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Ye ZN, Liu XT, Gu YM, Mao SX, Liang DH, Zhan K, Lei HQ, Huang SG. Risk factors for non-responsiveness to 5-aminosalicylic acid in patients with ulcerative colitis identified using retrospective clinical study and Mendelian randomization. Sci Rep 2025; 15:9182. [PMID: 40097461 PMCID: PMC11914660 DOI: 10.1038/s41598-025-89620-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/06/2025] [Indexed: 03/19/2025] Open
Abstract
This study aimed to identify risk factors and potential targets associated with non-responsiveness to 5-Aminosalicylic acid (5-ASA) in patients with ulcerative colitis (UC). Patients with mild to moderate UC were grouped based on their responsiveness to 5-ASA. Regression analysis was conducted to identify risk factors for non-responsiveness, while Mendelian randomization (MR) analysis was used to evaluate the potential targets. Among 50 patients (11 non-responders and 39 responders), non-responders exhibited higher incidences of fever, back pain, allergy history, and ankylosing spondylitis, as well as elevated monocyte count and alanine aminotransferase (ALT) level, but a lower aspartate aminotransferase-to-ALT (AST/ALT) ratio (all P < 0.05). Allergy history was a risk factor (OR 140.50, P = 0.021), while a high AST/ALT ratio was a protective factor (OR 0.001, P = 0.023) for non-responsiveness. The area under the receiver operating characteristic curve for the AST/ALT ratio was 0.80. MR analysis showed that inhibition of the inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK) by 5-ASA, targeting ALT, increased the risk of UC (OR 1.02, P = 0.002). Our findings suggested that allergy history and the AST/ALT ratio were associated with non-responsiveness to 5-ASA, and CHUK was identified as a potential target for ALT-related non-responsiveness.Trial Registration: ChiCTR2400084086|| http://www.chictr.org.cn/ , Chinese Clinical Trial Registry, 2024-05-10.
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Affiliation(s)
- Zhi-Ning Ye
- The Affiliated Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
- The Ninth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Xin-Tian Liu
- The Affiliated Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
- The Ninth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Yue-Ming Gu
- The Affiliated Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
- The Ninth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Shu-Xian Mao
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, No. 16, Airport Road, Guangzhou, 510120, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Dan-Hong Liang
- The Affiliated Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
- The Ninth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Kai Zhan
- The Affiliated Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan, China
- The Ninth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, China
| | - Hao-Qiang Lei
- Huangpu People's Hospital of Zhongshan, Zhongshan, China
| | - Shao-Gang Huang
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, No. 16, Airport Road, Guangzhou, 510120, China.
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China.
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Fu P, Gong B, Li H, Luo Q, Huang Z, Shan R, Li J, Yan S. Combined identification of three lncRNAs in serum as effective diagnostic and prognostic biomarkers for hepatitis B virus-related hepatocellular carcinoma. Int J Cancer 2022; 151:1824-1834. [PMID: 35802466 DOI: 10.1002/ijc.34201] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/05/2022] [Accepted: 06/22/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. This study aimed to identify the effective diagnostic and prognostic biomarkers for HBV-related HCC. With HBV-related HCC RNA-sequencing data of The Cancer Genome Atlas (TCGA) database, 159 differentially expressed long non-coding RNAs (lncRNAs) between HBV-related HCC and para-carcinoma normal samples were identified, and 12 lncRNAs were eventually assessed for deeper research. Classification analysis developed a three-lncRNA signature of AC005332.5, ELF3-AS1, and LINC00665, which was demonstrated to be the most discriminatory with an AUC (Area Under the Curve) value of 0.913 (95% CI: 0.8610-0.9665) and verified in validation patients. The expression levels of AC005332.5, ELF3-AS1, and LINC00665 were significantly changed with different tumor stages or grades. Survival analysis revealed that AC005332.5, ELF3-AS1, and LINC00665 were highly associated with the prognosis of overall survival. Additionally, the lncRNA signature yielded statistical significance to predict clinical outcomes independently from other clinical variables in validation patients, as suggested in the multivariate Cox hazards analysis. Conclusively, a three-lncRNA signature of AC005332.5, ELF3-AS1, and LINC00665 may serve as an excellent diagnostic biomarker for HBV-related HCC and potential prognostic significance for HBV-related HCC sufferers. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Peng Fu
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Binbin Gong
- Department of Urology, The First Afliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huiming Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qing Luo
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zikun Huang
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Renfeng Shan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Junming Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Shaoying Yan
- Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Sharifi H, Safarpour H, Moossavi M, Khorashadizadeh M. Identification of Potential Prognostic Markers and Key Therapeutic Targets in Hepatocellular Carcinoma Using Weighted Gene Co-Expression Network Analysis: A Systems Biology Approach. IRANIAN JOURNAL OF BIOTECHNOLOGY 2022; 20:e2968. [PMID: 36381283 PMCID: PMC9618018 DOI: 10.30498/ijb.2022.269817.2968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND As the most prevalent form of liver cancer, hepatocellular carcinoma (HCC) ranks the fifth highest cause of cancer-related death worldwide. Despite recent advancements in diagnostic and therapeutic techniques, the prognosis for HCC is still unknown. OBJECTIVES This study aimed to identify potential genes contributing to HCC pathogenicity. MATERIALS AND METHODS To this end, we examined the GSE39791 microarray dataset, which included 72 HCC samples and 72 normal samples. An investigation of co-expression networks using WGCNA found a highly conserved blue module with 665 genes that were strongly linked to HCC. RESULTS APOF, NAT2, LCAT, TTC36, IGFALS, ASPDH, and VIPR1 were the blue module's top 7 hub genes. According to the results of hub gene enrichment, the most related issues in the biological process and KEGG were peroxisome organization and metabolic pathways, respectively. In addition, using the drug-target network, we discovered 19 FDA-approved medication candidates for different reasons that might potentially be employed to treat HCC patients through the modulation of 3 hub genes of the co-expression network (LCAT, NAT2, and VIPR1). Our findings also demonstrated that the 3 scientifically validated miRNAs regulated the co-expression network by the VIPR1 hub gene. CONCLUSION We found co-expressed gene modules and hub genes linked with HCC advancement, offering insights into the mechanisms underlying HCC progression as well as some potential HCC treatments.
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Affiliation(s)
- Hengameh Sharifi
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Maryam Moossavi
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohsen Khorashadizadeh
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran,
Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran,
3Department of Medical Biotechnology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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Chorfi L, Fercha A, Derouiche F, Sebihi FZ, Houhou D, Chorfi K, Bendjemana K. N-Acetyltransferase 2, Glutathione S-transferase gene polymorphisms and susceptibility to hepatocellular carcinoma in an Algerian population. Xenobiotica 2022; 52:99-104. [PMID: 35138223 DOI: 10.1080/00498254.2022.2040642] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
This study was conducted to investigate the potential association of genetic polymorphisms of glutathione S-transferase M1/T1 (GSTM1, GSTT1), and N-acetyltransferase 2 (NAT2) genes and epidemiological parameters with the risk of HCC in the Algerian population.A case-control study including 132 confirmed HCC patients and 141 cancer-free controls was performed. Genotyping analysis was performed using conventional multiplex PCR and PCR-RFLP. Statistical analysis was performed using the Chi-square test. Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (95% CI).GSTM1 null and NAT2 slow acetylator genotypes confer an increased risk to HCC (OR =1.88, 95% CI 1.16-3.05; OR =2.30, 95% CI 1.26-4.18, respectively). This association was prevalent in smokers (OR =2.00, 95% CI 1.05-3.8 and OR =2.55, 95% CI 1.22-5.34, respectively). No significant association was observed for GSTT1 null genotype in the contribution to HCC risk (OR =0.76, 95% CI 0.46-1.27).In conclusion, the GSTM1 and NAT2 gene polymorphisms are positively associated with the risk of HCC in older men and especially in smokers.
