drugs 2013; 31:1559-67. [PMID: 24114122 DOI: 10.1007/s10637-013-0034-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 09/24/2013] [Indexed: 12/16/2022]
Abstract
PURPOSE We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). EXPERIMENTAL DESIGN Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m(2)) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD. RESULTS 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/- 278 and 350 +/- 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/- 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups. CONCLUSIONS UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).
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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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Hyperbilirubinemia in healthy newborns born to immigrant mothers from southeastern Asia compared to Italian ones. Indian J Pediatr 2013; 80:455-9. [PMID: 23299440 DOI: 10.1007/s12098-012-0943-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 11/30/2012] [Indexed: 10/27/2022]
Abstract
OBJECTIVE To compare the characteristics of jaundice and hyperbilirubinemia in the newborn population of both immigrant and Italian mothers. METHODS The authors studied a group of 1,680 infants born at "A. Gemelli" hospital during 1 y. All were with appropriate weight for gestational age, weighting more than 2,500 g, born to low-risk pregnancy. Maternal ethnicity, clinically evident jaundice (that is total serum bilirubin (TSB) > 7 mg/dL), hyperbilirubinemia (TSB > 12 mg/dL), the duration of hospital stay and their need of phototherapy were evaluated. RESULTS In infants born to Asian mothers, hyperbilirubinemia was significantly more frequent (48.8 % vs. 26.5 %, p = 0.003) and they reached mean TSB peak significantly later (86.5 ± 38.5 vs. 74.5 ± 20.6 h, P = 0.0001) compared with Italian infants. The average length of hospitalization of infants of Asian and Latin American mothers is significantly longer compared to Italian newborns (4.5 ± 1.9 vs. 3.6 ± 1.1, p <0.0001 and 4.2 ± 1.6 vs. 3.6 ± 1.1, p = 0.0004). With regard to the use of phototherapy, and to its duration, there are no significant differences between the populations studied. CONCLUSIONS Having studied all infants at low risk, the greater length of hospitalization is due to later peak and the higher frequency of jaundice in newborns of immigrant mother, especially in Asia. Therefore, as it happens to the Italian newborns, it would be desirable to build forecasting nomograms in these populations, to reduce the length of hospitalization and facilitate protected discharge.
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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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Kaga A, Ohkubo Y, Watanabe Y, Saito S, Matsuki T, Usuda H, Kanda S, Suzuki Y, Tanabu M, Kure S. Development of icterus gravis in a preterm infant with G71R UGT1A1 polymorphism. BMC Res Notes 2013; 6:51. [PMID: 23388413 PMCID: PMC3639837 DOI: 10.1186/1756-0500-6-51] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 01/04/2013] [Indexed: 11/12/2022] Open
Abstract
Background Uridine diphosphate-glucuronosyltransferase (UGT) gene family is involved in the detoxification of biomaterials and drugs in the liver. Among the UGT gene family members, only UGT1A1 is involved in bilirubin conjugation. As a result, deficient UGT1A1 activity causes jaundice. One disease that is characterized by reduced UGT1A1 activity is Gilbert’s syndrome. Two prevalent UGT1A1 polymorphisms responsible for Gilbert’s syndrome have been identified: G71R in exon 1 and A(TA)7TAA in the TATA box of the promoter region. Recently, the G71R polymorphism has been associated with breastfeeding jaundice and neonatal hyperbilirubinemia in term infants. However, its association with jaundice in very low birth weight infants (VLBWIs) has never been reported. Case presentation The patient was a female born at 28 weeks, 4 days gestation with a birth weight of 1172 g. On day 21, intense yellowing of the skin and eyes was noted, and the patient’s total bilirubin level was 23.7 mg/dL (her direct bilirubin level was 2.1 mg/dL). Therefore, an exchange transfusion was conducted. She had neither blood type incompatibility nor a family history of constitutional jaundice. Metabolic screens for amino and organic acids were negative. No elevation of any of the examined antibody titers was noted, and no evidence of an inflammatory reaction was observed. In addition, no hematological abnormalities were detected. The direct/indirect Coombs test, irregular antibody test and red blood cell antibody dissociation test were all negative, and her thyroid function was normal. We performed sequence analysis of the UGT1A1 gene after the patient’s parents provided written informed consent. Exon 1 of the UGT1 gene on chromosome 2 was analyzed by direct sequencing. A heterozygous substitution from G to A (211G→A: G71R) in base 211 was noted. Conclusion We speculated that this preterm infant with carrying the G71R polymorphism reduced UGT1A1 activity and developed severe jaundice that was likely triggered by factors such as breast feeding and medications. The polymorphism appears at some frequency among VLBWIs, which would necessitate adequate care of severe jaundice even after the acute phase.
