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1
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Grant WB. Long Follow-Up Times Weaken Observational Diet-Cancer Study Outcomes: Evidence from Studies of Meat and Cancer Risk. Nutrients 2023; 16:26. [PMID: 38201857 PMCID: PMC10781074 DOI: 10.3390/nu16010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
For years, prospective cohort studies of diet and cancer incidence have reported smaller effects than do retrospective case-control (CC) studies. The differences have been attributed to problems with CC studies, including dietary recall bias, poor matching of cases and controls, and confounding. The hypothesis evaluated here is that long follow-up periods between ascertainment of diet and cancer incidence weaken the findings. Prospective studies of cancer incidence with respect to serum 25-hydroxyvitamin D concentration have already shown reduced benefit of higher concentrations for longer follow-up periods. Evaluating that hypothesis for dietary factors involved searching the journal literature for meta-analyses of red meat and processed meat and cancer incidence. I used findings from observational studies for bladder, breast, colorectal, and gastric cancers. To evaluate the effect of duration of follow-up time, I used two approaches. First, I plotted the relative risks for CC studies for gastric cancer with respect to consumption of 100 g/day of red meat and for bladder cancer for 50 g/day of processed meat against the interval between the dietary data and cancer incidence. Second, I compared nested CC studies of meat and cancer incidence for five breast cancer studies and one colorectal cancer study. Both approaches yielded an inverse correlation between interval or follow-up time and relative risk. My findings strongly suggest that diet near time of cancer diagnosis is more important than for longer intervals, that results from meta-analyses should be revised when possible with appropriate adjustments for duration of follow-up, and that dietary guidelines be revised accordingly.
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Affiliation(s)
- William B Grant
- Sunlight, Nutrition, and Cancer Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
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2
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Relationship between gut microbiota and colorectal cancer: Probiotics as a potential strategy for prevention. Food Res Int 2022; 156:111327. [DOI: 10.1016/j.foodres.2022.111327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/15/2022]
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3
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Le Marchand L. The role of heterocyclic aromatic amines in colorectal cancer: the evidence from epidemiologic studies. Genes Environ 2021; 43:20. [PMID: 34099058 PMCID: PMC8183058 DOI: 10.1186/s41021-021-00197-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 05/31/2021] [Indexed: 11/29/2022] Open
Abstract
Since Dr. Sugimura’s discovery of heterocyclic aromatic amines (HAA) in broiled fish, many epidemiological studies have been conducted to investigate their role in human cancers, often focusing on colorectal cancer. The difficulty in measuring HAA exposure from meat and fish intake in these studies has resulted in inconsistent findings. Because studying individuals who may be particularly susceptible to the carcinogenic effects of HAA might facilitate the demonstration of a link with cancer, multiple studies have focused on individuals with the high activity phenotype for CYP1A2 and/or NAT2, the two main metabolic enzymes involved in the bioactivation of HAA. These investigations have also yielded inconsistent results. Two recent large pooled analyses of colorectal cancer studies have helped clarify the overall evidence. One was conducted in whites and reported no interaction of red meat intake and NAT2 genotype on risk in Whites. The other was conducted in Japanese and African Americans, two populations with high rates of the disease and a prevalence of the at-risk rapid NAT2 phenotype 10- and 2-fold greater than in whites, respectively. In those groups, a significant interaction was found, with the association of red meat with colorectal cancer being strongest among individuals with the rapid NAT2 phenotype, intermediate among those with the intermediate phenotype and not significant among those with the slow NAT2 phenotype. Recent research on biomarkers has focused on PhIP hair content, as a marker of exposure to HAA, and on DNA adducts using new sensitive quantitative methods, as markers of early biological effects. These advances, when brought to bear, may contribute greatly to the further elucidation of the carcinogenicity of HAA in humans.
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Affiliation(s)
- Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 9681, USA.
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4
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Hattinger CM, Biason P, Iacoboni E, Gagno S, Fanelli M, Tavanti E, Vella S, Ferrari S, Roli A, Roncato R, Giodini L, Scotlandi K, Picci P, Toffoli G, Serra M. Candidate germline polymorphisms of genes belonging to the pathways of four drugs used in osteosarcoma standard chemotherapy associated with risk, survival and toxicity in non-metastatic high-grade osteosarcoma. Oncotarget 2018; 7:61970-61987. [PMID: 27566557 PMCID: PMC5308704 DOI: 10.18632/oncotarget.11486] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 07/29/2016] [Indexed: 02/03/2023] Open
Abstract
This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery. Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort). Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2_1249A/G, GGH_452T/C, TP53_IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1_1236T/C, ABCC2_1249A/G, ABCC2_3972A/G, ERCC1_8092T/G, XPD_23591A/G, XRCC3_18067T/C, MTHFR_1298A/C and GGH_16T/C were associated with elevated risk for toxicity development (p < 0.05). The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future.