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Affiliation(s)
- Lamia Chorfi
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
| | - Azzedine Fercha
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
| | - Faouzia Derouiche
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
| | - Fatima Zohra Sebihi
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Molecular and Cellular Biology, Frères Mentouri University, Constantine 25017, Algeria
| | - Dallal Houhou
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
| | - Keltoum Chorfi
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
| | - Katia Bendjemana
- Department of Molecular and Cellular Biology, Faculty of Nature and Life Sciences, Abbes Laghrour University, Khenchela, Algeria.,Laboratory of Biotechnology, Water, Environment and Health, Abbes Laghrour University, Khenchela, Algeria
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Wang J, Yu L, Jiang H, Zheng X, Zeng S. Epigenetic Regulation of Differentially Expressed Drug-Metabolizing Enzymes in Cancer. Drug Metab Dispos 2020; 48:759-768. [PMID: 32601104 DOI: 10.1124/dmd.120.000008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Drug metabolism is a biotransformation process of drugs, catalyzed by drug-metabolizing enzymes (DMEs), including phase I DMEs and phase II DMEs. The aberrant expression of DMEs occurs in the different stages of cancer. It can contribute to the development of cancer and lead to individual variations in drug response by affecting the metabolic process of carcinogen and anticancer drugs. Apart from genetic polymorphisms, which we know the most about, current evidence indicates that epigenetic regulation is also central to the expression of DMEs. This review summarizes differentially expressed DMEs in cancer and related epigenetic changes, including DNA methylation, histone modification, and noncoding RNAs. Exploring the epigenetic regulation of differentially expressed DMEs can provide a basis for implementing individualized and rationalized medication. Meanwhile, it can promote the development of new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer. SIGNIFICANCE STATEMENT: This review summarizes the aberrant expression of DMEs in cancer and the related epigenetic regulation of differentially expressed DMEs. Exploring the epigenetic regulatory mechanism of DMEs in cancer can help us to understand the role of DMEs in cancer progression and chemoresistance. Also, it provides a basis for developing new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer.
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Affiliation(s)
- Jiaqi Wang
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Huidi Jiang
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Xiaoli Zheng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
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Liu H, Zhao P, Jin X, Zhao Y, Chen Y, Yan T, Wang J, Wu L, Sun Y. A 9‑lncRNA risk score system for predicting the prognosis of patients with hepatitis B virus‑positive hepatocellular carcinoma. Mol Med Rep 2019; 20:573-583. [PMID: 31115573 PMCID: PMC6579967 DOI: 10.3892/mmr.2019.10262] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 12/28/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and can be induced by hepatitis B virus (HBV) infection. The aim of the present study was to screen prognosis‑associated long noncoding RNAs (lncRNAs) and construct a risk score system for the disease. The RNA‑sequencing data of patients with HCC (including 100 HCC samples and 26 normal samples) were extracted from The Cancer Genome Atlas (TCGA) database. In addition, GSE55092, GSE19665 and GSE10186 datasets were downloaded from the Gene Expression Omnibus database. Combined with weighted gene co‑expression network analysis, the identification and functional annotation of stable modules was performed. Using the MetaDE package, the consensus differentially expressed RNAs (DE‑RNAs) were analyzed. To construct a risk score system, prognosis‑associated lncRNAs and the optimal lncRNA combination were separately analyzed by survival and penalized packages. Finally, pathway enrichment analysis for the nodes in an lncRNA‑mRNA network was conducted via Gene Set Enrichment Analysis. A total of four stable modules and 3,051 consensus DE‑RNAs were identified. The stable modules were significantly associated with the histological grades of HCC, tumor, node and metastasis stage, pathological stage, recurrence and exposure to radiation therapy. A 9‑lncRNA optimal combination [DiGeorge syndrome critical region gene 9, glucosidase, β, acid 3 (GBA3), HLA complex group 4, N‑acetyltransferase 8B, neighbor of breast cancer 1 gene 2, prostate androgen‑regulated transcript 1, ret finger protein like 1 antisense RNA 1, solute carrier family 22 member 18 antisense and T‑cell leukemia/lymphoma 6] was selected from the 14 prognosis‑associated lncRNAs, and was further supported by the validation dataset, GSE10186. The lncRNA‑mRNA co‑expression network revealed lncRNA GBA3 as a positive regulator of phosphoenolpyruvate carboxykinase 2, an important enzyme in the metabolic pathway of gluconeogenesis. A risk score system was established based on the optimal 9 lncRNAs, which may be valuable for predicting the prognosis of patients with HBV‑positive HCC and improving understanding of mechanisms associated with the pathogenesis of this disease. On the contrary, a larger, independent cohort of patients is required to further validate the risk‑score system.
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Affiliation(s)
- Honghong Liu
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Ping Zhao
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Xueyuan Jin
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yanling Zhao
- Department of Pharmacy, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yongqian Chen
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Tao Yan
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Jianjun Wang
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Liang Wu
- International Center for Liver Disease Treatment, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
| | - Yongqiang Sun
- Integrative Medical Center, 302 Hospital of The People's Liberation Army, Beijing 100039, P.R. China
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Kabir S, Rehman A. Carcinogenic potential of arylamine N-acetyltransferase in Asian populations. JOURNAL OF CANCER RESEARCH AND PRACTICE 2018. [DOI: 10.1016/j.jcrpr.2018.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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8
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Du L, Lei L, Zhao X, He H, Chen E, Dong J, Zeng Y, Yang J. The Interaction of Smoking with Gene Polymorphisms on Four Digestive Cancers: A Systematic Review and Meta-Analysis. J Cancer 2018; 9:1506-1517. [PMID: 29721061 PMCID: PMC5929096 DOI: 10.7150/jca.22797] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/22/2018] [Indexed: 12/15/2022] Open
Abstract
The main purpose of this study was to perform a meta-analysis to assess the interaction between smoking and nine genes (GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, SULT1A1, hOGG1, XRCC1 and p53) on colorectal cancer, gastric cancer, liver cancer and oesophageal cancer. Published articles from the PubMed, ISI and EMBASE databases were retrieved. A total of 67 case-control studies or nested case-control studies were identified for the analysis. The pooled jodds ratio (OR) with 95% confidence interval (CI) was calculated using the random effect model. The overall study showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among Asian population (OR 1.284, 95% CI: 1.122-1.470, p: 0). Subgroup analyses by cancer site showed that GSTM1 null genotype increased the gastric cancer risk in total population (OR 1.335, 95% CI: 1.145-1.556, p: 0). However, the association of GSTM1 null genotype with the oesophageal cancer risk was found in smokers (OR 1.382, 95% CI: 1.009-1.894, p:0.044), but not in non-smokers (OR 1.250, 95% CI: 0.826-1.891, p:0.290). Moreover, smokers with the CYP1A1 IIe462Val polymorphism were at an increased cancer risk in Asian population (OR=1.585, 95% CI 1.029-2.442, p: 0.037). None of the other gene-smoking interactions was observed in the above cancers. This meta-analysis reveals two potential gene-smoking interactions, one is between smoking and GSTM1 on oesophageal cancer, and the other is between smoking and CYP1A1 IIe462Val on the four cancers in Asian population. Future studies need to be conducted to verify the conclusions.