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Affiliation(s)
- Akimune Kaga
- Department of Pediatrics, Hachinohe City Hospital, 1 Bisyamontaira, Hachinohe, Aomori, 031-8555, Japan.
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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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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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Zhang X, Meng X, Wang Y, Yan W, Yang J. Comprehensive analysis of UGT1A1 genetic polymorphisms in Chinese Tibetan and Han populations. Biochem Genet 2012; 50:967-77. [PMID: 22983686 DOI: 10.1007/s10528-012-9536-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Accepted: 05/10/2012] [Indexed: 10/27/2022]
Abstract
The study of polymorphism of the UGT1A1 gene has not been reported in the Chinese Tibetan population, and there are no comparisons of genetic polymorphism in the gene between Chinese Han and Tibetan populations. In this study, we directly sequenced the functional regions of the UGT1A1 gene in 200 unrelated healthy Chinese volunteers, detecting 20 variations (including five novel ones). The distributions of allele and genotype frequencies differ between the two groups. UGT1A1*6 is the major reduced functional variant in the populations, and the *27 allele was detected only in the Han group. Differences in the frequencies of the UGT1A1*6/*63 genotype between the Tibetan and Han populations were statistically significant (P = 0.009). Our genetic data might provide fundamental information for the advance of personalized medicine and will facilitate genotype-phenotype studies in larger populations.
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Affiliation(s)
- Xiaoqing Zhang
- National Engineering Research Center for Miniaturized Detection System, College of Life Sciences, Northwest University, 386# Taibai North Road 229, Xi'an, 710069, Shaanxi, China
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Abstract
Background There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4–14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T. Methods This was a case–control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCR-RFLP analysis and gene sequencing. Results G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean ± 1SD; 0.3 ± 0.2 U/gHb vs. 14.0 ± 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean ± 1SD; 16.8 ± 5.4 mg/dl vs. 13.8 ± 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean ± 1SD 2.9 ± 1.6 vs. 4.3 ± 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups. Conclusions We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.
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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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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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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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41
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Kalotychou V, Karakosta M, Tzanetea R, Stamoulakatou A, Konstantopoulos K, Rombos Y. Contribution of G71R mutation to Gilbert’s syndrome phenotype in a Greek patient: A case report. World J Gastrointest Pharmacol Ther 2011; 2:42-5. [PMID: 22046580 PMCID: PMC3205121 DOI: 10.4292/wjgpt.v2.i5.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Revised: 09/20/2011] [Accepted: 09/28/2011] [Indexed: 02/06/2023] Open
Abstract
Gilbert’s syndrome is characterized by a benign indirect hyperbilirubinemia. It has often been underestimated and undiagnosed because of its mild symptoms; although it is not as rare as was once believed when its frequency was estimated using data originating from biochemical tests. Based on molecular techniques, the occurrence of Gilbert’s syndrome has changed, increasing to 10% in the Caucasian population. This molecular defect was described, by Bosma et al, in 1995, and affects the promoter region of the UGT 1A1 gene. In this case report, our aim is to present a new combination of two molecular defects in a Greek patient with Gilbert’s syndrome. A 13-year-old Greek girl was examined for Gilbert’s syndrome using molecular techniques, and an uncommon genotype was revealed comprising the rare mutation G71R in trans with A(TA)7TAA motif. The G71R mutation according to the literature, as well as our epidemiological data, is rare in Caucasians, while it is common in Asian populations. This is the first case study in the Greek population to report a new genotype for Gilbert’s syndrome manifestation in the Caucasian population.
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Affiliation(s)
- Vassiliki Kalotychou
- Vassiliki Kalotychou, Maria Karakosta, Revekka Tzanetea, Kostas Konstantopoulos, Yannis Rombos, 1st Department of Internal Medicine, University of Athens, Athens, 11527, Greece
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Soh TIP, Yong WP, Innocenti F. Recent progress and clinical importance on pharmacogenetics in cancer therapy. Clin Chem Lab Med 2011; 49:1621-32. [PMID: 21950596 PMCID: PMC3858908 DOI: 10.1515/cclm.2011.715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Recent advances have provided unprecedented opportunities to identify prognostic and predictive markers of efficacy of cancer therapy. Genetic markers can be used to exclude patients who will not benefit from therapy, exclude patients at high risk of severe toxicity and adjust dosing. Genomic approaches for marker discovery now include genome-wide association studies and tumor DNA sequencing. The challenge is now to select markers for which there is enough evidence to transition them to the clinic. The hurdles include the inherent low frequency of many of these markers, the lengthy validation process through trials, as well as legislative and economic hurdles. Attempts to answer questions about certain markers more quickly have led to an increased popularity of trials with enrichment design, especially in light of the dramatic phase I results seen in recent months. Personalized medicine in oncology is a step closer to reality.
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Affiliation(s)
- Thomas I Peng Soh
- Department of Hematology-Oncology, National University Cancer Institute SINGAPORE
| | - Wei Peng Yong
- Department of Hematology-Oncology, National University Cancer Institute SINGAPORE
| | - Federico Innocenti
- University of North Carolina at Chapel Hill, Institute for Pharmacogenomics and Individualized Therapy
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43
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Soh TIP, Yong WP. Germline Genetic Testing to Predict Drug Response and Toxicity in Oncology— Reality or Fiction? ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2011. [DOI: 10.47102/annals-acadmedsg.v40n8p350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In addition to 6-mercaptopurine, 5-fluorouracil and irinotecan, the United States Food and Drug Administration (US FDA) has recently recommended label change for tamoxifen, to include pharmacogenetic information on treatment outcome. With the increasing availability of pharmacogenetic testing, on germline as well as somatic mutations, oncologists are now able to identify individuals at risk of severe treatment toxicity or poor treatment response. However, there are still knowledge gaps to fill before rationalised therapy based on pharmacogenetics can be fully integrated into clinical practice. This review provides an overview on the application of pharmacogenetic testing for germ line mutations in oncology to predict response and toxicity.
Key words: Pharmacogenetics, Response, Toxicity
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Kisaki O, Kato S, Shinohara K, Hiura H, Samori T, Sato H. High-throughput single-base mismatch detection for genotyping of UDP-glucuronosyltransferase (UGT1A1) with probe capture assay coupled with modified allele-specific primer extension reaction (MASPER). J Clin Lab Anal 2010; 24:85-91. [PMID: 20333765 DOI: 10.1002/jcla.20359] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
We have developed a new method based on specific primer extension reactions coupled with plate hybridization for high-throughput genotyping of single-base mutations. To improve the switching characteristics of the primer extension reaction, we introduced an artificial mismatch two bases upstream of the 3'-terminal base in the detection primers. A set of primers that correspond to wild-type and mutant DNA segments can be used to accurately analyze single-base mutations. The termini of these primers are at the mutation positions. The primer extension products produced by polymerase chain reaction (PCR) were captured by an oligonucleotide probe immobilized on the surface of microtiter wells and were detected by a colorimetric assay using the streptavidin-conjugated horseradish peroxidase. We used the new method to genotype 96 individuals for 211G>A (G71R) and 119 for 1456T>G (Y486D) in the UDP-glucuronosyltransferase1A1 gene; the results were completely concordant with those found by direct sequencing. The proposed method includes ordinary PCR and a microplate assay format, and may be used in routine laboratory tests.
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Affiliation(s)
- Osamu Kisaki
- Japan Clinical Laboratories, Kumiyama, Kuze-gun, Kyoto, Japan
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45
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Yong WP, Innocenti F, Ratain MJ. The role of pharmacogenetics in cancer therapeutics. Br J Clin Pharmacol 2006; 62:35-46. [PMID: 16842377 PMCID: PMC1885075 DOI: 10.1111/j.1365-2125.2006.02591.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2005] [Accepted: 10/23/2005] [Indexed: 01/06/2023] Open
Abstract
The variability in treatment responses and narrow therapeutic index of anticancer drugs are some of the key challenges oncologists face. The knowledge of pharmacogenetics can potentially aid in the discovery, development and ultimately individualization of anticancer drugs. The identification of genetic variations that predict for drug response is the first step towards the translation of pharmacogenetics into clinical practice. This review provides an update on the results of studies assessing the effects of germline polymorphisms and somatic mutations on therapeutic outcomes and highlights the potential applications and future challenges in pharmacogenetic research pertaining to cancer therapeutics.