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Affiliation(s)
- Le Du
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Lei Lei
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Xiaojuan Zhao
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Hongjuan He
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Erfei Chen
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Jing Dong
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Yuan Zeng
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
| | - Jin Yang
- Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.,Institute of Preventive Genomic Medicine, Xi'an 710069, China
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Alcohol consumption and liver cancer risk: a meta-analysis. Cancer Causes Control 2015; 26:1205-31. [PMID: 26134046 DOI: 10.1007/s10552-015-0615-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Abstract
PURPOSE Alcohol is a confirmed risk factor of liver cancer. Yet, its dose-response function and synergistic effects with other risk factors remain unclear. METHODS We performed a meta-analysis on publications up to May 2014. A total of 112 publications were identified. The meta-relative risk (mRR) and the dose-response trend were calculated. Tests for heterogeneity, publication bias, and sensitivity analyses were performed. The synergy index (SI) was recorded or calculated, whenever possible. RESULTS Compared to individuals who never drank or drank at very low frequencies, the mRR for ever drinkers was 1.29 (95% confidence interval, CI 1.16-1.42) and 1.46 (95% CI 1.27-1.65) for case-control studies, and 1.07 (95% CI 0.87-1.27) for cohort studies. Being a current drinker was associated with an increased liver cancer risk in case-control studies (mRR = 1.55, 95% CI 0.38-2.73), but not in cohort studies (mRR = 0.86, 95% CI 0.74-0.97). The dose-response relation between alcohol and liver cancer was apparent with RR = 1.08 (95% CI 1.04-1.11) for 12 g/day (~1 drink), 1.54 (95% CI 1.36-1.74) for 50 g/day, 2.14 (95% CI 1.74-2.62) for 75 g/day, 3.21 (95% CI 2.34-4.40) for 100 g/day, and 5.20 (95% CI 3.25-8.29) for 125 g/day of alcohol consumption. There were synergistic effects of alcohol consumption with hepatitis (S = 2.14, 95% CI 1.31-2.98) and with diabetes (S = 3.57, 95% CI 2.29-4.84) on the risk of liver cancer, although this may be subject to publication bias. CONCLUSION Overall, one alcoholic drink per day (~12 g/day) may be associated with a 1.1 times higher liver cancer risk. Further studies on the synergistic effects of alcohol consumption and other major risk factors are warranted.
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Zhang K, Gao L, Wu Y, Chen J, Lin C, Liang S, Su J, Ye J, He X. NAT1 polymorphisms and cancer risk: a systematic review and meta-analysis. Int J Clin Exp Med 2015; 8:9177-9191. [PMID: 26309576 PMCID: PMC4537954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 05/02/2015] [Indexed: 06/04/2023]
Abstract
PURPOSE To investigate the association between the N-acetyltransferase 1 (NAT1) slow and rapid acetylation phenotypes with cancer risk based on a meta-analysis. METHODS Previously published case-control studies were retrieved from PubMed, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined to assess the relationship between NAT1 polymorphisms and cancer risk. RESULTS A total of 73 studies (24874 cases and 30226 controls) were included in this meta-analysis. No significant association was identified between NAT1 polymorphisms (slow acetylation versus rapid acetylation genotypes: OR = 0.978, 95% CI = 0.927-1.030, P < 0.001 for heterogeneity, I(2) = 45.5%) and cancer risk, whereas a significantly reduced risk of pancreatic cancer was identified in individuals with NAT1 slow acetylation genotype (OR = 0.856, 95% CI = 0.733-0.999, P =0.509 for heterogeneity, I(2) = 0). When the NAT1 slow acetylation genotype was analysed on the basis of stratified analyses of ethnicity, a significantly reduced risk of head and neck cancers was found among Asian (OR=0.281, 95% CI = 0.127-0.622). When the NAT1 slow acetylation genotype was analysed on the basis of stratified analyses of source of control, only significantly reduced risks of colorectal cancer (OR = 0.882, 95% CI = 0.798- 0.974, P = 0.212 for heterogeneity, I(2) = 22.9) and pancreatic cancer (OR=0.856, 95% CI = 0.733-0.999, P = 0.509 for heterogeneity, I(2) = 0) were found among hospital-based studies. CONCLUSIONS No significant association between the NAT1 polymorphisms and the risk of cancer was found except for pancreatic cancer.
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Affiliation(s)
- Kunyi Zhang
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Lijuan Gao
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Yuqi Wu
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Jianyi Chen
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Chengguang Lin
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Shaohua Liang
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Jianxin Su
- Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Department of Radiation Oncology, Cancer Center, Sun Yat-Sen UniversityGuangzhou 510060, People’s Republic of China
| | - Jinming Ye
- Internal Medicine, Guangdong Provincial Police HospitalNo. 88 West Shitan Road, Guangzhou 510430, PR. China
| | - Xuyu He
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences106 Zhongshan Road 2, Guangzhou 510080, China
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11
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Zhang J, Xu F, Ouyang C. Joint effect of polymorphism in the N-acetyltransferase 2 gene and smoking on hepatocellular carcinoma. Tumour Biol 2012; 33:1059-63. [PMID: 22293947 DOI: 10.1007/s13277-012-0340-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 01/19/2012] [Indexed: 12/22/2022] Open
Abstract
The N-acetyltransferase 2 gene (NAT2) has been implicated in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the association between NAT2 polymorphism and HCC risk. Published literatures from PubMed, EMBASE, CNKI, and Wan Fang Data were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Eight studies including 1,084 HCC cases and 1,682 controls were identified for the data analysis. The overall result showed that there was no statistically significant association between NAT2 genotypes and HCC risk (slow acetylation vs. rapid/intermediate acetylation: OR01.03, 95% CI 0.86–1.24). In the stratified analyses, NAT2 genotypes were also not significantly associated with HCC risk among both Europeans (OR01.11, 95% CI 0.86–1.43) and East Asians (OR01.01, 95% CI 0.65–1.56). Further subgroup analyses based on the smoking status showed that the effect size was statistically significant among the smokers (OR02.09, 95% CI 1.07–4.09), but not among those who never smoked (OR01.26, 95% CI 0.88–1.82). The present meta-analysis indicated that NAT2 genotypes were not associated with increased risk of HCC among the overall population but increased the risk of HCC among the smokers.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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12
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Chan KYK, Wong CM, Kwan JSH, Lee JMF, Cheung KW, Yuen MF, Lai CL, Poon RTP, Sham PC, Ng IOL. Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection. PLoS One 2011; 6:e28798. [PMID: 22174901 PMCID: PMC3234276 DOI: 10.1371/journal.pone.0028798] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 11/15/2011] [Indexed: 12/11/2022] Open
Abstract
One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (OR(combined) = 1.31-1.39; p(combined) = 2.71 × 10(-5)-5.19 × 10(-4); PAR(combined) = 26-31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Kelvin Yuen-Kwong Chan
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, The University of Hong Kong, Hong Kong
| | - Chun-Ming Wong
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, The University of Hong Kong, Hong Kong
| | | | - Joyce Man-Fong Lee
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, The University of Hong Kong, Hong Kong
| | - Ka Wai Cheung
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, The University of Hong Kong, Hong Kong
| | - Man Fung Yuen
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Ching Lung Lai
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Ronnie Tung-Ping Poon
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Pak Chung Sham
- Department of Psychiatry, The University of Hong Kong, Hong Kong
- * E-mail: (PCS); (IOLN)
| | - Irene Oi-Lin Ng
- State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
- Department of Pathology, The University of Hong Kong, Hong Kong
- * E-mail: (PCS); (IOLN)
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13
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Wan DW, Tzimas D, Smith JA, Kim S, Araujo J, David R, Lobach I, Sarpel U. Risk factors for early-onset and late-onset hepatocellular carcinoma in Asian immigrants with hepatitis B in the United States. Am J Gastroenterol 2011; 106:1994-2000. [PMID: 21912436 DOI: 10.1038/ajg.2011.302] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Routine screening for hepatocellular carcinoma (HCC) is recommended in chronic hepatitis B (HBV) patients with cirrhosis and select non-cirrhotic HBV populations including Asian males ages 40 and older and females ages 50 and older. However, many younger HBV patients develop HCC and there have been few studies examining this group. Additionally, studies of HCC in the Asian immigrant population in the United States have been limited. The objective of this study was to determine the associated risk factors for the development of early-onset (males and females under ages 40 and 50, respectively) and late-onset HCC in immigrants with chronic HBV in the United States. METHODS Clinical, demographic, and laboratory data were retrospectively collected on all Asian immigrants with HBV at Bellevue Hospital Center from 2003 to 2009. Patients with HCC were identified within this cohort. Features of early-onset and late-onset HCC cases were compared with age-matched HBV controls without HCC. RESULTS We identified 168 cases of HCC in Asians with HBV. In all, 74% (124/168) of cases were late-onset, and 26% (44/168) were early-onset. When comparing the 124 late-onset HCC cases with 199 age-matched HBV controls, gender (odds ratio (OR)=4.4; P<0.05) and cirrhosis (OR=9.6; P<0.05) or surrogate labs (i.e., platelets, international normalized ratio, total bilirubin, albumin) were found to be associated with HCC development. When comparing the 44 early-onset HCC cases with 432 age-matched HBV controls, family history of HCC (OR=2.7; P<0.05), and smoking history (OR=3.4; P<0.05) were independently associated risk factors in addition to gender (OR=2.7; P<0.05), and cirrhosis (OR=19.5; P<0.05) or surrogate labs. In all, 54.8% of late-onset HCC cases were cirrhotic and 29.5% of early-onset HCC cases were cirrhotic. CONCLUSIONS HCC occurs in Asian immigrant HBV patients younger than currently recommended screening guidelines. A large majority of these early-onset patients did not have cirrhosis at the time of their HCC diagnosis; therefore, factors other than cirrhosis need to be considered when evaluating HCC risk in young patients. Factors associated with HCC development across all ages include cirrhosis and male gender, while family history and smoking history may identify younger Asian immigrant HBV patients at risk for HCC. Prospective validation, including cost-effectiveness evaluation, is necessary, but our results suggest that younger Asian HBV patients, especially those with a smoking history or family history of HCC, appear to have an increased risk for HCC and should be considered for enrollment in early screening programs regardless of their age.
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Affiliation(s)
- David W Wan
- Division of Gastroenterology, Department of Medicine, NYU Langone Medical Center, New York, New York 10016, USA
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14
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Ananthakrishnan A, Gogineni V, Saeian K. Epidemiology of primary and secondary liver cancers. Semin Intervent Radiol 2011; 23:47-63. [PMID: 21326720 DOI: 10.1055/s-2006-939841] [Citation(s) in RCA: 272] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary liver cancer is the sixth most common cancer worldwide with a wide geographic distribution. The incidence of primary liver cancer is increasing and there is still a higher prevalence in developing countries. Early recognition remains an obstacle and lack of it results in poor outcomes for hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, and cholangiocarcinoma. The most common risk factors associated with HCC are hepatitis B and chronic hepatitis C infections, alcohol use, smoking, and aflatoxin exposure. Emerging risk factors such as obesity might play an important role in the future because of the increasing prevalence of this condition.
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Affiliation(s)
- Ashwin Ananthakrishnan
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin
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15
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Yang KC, Huang YS, Perng CL, Lin HC, Lee SD. Polymorphism of N-acetyltransferase 2 Gene and the Susceptibility to Alcoholic Liver Cirrhosis: Interaction With Smoking. Alcohol Clin Exp Res 2011; 35:1204-8. [DOI: 10.1111/j.1530-0277.2011.01453.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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16
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Recent advances in the research of hepatitis B virus-related hepatocellular carcinoma: epidemiologic and molecular biological aspects. Adv Cancer Res 2011; 108:21-72. [PMID: 21034965 DOI: 10.1016/b978-0-12-380888-2.00002-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, and more than half of HCC patients are attributable to persistent hepatitis B virus (HBV) infections. The best and cheapest way to prevent HBV-related HCC is the implementation of universal hepatitis B vaccination program, by which the incidence rates of childhood HCC have been reduced in several countries, including Taiwan. However, there are still hundreds of millions of HBV carriers in the world that remain a global health challenge. In the past decade, several hepatitis B viral factors such as serum HBV DNA level, genotype, and naturally occurring mutants have already been identified to influence liver disease progression and HCC development in HBV carriers. Several easy-to-use scoring systems based on clinical and viral characteristics are developed to predict HCC risk in HBV carriers and may facilitate the communication between practicing physicians and patients in clinical practice. In addition, the role of nonviral factors in HBV-related HCC has also been increasingly recognized. On the basis of these emerging data, it is recommended that HBV carriers should be screened and monitored to identify those who have a higher risk of liver disease progression and require antiviral treatments. Regarding the molecular carcinogenesis of HCC development, despite some progress in the research of cell biology of HCC in the past decade, aberrant pathways involved in maintaining HCC phenotypes have not been completely elucidated yet. In the future, through comprehensive and integrated approaches to analyze the genomes of human HCC, novel target genes or pathways critically involved in hepatocarcinogenesis may hopefully be identified.
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17
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He XX, Chang Y, Jiang HJ, Tang F, Meng FY, Xie QH, Li PY, Song YH, Lin JS. Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection. Viral Immunol 2010; 23:251-257. [PMID: 20565290 DOI: 10.1089/vim.2009.0102] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Genetic polymorphism of IFNAR-1 plays a large role in determining the clearance or chronicity after hepatitis B virus (HBV) exposure. However, it is not clear whether type I interferon receptor-1 (IFNAR-1) variations continuously exert their effects to influence the final outcomes following HBV chronicity, including acute-on-chronic hepatitis B liver failure (ACLF-HBV), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here we report that these four potential outcomes of chronic HBV infection are strongly associated with IFNAR-1 polymorphisms through a hospital-based case-control study of 663 cases. ACLF-HBV and HCC were each compared with CHB+LC. In comparison with the G/G genotype, the C/G and C/C genotypes at both single-nucleotide polymorphism (SNP) sites (rs1012335 and rs2257167) showed significant susceptibility to ACLF-HBV (the highest odds ratio [OR] reached 2.374; 95% CI = 1.488, 3.788; p < 0.001 for the C/G genotype at rs2257167), as well as HCC (OR = 2.475; 95% CI = 1.435, 4.426; p < 0.001 for the C/C genotype at rs1012335). The C allele at both loci was a susceptibility allele for ACLF-HBV and HCC, with the highest ORs reaching 1.653 (95% CI = 1.233, 2.216; p < 0.01 at rs1012335) in the ACLF-HBV group, and 1.659 (95% CI = 1.274, 2.159; p < 0.01 at rs1012335) in the HCC group. A strongly linked disequilibrium was also found within these two alleles (p < 0.001). Our research indicates that genetic polymorphisms of IFNAR-1 not only contribute to the determination of clearance or chronicity in the early stages of HBV exposure, but they also persistently influence pathogenesis over the long-term process of chronic HBV infection.