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Affiliation(s)
- Wei Peng Yong
- University of Chicago, Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine and Cancer Research Center, Chicago, IL 60637, USA
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46
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Ando M, Hasegawa Y, Ando Y. Pharmacogenetics of irinotecan: a promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan. Invest New Drugs 2006; 23:539-45. [PMID: 16267624 DOI: 10.1007/s10637-005-4022-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
This review focuses on a pharmacogenetic association between genetic polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan. Although many studies used pharmacokinetic parameters as surrogate measures for predicting clinical outcomes of irinotecan chemotherapy, they have not produced consistent evidence. On the other hand, genotyping results of UGT1A1 gene appear to predict severe adverse reactions more straightforward than the pharmacokinetic parameters or the phenotypes of the enzymatic activity. A case-control study of Japanese cancer patients revealed that those with the variant UGT1A1 alleles were at significantly higher risk of severe adverse reactions to irinotecan, suggesting that the genotyping strategy would be clinically useful. Nevertheless, clinical importance of the pharmacogenetic testing should differ for different patient groups and for different clinical situations. We need to keep this issue in mind in applying the pharmacogenetic evidence in clinical practice.
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Affiliation(s)
- Maki Ando
- Department of Medicine, Division of Respiratory Diseases, Nagoya University Graduated School of Medicine, Nagoya, Japan
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Tang KS, Chiu HF, Chen HH, Eng HL, Tsai CJ, Teng HC, Huang CS. Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes. World J Gastroenterol 2005; 11:3250-4. [PMID: 15929176 PMCID: PMC4316057 DOI: 10.3748/wjg.v11.i21.3250] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucurono-syltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC).
METHODS: A case-control study was designed in order to investigate the genotypes of the UGT1A7 and UGT1A1 genes, which were identified by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) method, for 268 CRC patients and 441 healthy controls.
RESULTS: The results of simple logistical regressions revealed odds ratios (ORs) of 1.97 (P<0.001), 1.91 (P<0.001), and 2.03 (P<0.001) for patients who carried the UGT1A7*1/*3 genotype, UGT1A7*3 allele, and variant-211 UGT1A1 allele. The interaction of UGT1A7*3 allele and variant-211 UGT1A1 allele produced an additive effect on the risk for the development of CRC [observed OR (2.34) greater than expected OR (1.59)]. For the 268 patients, the results of simple logistical regressions indicated that the OR of developing metastases was 4.90 (P<0.001) and 4.89 (P<0.001) for the individuals possessing UGT1A7*3 allele and variant-211 UGT1A1 allele, respectively. The results of multivariate logistical regressions confirmed these findings (OR = 2.51, P = 0.01; and OR = 2.71, P = 0.01, respectively). The interaction of these two variants resulted in an additive effect on the risk for metastases amongst patients [observed OR (6.83) greater than expected OR (4.56)].
CONCLUSION: In conclusion, carriage of the UGT1A7*3 allele, as well as variant-211 UGT1A1 allele represents a risk factor for the development of, and a determinant for, metastases associated with CRC patients.
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Affiliation(s)
- Kung-Sheng Tang
- Department of Medical Technology, Fooyin University, 151 Chin-Hsueh Road, Ta-Liao Hsiang, Kaohsiung Hsien 831, Taiwan, China
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Huang MJ, Yang SS, Lin MS, Huang CS. Polymorphisms of uridine-diphosphoglucuronosyltransferase 1A7 gene in Taiwan Chinese. World J Gastroenterol 2005; 11:797-802. [PMID: 15682470 PMCID: PMC4250586 DOI: 10.3748/wjg.v11.i6.797] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Single nucleotide polymorphisms (SNPs) of uridine-diphosphoglucuro-nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. We performed this research to establish the techniques for determining UGT1A7 gene and basic data of this gene for Taiwan Chinese.
METHODS: We collected blood samples from 112 healthy adults and 505 subjects carrying different genotypes of UGT1A1, and determined the promoter area and the entire sequence of UGT1A7 exon 1 by polymerase chain reaction. We designed appropriate primers and restriction enzymes to detect variant UGT1A7 genotypes found in the study subjects.