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Affiliation(s)
- Xing-Xing He
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Zhang YJ. Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma. World J Hepatol 2010; 2:94-102. [PMID: 21160980 PMCID: PMC2999273 DOI: 10.4254/wjh.v2.i3.94] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Revised: 01/16/2010] [Accepted: 01/23/2010] [Indexed: 02/06/2023] Open
Abstract
In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B(1) (AFB(1)) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB(1) exposure and mutations in the K-ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N-acetyltransferases and glutathione S-transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk.
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Affiliation(s)
- Yu-Jing Zhang
- Yu-Jing Zhang, Department of Environmental Health Sciences, Mailman School of Public Health and Cancer Center of Columbia University, New York, NY 10032, United States
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19
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Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS One 2010; 5:e9749. [PMID: 20305825 PMCID: PMC2840036 DOI: 10.1371/journal.pone.0009749] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2009] [Accepted: 03/01/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is characterized by late detection and fast progression, and it is believed that epigenetic disruption may be the cause of its molecular and clinicopathological heterogeneity. A better understanding of the global deregulation of methylation states and how they correlate with disease progression will aid in the design of strategies for earlier detection and better therapeutic decisions. METHODS AND FINDINGS We characterized the changes in promoter methylation in a series of 30 HCC tumors and their respective surrounding tissue and identified methylation signatures associated with major risk factors and clinical correlates. A wide panel of cancer-related gene promoters was analyzed using Illumina bead array technology, and CpG sites were then selected according to their ability to classify clinicopathological parameters. An independent series of HCC tumors and matched surrounding tissue was used for validation of the signatures. We were able to develop and validate a signature of methylation in HCC. This signature distinguished HCC from surrounding tissue and from other tumor types, and was independent of risk factors. However, aberrant methylation of an independent subset of promoters was associated with tumor progression and etiological risk factors (HBV or HCV infection and alcohol consumption). Interestingly, distinct methylation of an independent panel of gene promoters was strongly correlated with survival after cancer therapy. CONCLUSION Our study shows that HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression stage, with potential clinical applications in diagnosis and prognosis.
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20
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Association of a variant in MIR 196A2 with susceptibility to hepatocellular carcinoma in male Chinese patients with chronic hepatitis B virus infection. Hum Immunol 2010; 71:621-6. [PMID: 20188135 DOI: 10.1016/j.humimm.2010.02.017] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Revised: 02/05/2010] [Accepted: 02/18/2010] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in MIR196A2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of nonsmall cell lung cancer. To assess whether this polymorphism is associated with susceptibility to and clinicopathologic characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), a total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and MIR196A2 polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). In our study group, there was no significant association between MIR196A2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with MIR196A2 rs11614913 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathologic characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. However, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. Our results suggested that MIR196A2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population.
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21
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Qi P, Wang H, Chen YM, Sun XJ, Liu Y, Gao CF. No association of EGF 5'UTR variant A61G and hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. Pathology 2010; 41:555-60. [PMID: 19900104 DOI: 10.1080/00313020903071603] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Epidermal growth factor (EGF) has many biological functions, including mitogenesis, tumorigenesis, and proliferation of epidermal tissues. Previous studies have reported that the EGF +61 (A/G) single nucleotide polymorphism in the 5'-untranslated region of the EGF gene is functional, and is associated with development of hepatocellular carcinoma (HCC) in liver cirrhosis and various malignancy. Our aim was to investigate whether EGF gene A61G polymorphism could be implicated in susceptibility to and/or clinicopathological characteristics of HCC in Chinese patients with chronic hepatitis B virus (HBV) infection. METHODS This polymorphism was studied in 387 patients with chronic HBV infection and in 208 healthy volunteers using restriction fragment-length polymorphism. The patients were divided into two groups: those without (n = 172) and those with HCC (n = 215). These 215 HCC patients with chronic HBV infection were designated as cases, and the remaining 172 patients without HCC served as controls. RESULTS There were no significant differences in EGF genotype or allelic frequencies between cases and controls nor was EGF genotype or allelic frequencies associated with tumour number, size, growth phase, stage, and invasiveness. We also found ethnic heterogeneity in the functional EGF polymorphism. CONCLUSIONS The present results show that although EGF gene A61G polymorphism is associated with development of HCC in liver cirrhosis, it is not sufficient for HCC in Chinese patients with chronic HBV infection.
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Affiliation(s)
- Peng Qi
- Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai. PR China
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22
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Metry KJ, Neale JR, Bendaly J, Smith NB, Pierce WM, Hein DW. Effect of N-acetyltransferase 2 polymorphism on tumor target tissue DNA adduct levels in rapid and slow acetylator congenic rats administered 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline. Drug Metab Dispos 2009; 37:2123-6. [PMID: 19666988 PMCID: PMC2774981 DOI: 10.1124/dmd.109.029512] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Accepted: 08/06/2009] [Indexed: 01/11/2023] Open
Abstract
2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are suspected human carcinogens generated in well done meats. After N-hydroxylation, they are O-acetylated by N-acetyltransferase 2 (NAT2) to electrophiles that form DNA adducts. dG-C8-MeIQx and dG-C8-PhIP adducts have been identified in human tissues. In the female rat, administration of PhIP leads to mammary and colon tumors, whereas MeIQx induces liver tumors. Both humans and rats exhibit NAT2 genetic polymorphism yielding rapid and slow acetylator phenotypes. Because O-acetylation is an activation pathway, we hypothesized that MeIQx- and PhIP-induced DNA damage would be greater in tumor target tissues and higher in rapid than slow NAT2 acetylators. Adult female rapid and slow acetylator rats congenic at the Nat2 locus received a single dose of 25 mg/kg MeIQx or 50 mg/kg PhIP by gavage, and tissue DNA was isolated after 24 h. Deoxyribonucleoside adducts were identified and quantified by capillary liquid chromatography-tandem mass spectrometry using isotope dilution methods with deuterated internal standards. Major adducts were those bound to the C8 position of deoxyguanosine. dG-C8-PhIP DNA adducts were highest in colon, lowest in liver and did not significantly differ between rapid and slow acetylator congenic rats in any tissue tested. In contrast, dG-C8-MeIQx adducts were highest in liver and significantly (p < 0.001) higher in rapid acetylator liver than in slow acetylator liver. Our results are consistent with the tumor target specificity of PhIP and MeIQx and with increased susceptibility to MeIQx-induced liver tumors in rapid NAT2 acetylators.
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Affiliation(s)
- Kristin J. Metry
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Jason R. Neale
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Jean Bendaly
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Ned B. Smith
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - William M. Pierce
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
| | - David W. Hein
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky
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Shih WL, Yu MW, Chen PJ, Wu TW, Lin CL, Liu CJ, Lin SM, Tai DI, Lee SD, Liaw YF. Evidence for association with hepatocellular carcinoma at the PAPSS1 locus on chromosome 4q25 in a family-based study. Eur J Hum Genet 2009; 17:1250-1259. [PMID: 19337310 PMCID: PMC2986632 DOI: 10.1038/ejhg.2009.48] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 02/17/2009] [Accepted: 02/18/2009] [Indexed: 02/07/2023] Open
Abstract
A region on chromosome 4q25 has recently been highlighted as linked to hepatocellular carcinoma (HCC). In this study, we performed a family-based association analysis with 67 single-nucleotide polymorphisms (SNPs) to map this linkage region in 240 families with HCC, 212 (88.3%) of which were ascertained through hepatitis B virus surface antigen (HBsAg)-positive index cases. Individual SNP analysis with correction for multiple testing identified 10 SNPs in two correlated haplotype blocks, located in or around the 3'-phosphoadenosine 5'-phosphosulfate synthetase-1 (PAPSS1) gene (all P-values: <0.0075). Our linkage data and GIST (Genotype identity-by-descent sharing test) indicate that 6 of these 10 SNPs contributed to the linkage signal. The haplotype block of the strongest association with HCC extended from the intron 5 to the 3'-flanking region of PAPSS1; multiple consecutive three-SNP haplotypes in this region were significant. The most significant haplotype showed odd ratios of 3.41 (95% confidence interval (CI)=1.36-8.53) for homozygous individuals in a case-unaffected sibling analysis. This haplotype also revealed an association with elevated serum alpha-fetoprotein and with poor survival in familial cases and an independent series of HBsAg-positive cases with small tumor present at the time of hospital admission. These results implicate PAPSS1 as a candidate HCC-susceptibility gene in hepatitis B carriers.
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Affiliation(s)
- Wei-Liang Shih
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ming-Whei Yu
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Wei Wu
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shi-Ming Lin
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Dar-In Tai
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Shou-Dong Lee
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Imaizumi T, Higaki Y, Hara M, Sakamoto T, Horita M, Mizuta T, Eguchi Y, Yasutake T, Ozaki I, Yamamoto K, Onohara S, Kawazoe S, Shigematsu H, Koizumi S, Kudo S, Tanaka K. Interaction between cytochrome P450 1A2 genetic polymorphism and cigarette smoking on the risk of hepatocellular carcinoma in a Japanese population. Carcinogenesis 2009; 30:1729-34. [PMID: 19643819 DOI: 10.1093/carcin/bgp191] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Limited epidemiological evidence suggests that genetic polymorphisms of drug-metabolizing enzymes such as cytochrome P450 (CYP), glutathione S-transferase (GST) and N-acetyltransferase (NAT) may be involved in tobacco-related hepatocarcinogenesis. We conducted a case-control study, including 209 incident cases with hepatocellular carcinoma (HCC) and two different control groups [275 hospital controls and 381 patients with chronic liver disease (CLD) without HCC], to investigate whether CYP1A1, CYP1A2, CYP2A6, CYP2E1, GSTM1 and NAT2 polymorphisms are related to the risk of HCC with any interaction with cigarette smoking. Overall, no significant associations with HCC were observed for any genotypes against either control group. However, we found a significant interaction (P = 0.0045) between CYP1A2 -3860G>A polymorphism and current smoking on HCC risk when we compared HCC cases with CLD patients; adjusted odds ratios [ORs; and 95% confidence intervals (CIs)] for G/A and A/A genotypes relative to G/G genotype were 0.28 (0.12-0.66) and 0.18 (0.04-0.94), respectively, among current smokers (P trend = 0.002), as compared with 1.28 (0.80-2.06) and 0.76 (0.34-1.71), respectively, among never/former smokers (P trend = 0.96). Similarly, in CYP1A2 G/G genotype, significant risk increase was observed for current smoking (OR = 4.08, 95% CI = 2.02-8.25) or more recent cigarette use (e.g. pack-years during last 5 years, P trend = 0.0003) but not in G/A and A/A genotypes combined (OR for current smoking = 1.39, 95% CI = 0.63-3.03; P trend for pack-years during last 5 years = 0.40). These results suggest that the CYP1A2 -3860G>A polymorphism modifies the smoking-related HCC risk among CLD patients.
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Affiliation(s)
- Takeshi Imaizumi
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Nabeshima, Saga, Japan
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Kim YJ, Lee HS. [Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 15:7-14. [PMID: 19346781 DOI: 10.3350/kjhep.2009.15.1.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Arif E, Vibhuti A, Alam P, Deepak D, Singh B, Athar M, Pasha MAQ. Association of CYP2E1 and NAT2 gene polymorphisms with chronic obstructive pulmonary disease. Clin Chim Acta 2007; 382:37-42. [PMID: 17442289 DOI: 10.1016/j.cca.2007.03.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Revised: 03/12/2007] [Accepted: 03/12/2007] [Indexed: 11/17/2022]
Abstract
BACKGROUND Detoxification genes are potential candidates in the susceptibility of patients with chronic obstructive pulmonary disease. Polymorphisms in these genes alter the metabolism of xenobiotics such as present in cigarette smoke. METHODS We conducted a case-control study to investigate total 9 polymorphisms of CYP2E1, CYP2D6 and NAT2 genes by PCR-RFLP. RESULTS The -1053C/T and -1293G/C promoter polymorphisms of CYP2E1 were found to be in complete linkage disequilibrium (LD) (D'=1.00, r(2)=1.0, p<0.0001), whereas -1293G/C and 7632T/A polymorphisms of the same gene were also in significant LD (D'=0.5183, r(2)=1.0, p=0.01) in patients. The patients over-represented the -1293GC+CC genotypes of -1293G/C polymorphism of CYP2E1 (p=0.03) and NAT2*4/7, NAT2()5/6, NAT2*5/7, NAT2*6/6 and NAT2*6/7 genotypes of NAT2 (p=0.01, p=0.039, p=0.01, p=0.032, p=0.006, respectively), resulting in to higher frequency of -1293C (OR=7.02, 95% CI=1.63-30.15, p=0.002), NAT2*6 (OR=1.90, 95% CI=1.27-2.83, p=0.001) and NAT2*7 (OR=2.91, 95% CI=1.65-5.12, p=0.0001) alleles. The 7632T/A and 9893C/G polymorphisms of CYP2E1 and 1934G/A polymorphism of CYP2D6 did not associate with the disease (p>0.05). The haplotypes -1293G:9893C and -1293G:7632T:9893C were under-represented (p<0.001), whereas haplotypes -1293C:7632T, -1293C:9893C, -1293C:9893G and -1293C:7632T:9893C of the 4 CYP2E1 polymorphisms were over-represented in patients (p<0.05). CONCLUSION The CYP2E1 and NAT2 variants associated with COPD.
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Affiliation(s)
- Ehtesham Arif
- Functional Genomics Unit, Institute of Genomics and Integrative Biology, Delhi, India
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Takahara Y, Takahashi M, Wagatsuma H, Yokoya F, Zhang QW, Yamaguchi M, Aburatani H, Kawada N. Gene expression profiles of hepatic cell-type specific marker genes in progression of liver fibrosis. World J Gastroenterol 2006; 12:6473-99. [PMID: 17072980 PMCID: PMC4100637 DOI: 10.3748/wjg.v12.i40.6473] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [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 determine the gene expression profile data for the whole liver during development of dimethylni-trosamine (DMN)-induced hepatic fibrosis.
METHODS: Marker genes were identified for different types of hepatic cells, including hepatic stellate cells (HSCs), Kupffer cells (including other inflammatory cells), and hepatocytes, using independent temporal DNA microarray data obtained from isolated hepatic cells.
RESULTS: The cell-type analysis of gene expression gave several key results and led to formation of three hypotheses: (1) changes in the expression of HSC-specific marker genes during fibrosis were similar to gene expression data in in vitro cultured HSCs, suggesting a major role of the self-activating characteristics of HSCs in formation of fibrosis; (2) expression of mast cell-specific marker genes reached a peak during liver fibrosis, suggesting a possible role of mast cells in formation of fibrosis; and (3) abnormal expression of hepatocyte-specific marker genes was found across several metabolic pathways during fibrosis, including sulfur-containing amino acid metabolism, fatty acid metabolism, and drug metabolism, suggesting a mechanistic relationship between these abnormalities and symptoms of liver fibrosis.
CONCLUSION: Analysis of marker genes for specific hepatic cell types can identify the key aspects of fibrogenesis. Sequential activation of inflammatory cells and the self-supporting properties of HSCs play an important role in development of fibrosis.