RESULTS: Six SNPs at nucleotides 33, 387, 391, 392, 622, and 756 within the coding region of UGT1A7 exon 1 were found. The incidence of UGT1A7 *1/*2 (N129R131W208/ K129K131W208) was predominant (35.7%) while that of UGT1A7 *3/*3 (K129K131R208/K129K131R208) was the least (2.7%). The allele frequency of UGT1A7*3, which exists in a considerable proportion of Caucasians (0.361) and Japanese (0.255), was identified only to be 0.152 in our study subjects. A novel variation at nucleotide -57 in the upstream was found, which was associated with SNPs at nucleotides 33, 387, 391, 392, and 622 in one of the variant haplotypes. The nucleotide changes at positions 387, 391, 392 and 756 were in linkage in another variant haplotype. The allele frequency of UGT1A7*3 was 0.018, 0.158, 0.242, 0.433, and 0.920 in subjects carrying wild, A(TA)6TAA/A(TA)7TAA, A(TA)7TAA/A(TA)7TAA, 211G/211A, and 211A/211A variants of UGT1A1 gene, respectively. By using natural or mutagenesis primers, we successfully detected the variations at nucleotides -57, 33, 387, and 622 with the restriction enzymes HpyCH4 IV, Taq I, Afl II, and Rsa I, respectively.
CONCLUSION: The results indicate that the allele frequencies of UGT1A7 gene in Taiwan Chinese are different from those in Caucasians and Japanese. Carriage of the nucleotide 211- variant UGT1A gene is highly associated with UGT1A7*3. The restriction-enzyme-digestion method for the determination of nucleotides -57 (or 33, or 622) and 387 can rapidly identify genotypes of UGT1A7 in an individual.
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Affiliation(s)
- May-Jen Huang
- Department of Laboratory Medicine, Cathay General Hospital, 280, Jen Ai-Road, Section 4, Taipei 106, Taiwan, China
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Iwai M, Maruo Y, Ito M, Yamamoto K, Sato H, Takeuchi Y. Six novel UDP-glucuronosyltransferase (UGT1A3) polymorphisms with varying activity. J Hum Genet 2004; 49:123-128. [PMID: 14986168 DOI: 10.1007/s10038-003-0119-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2003] [Accepted: 12/02/2003] [Indexed: 01/31/2023]
Abstract
Human UDP-glucuronosyltransferase (UGT) is a part of a major excretion pathway for endobiotics and xenobiotics. The UGT family of genes is highly polymorphic, and our aim is to describe novel polymorphisms at the UGT1A3 locus and determine how they alter substrate metabolism and drug reactions. One hundred healthy Japanese adults volunteered for the present study. We sequenced PCR-amplified fragments of the gene directly, and calculated the frequency of the genetic variations detected. To measure variant enzyme activity, we constructed five expression models and used estrone as the substrate in the assays. We identified six novel single nucleotide polymorphisms (SNPs). Of these, four caused amino acid substitutions (17A-->G: Q6R, 31T-->C: W11R, 133C-->T: R45W, and 140T-->C: V47A) and the remaining two were silent (81G-->A: E27E and 447A-->G: A159A). We found five types of alleles having differing SNP combinations: wild type (frequency=0.61), W11R-E27E-A159A (0.10), Q6A-W11R-E27E-A159A (0.055), W11R-E27E-V47A-A159A (0.125), and R45W (0.11). Expression studies found that the variants changed the enzyme efficiencies ( Km/ Vmax) to 121% of the wild type for W11R, 86% for Q6R-W11R, 369% for W11R-V47A, and 70% for R45W. Several UGT 1A3 polymorphisms exist in the Japanese population, having different levels of activity. These polymorphisms are capable of affecting the steady state levels of estrogens, and may increase sensitivity to adverse drug effects.
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Affiliation(s)
- Masaru Iwai
- Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
| | - Masaki Ito
- Department of Internal Medicine, Division of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Kazuo Yamamoto
- Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Hiroshi Sato
- Department of Bioscience, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
| | - Yoshihiro Takeuchi
- Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Desai AA, Innocenti F, Ratain MJ. Pharmacogenomics: road to anticancer therapeutics nirvana? Oncogene 2003; 22:6621-8. [PMID: 14528287 DOI: 10.1038/sj.onc.1206958] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Interindividual differences in the toxicity and response to anticancer therapies are currently observed for essentially all available treatment regimens. Such 'unpredictable' drug responses are particularly dangerous in the context of anticancer agents that have narrow therapeutic indices. Pharmacogenomics attempts to elucidate the inherited basis of interindividual differences in drug response, with the eventual goal of minimizing such variability through the use of 'individualized' treatments. There are several emerging examples of genetic polymorphisms of drug-metabolizing enzymes, DNA repair genes and drug targets that have been shown to influence the toxicity and efficacy of anticancer treatment. This review discusses the role of genetic variants of UGT1A1, TS and EGFR to exemplify the potential impact of phramacogenomics on the field of anticancer therapeutics.
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Affiliation(s)
- Apurva A Desai
- Department of Medicine, The University of Chicago, Chicago, IL, USA
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