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Affiliation(s)
- Yoshiyuki Takahara
- Exploratory and Applied Pharmaceutical Research Department, Pharmaceutical Company, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan.
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28
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Zhu ZZ, Cong WM, Liu SF, Xian ZH, Wu WQ, Wu MC, Gao B, Hou LF, Zhu GS. A p53 polymorphism modifies the risk of hepatocellular carcinoma among non-carriers but not carriers of chronic hepatitis B virus infection. Cancer Lett 2005; 229:77-83. [PMID: 15979781 DOI: 10.1016/j.canlet.2005.04.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Revised: 04/08/2005] [Accepted: 04/11/2005] [Indexed: 12/28/2022]
Abstract
To clarify the modifying effect of the codon 72 p53 polymorphism on hepatocellular carcinoma (HCC) stratified by chronic hepatitis B virus (HBV) infection status, 111 incident cases of HCC and 424 controls in HBV-negative subjects and 135 cases and 125 controls in HBV-positive subjects were identified. No correlation between the polymorphism and HCC risk was found when comparing the HBV-positive cases to controls. However, in HBV-negative subjects, Arg/Pro and Pro/Pro genotypes had a 1.97-fold and a 3.36-fold increased risk for HCC, respectively. In subjects with the Pro allele and family history of HCC yielded an 11.81-fold increased risk of HCC.
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Affiliation(s)
- Zhong-Zheng Zhu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, No. 225 Changhai Road, 200438 Shanghai, People's Republic of China
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Zhang XF, Bian JC, Zhang XY, Zhang ZM, Jiang F, Wang QM, Wang QJ, Cao YY, Tang BM. Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China? World J Gastroenterol 2005; 11:1457-62. [PMID: 15770721 PMCID: PMC4305687 DOI: 10.3748/wjg.v11.i10.1457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify whether the polymorphisms of the N-acetyltransferase (NAT) genes are susceptible to primary liver cancer (PLC) in Luoyang, a PLC low-incidence area of China.
METHODS: The NAT1 and NAT2 genotypes of 96 PLC cases and 173 controls were determined by PCR-RFLP. Both interaction between NAT1 or NAT2 and environmental risk factors were analyzed based on case control study.
RESULTS: Compared to the control group, the frequencies of alleles NAT1*3, NAT1*4, NAT1*10, NAT1*14B and alleles NAT2*4, NAT2*6, NAT2*7 in PLC group showed no statistically significant difference (χ2 = 2.61 and 4.16, respectively, both P>0.05). The frequencies of NAT1 genotypes NAT1*3/*3, NAT1*3/*4, NAT1*3/*10, NAT1*3/*14B, NAT1*4/*4, NAT1*4/*10, NAT1*4/*14B, NAT1*10/*10, NAT1*10/*14B, and NAT2 genotypes NAT2*4/*4, NAT2*4/*6, NAT2*4/*7, NAT2*6/*6, NAT2*6/*7 and NAT2*7/*7 also had no statistically significant difference between the two groups (χ2 = 11.86 and 2.94 respectively both, P>0.05). Neither the frequencies of rapid and slow NAT1 acetylators nor the frequencies of rapid and slow NAT2 acetylators were significantly different between the two groups (χ2 = 0.598 and 0.44, respectively, both P>0.05). The interaction between NAT1*10 and occupational exposures was found significant with an odds ratio of 3.40 (χ2 = 8.42, P = 0.004, OR 95%CI:1.03-11.22). But no interaction was found between NAT2 and any environmental risk factors.
CONCLUSION: The polymorphisms of NAT1 and NAT2 are not susceptible to PLC in Luoyang. Allele NAT1*10 interacts with occupational exposures.
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Affiliation(s)
- Xiu-Feng Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China.
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Kim YJ, Lee HS. Single Nucleotide Polymorphisms Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection. Intervirology 2005; 48:10-5. [PMID: 15785084 DOI: 10.1159/000082089] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and there are likely to explain much of the genetic diversity of individuals. Hepatocellular carcinoma (HCC) is etiologically associated with hepatitis B virus (HBV) in 80% of cases, and is the dominant cause of death among HBV carriers. Among patients with chronic HBV infection, family history is a known risk factor for the development of HCC; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be investigated. In this review, we discussed that the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC. Also, we reviewed that several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Gelatti U, Covolo L, Talamini R, Tagger A, Barbone F, Martelli C, Cremaschini F, Franceschi S, Ribero ML, Garte S, Nardi G, Donadon V, Donato F. N-Acetyltransferase-2, glutathione S-transferase M1 andT1 genetic polymorphisms, cigarette smoking and hepatocellular carcinoma: A case-control study. Int J Cancer 2005; 115:301-6. [PMID: 15688397 DOI: 10.1002/ijc.20895] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Our aim was to evaluate the role of N-acetyltransferase (NAT2) and glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) polymorphisms in hepatocellular carcinoma (HCC) according to cigarette smoking, taking into account hepatitis B (HBV) and C (HCV) viral infection as well as alcohol consumption. A hospital-based case-control study was conducted in 2 areas of north Italy. Cases (n = 200) were patients hospitalized for HCC, and controls (n = 400) were patients admitted for reasons other than liver disease, neoplasms and tobacco- and alcohol-related diseases. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method. The putative risk genotypes NAT2 slow acetylator, GSTM1 null and GSTT1 null were not associated with HCC (OR = 1.3, 95% CI 0.8-2.0; OR = 1.0, 95% CI 0.6-1.5; OR = 0.8, 95% CI 0.4-1.4, respectively). Although not statistically significant, an increase in HCC risk was observed among light smokers (1-20 pack-years) carrying GSTT1 null (OR = 1.7, 95% CI 0.6-4.7) and NAT2 slow acetylator (OR = 1.3, 95% CI 0.6-3.0) genotypes. In conclusion, there was no evidence for a gene-environment interaction in HCC risk for GSTM1, GSTT1 and NAT2 genotypes.
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Affiliation(s)
- Umberto Gelatti
- Institute of Hygiene, University of Brescia, Brescia, Italy.
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Chen ZM, Liu BQ, Boreham J, Wu YP, Chen JS, Peto R. Smoking and liver cancer in China: case-control comparison of 36,000 liver cancer deaths vs. 17,000 cirrhosis deaths. Int J Cancer 2003; 107:106-12. [PMID: 12925964 DOI: 10.1002/ijc.11342] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Liver cancer and liver cirrhosis are common causes of death in China, where chronic lifelong hepatitis B infection is a major cause of both diseases. To help determine whether smoking is a cofactor for the development of liver cancer, we ascertained retrospectively the smoking habits of 36,000 adults who had died from liver cancer (cases) and 17,000 who had died from cirrhosis (controls) in 24 Chinese cities and 74 rural counties. Calculations of the smoker vs. nonsmoker risk ratios (RR) for liver cancer mortality were standardised for age and locality. Among adult men (aged 35+) there was a 36% excess risk of death from liver cancer among smokers (smoker vs. nonsmoker standardised risk ratio [RR] =1.36, with 95% confidence interval [CI] 1.29-1.43, 2p<0.00001; attributable fraction 18%). In the general male population this indicates absolute risks of death from liver cancer before age 70 of about 4% in smokers and 3% in nonsmokers (in the absence of other causes). Most liver cancer, however, occurs among the 10-12% of men with haematological evidence of chronic hepatitis B infection, so among them the corresponding risks would be about 33% in smokers and 25% in nonsmokers. The RR was approximately independent of age, was similar in urban and rural areas, was not significantly related to the age when smoking started but was significantly (p<0.001) greater for cigarette smokers than for smokers of other forms of tobacco. Among men who smoked only cigarettes, the RR was significantly (p<0.001 for trend) related to daily consumption, with a greater hazard among those who smoked 20/day (RR 1.50, 95% CI 1.39-1.62) than among those who smoked fewer (mean 10/day: RR=1.32, 95% CI 1.23-1.41). Smoking was also associated with a significant excess of liver cancer death in women (RR 1.17, 95% CI 1.06-1.29, 2p=0.003; attributable fraction 3%), but fewer women (17%) than men (62%) were smokers, and their cigarette consumption per smoker was lower. Among women who smoked only cigarettes, there was a significantly greater hazard among those who smoked at least 20/day (mean 22/day: RR=1.45, 95% CI 1.18-1.79) than among those who smoked fewer (mean 8/day: RR=1.09, 95% CI 0.94-1.25). These associations indicate that tobacco is currently responsible for about 50,000 liver cancer deaths each year in China, chiefly among men with chronic HBV infection.
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Affiliation(s)
- Zheng-Ming Chen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Radcliffe Infirmary, University of Oxford, United Kingdom.
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Farker K, Schotte U, Scheele J, Hoffmann A. Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC)--an investigation in a department of surgical medicine. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2003; 54:387-91. [PMID: 12877350 DOI: 10.1078/0940-2993-00275] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In the multifactorial aetiology of hepatocellular carcinoma (HCC), an association and interaction between genetic polymorphisms of xenobiotic metabolizing enzymes, lifestyle factors, and cancer risk has been postulated. N-acetyltransferase (NAT2) is involved in the metabolic activation and detoxification of aromatic amines. Aromatic amines are potential hepatocarcinogens in humans. In the present study, we investigated if genetic NAT2 polymorphism is related to HCC. Genotyping of NAT2 was performed in 70 HCC patients and 87 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results of this investigation show that 46 out 70 HCC patients (65.7%) and 50 out of 87 controls (57.5%) were of the slow acetylator genotypes. The frequency of distribution of slow and rapid acetylators (genotypes) was not significantly different between cases and controls (p > 0.05). Slow acetylator genotypes were not associated with a significantly increased HCC risk (odds ratio, 1.4; 95% confidence interval, 0.74-2.72). A significant association between NAT2 genetic polymorphism and HCC was observed among smokers. Slow acetylator genotypes significantly increased the HCC risk in cigarette smokers (odds ratio, 3.5; 95% confidence interval, 1.38-9.05). Our results suggest that genetic NAT2 polymorphism may play a role in lifestyle factors-related hepatocarcinogenesis. NAT2 activity may be particulary critical in smoking related hepatocarcinogenesis.
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Affiliation(s)
- Katrin Farker
- Institute of Clinical Pharmacology, Friedrich Schiller University Jena, Germany
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Huang YS, Chern HD, Wu JC, Chao Y, Huang YH, Chang FY, Lee SD. Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma. Am J Gastroenterol 2003; 98:1417-22. [PMID: 12818290 DOI: 10.1111/j.1572-0241.2003.07452.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits. METHODS Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire. RESULTS There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; p(trend) = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007). CONCLUSIONS Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.
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Affiliation(s)
- Yi-Shin Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan
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Chen CJ, Chen DS. Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology. Hepatology 2002; 36:1046-9. [PMID: 12395312 DOI: 10.1053/jhep.2002.37084] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Yu MW, Chang HC, Chen PJ, Liu CJ, Liaw YF, Lin SM, Lee SD, Lin SC, Lin CL, Chen CJ. Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan. Int J Epidemiol 2002; 31:1008-15. [PMID: 12435776 DOI: 10.1093/ije/31.5.1008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND There is a tendency for familial aggregation of hepatocellular carcinoma (HCC). The aims of this study were to assess the degree to which familial aggregation of hepatitis B surface antigen (HBsAg) carriers accounts for familiality of HCC in families of hepatitis B-related HCC patients, and whether HCC shares a familial predisposition with liver cirrhosis among HBsAg carriers. METHODS A total of 671 first-degree relatives of HBsAg-positive HCC cases were recruited using abdominal ultrasonography and tests for HBsAg and serum aminotransferases. They were from 165 simplex families defined as having only one HCC case and 72 multiplex families with more than one case. In analyses of family history of HCC and cirrhosis, the data set consisted of 4,471 unrelated asymptomatic HBsAg carriers recruited in a prospective study. RESULTS There was no significant difference in the HBsAg-positive rate among relatives between multiplex (55.7%) and simplex (48.1%) families. Sonographic evidence of liver cirrhosis was present in 14.4% of HBsAg-positive relatives from multiplex families but in only 7.8% of HBsAg-positive relatives from simplex families (multiplex versus simplex families: adjusted odds ratio [OR] = 2.29; 95% CI: 1.10-4.77). Among unrelated asymptomatic HBsAg carriers, the adjusted OR of liver cirrhosis associated with a first-degree family history of HCC was 2.80 (95% CI: 1.68-4.66). This association was stronger in HBsAg carriers <50 years. No association was seen between family history of HCC and hepatitis activity based on elevated levels of aminotransferases. CONCLUSIONS Familial aggregation of HCC in HBsAg carriers is associated with familial clustering of liver cirrhosis.
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Affiliation(s)
- Ming-Whei Yu
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
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Yu MW, Yang YC, Yang SY, Chang HC, Liaw YF, Lin SM, Liu CJ, Lee SD, Lin CL, Chen PJ, Lin SC, Chen CJ. Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology 2002; 36:156-63. [PMID: 12085360 DOI: 10.1053/jhep.2002.33897] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
The androgen receptor (AR) gene is localized on chromosome X, and shorter CAG repeats in exon 1 of the AR gene were recently suggested to increase hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) risk among men. To examine whether the relationship between the AR-CAG repeats and HCC was also evident among women, we conducted a case-control study in Taiwan. The number of AR-CAG repeats was determined for 238 women with HCC and 354 unrelated control subjects (comprising 188 first-degree and 166 nonbiological relatives) selected from female relatives of patients with HCC. Women harboring 2 AR alleles with more than 23 CAG repeats had an increased risk of HCC (age-adjusted odds ratio [OR], 1.82; 95% CI, 1.06-3.14), compared with women with only short alleles or a single long allele. The association between harboring 2 AR alleles containing longer CAG repeats and HCC was more striking among HBV carriers (age-adjusted OR for more than 22 repeats, 2.23; 95% CI, 1.14-4.34) and particularly prominent among HBV carriers under age 53 years (age-adjusted OR, 3.16; 95% CI, 1.13-8.82). When CAG repeats were analyzed as a continuous variable, the increase in HCC risk associated with each incremental repeat in the shorter of 2 alleles in a given genotype was statistically significant among women with a first-degree relative with HCC (age-adjusted OR, 1.18; 95% CI, 1.01-1.37). No such relationship was detected among women without the family history. In conclusion, our observations suggest that the AR-CAG alleles may contribute to HCC predisposition among women through a mechanism different from that for men.
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Affiliation(s)
- Ming-Whei Yu
- Department of Public Health and Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, No. 1 Jen-Ai Road, Section 1, Room 1550, Taipei 100, Taiwan.
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Hein DW, Leff MA, Ishibe N, Sinha R, Frazier HA, Doll MA, Xiao GH, Weinrich MC, Caporaso NE. Association of prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 acetylator genotypes in a pilot case-control study. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2002; 40:161-167. [PMID: 12355549 DOI: 10.1002/em.10103] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
N-acetyltransferase-1 (NAT1) and N-acetyltransferase-2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital-based case-control study were frequency-matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08-4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56-16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55-15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations.
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Affiliation(s)
- David W Hein
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
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