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Affiliation(s)
- Claudia M Hattinger
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Paola Biason
- National Institute of Health and Medical Research (INSERM), Unity 892, University of Medicine of Angers, Angers, France
| | - Erika Iacoboni
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Sara Gagno
- Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy
| | - Marilù Fanelli
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Elisa Tavanti
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Serena Vella
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Stefano Ferrari
- Chemotherapy Ward of Muscoloskeletal Tumours, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Andrea Roli
- Department of Computer Science and Engineering (DISI), University of Bologna, Cesena, Italy
| | - Rossana Roncato
- Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy
| | - Luciana Giodini
- Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy
| | - Katia Scotlandi
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Piero Picci
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, National Cancer Institute, Aviano, Italy
| | - Massimo Serra
- Laboratory of Experimental Oncology, Orthopaedic Rizzoli Institute, Bologna, Italy
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5
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Huang J, Liu Y, Vitale S, Penning TM, Whitehead AS, Blair IA, Vachani A, Clapper ML, Muscat JE, Lazarus P, Scheet P, Moore JH, Chen Y. On meta- and mega-analyses for gene-environment interactions. Genet Epidemiol 2017; 41:876-886. [PMID: 29110346 DOI: 10.1002/gepi.22085] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 08/01/2017] [Accepted: 08/09/2017] [Indexed: 01/09/2023]
Abstract
Gene-by-environment (G × E) interactions are important in explaining the missing heritability and understanding the causation of complex diseases, but a single, moderately sized study often has limited statistical power to detect such interactions. With the increasing need for integrating data and reporting results from multiple collaborative studies or sites, debate over choice between mega- versus meta-analysis continues. In principle, data from different sites can be integrated at the individual level into a "mega" data set, which can be fit by a joint "mega-analysis." Alternatively, analyses can be done at each site, and results across sites can be combined through a "meta-analysis" procedure without integrating individual level data across sites. Although mega-analysis has been advocated in several recent initiatives, meta-analysis has the advantages of simplicity and feasibility, and has recently led to several important findings in identifying main genetic effects. In this paper, we conducted empirical and simulation studies, using data from a G × E study of lung cancer, to compare the mega- and meta-analyses in four commonly used G × E analyses under the scenario that the number of studies is small and sample sizes of individual studies are relatively large. We compared the two data integration approaches in the context of fixed effect models and random effects models separately. Our investigations provide valuable insights in understanding the differences between mega- and meta-analyses in practice of combining small number of studies in identifying G × E interactions.
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Affiliation(s)
- Jing Huang
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Yulun Liu
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Steve Vitale
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Trevor M Penning
- Department of Systems Pharmacology and Translational Therapeutics, Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Alexander S Whitehead
- Department of Systems Pharmacology and Translational Therapeutics, Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Ian A Blair
- Department of Systems Pharmacology and Translational Therapeutics, Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Anil Vachani
- Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Margie L Clapper
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America
| | - Joshua E Muscat
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania, United States of America
| | - Philip Lazarus
- Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, United States of America
| | - Paul Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jason H Moore
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Yong Chen
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
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6
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Procopciuc LM, Osian G, Iancu M. N-acetyl transferase 2/environmental factors and their association as a modulating risk factor for sporadic colon and rectal cancer. J Clin Lab Anal 2016; 31. [PMID: 27883249 DOI: 10.1002/jcla.22098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/26/2016] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES The aim of this study was to evaluate the association between environmental factors and colon or rectal cancer after adjusting for N-acetyl transferase 2 (NAT2) phenotypes. METHODS Ninety-six patients with sporadic colon cancer, 54 with sporadic rectal cancer and 162 control subjects were genotyped for NAT2-T341C, G590A, G857A, A845C, and C481T using sequencing and PCR-RFLP analysis. RESULTS The risk for colon cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*6B-G590A, NAT2*7B-G857A, NAT2*18-A845C, and NAT2*5A-C481T. The risk for rectal cancer was increased in carriers of the homozygous negative genotypes for NAT2*5C-T341C, NAT2*7B-G857A, and NAT2*5A-C481T. High fried red meat intake associated with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele determines a risk of 2.39 (P=.002), 2.39 (P=.002), 2.37 (P=.002), 2.28 (P=.004), and 2.51 (P=.001), respectively, for colon cancer, whereas in the case of rectal cancer, the risk increased to 7.55 (P<.001), 7.7 (P<.001), 7.83 (P<.001), 7.51 (P<.001), and 8.62 (P<.001), respectively. Alcohol consumption associated with the NAT2 -T341C, G590A, G857A, A845C, and C481T rapid acetylator allele induces a risk of 10.63 (P<.001), 12.04 (P<.001), 9.76 (P<.001), 10.25 (P<.001), and 9.54 (P<.001), respectively, for colon cancer, whereas the risk for rectal cancer is 9.72 (P<.001), 11.24 (P<.001), 13.07 (P<.001), 10.04 (P<.001), and 9.43 (P<.001), respectively. Smokers with NAT2-T341C, G590A, G857A, A845C, and C481T rapid acetylator allele have a risk of 4.87, 4.25, 4.18, 3.81, and 3.82, respectively, to develop colon cancer. CONCLUSIONS Fried red meat, alcohol, and smoking increase the risk of sporadic CRC, especially of colon cancer, in the case of rapid acetylators for the NAT2 variants.
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Affiliation(s)
- Lucia M Procopciuc
- Department of Medical Biochemistry, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Gelu Osian
- Multi Organ Transplant Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Mihaela Iancu
- Department of Medical Informatics and Biostatistics, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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7
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Kasajova P, Holubekova V, Mendelova A, Lasabova Z, Zubor P, Kudela E, Biskupska-Bodova K, Danko J. Active cigarette smoking and the risk of breast cancer at the level of N-acetyltransferase 2 (NAT2) gene polymorphisms. Tumour Biol 2016; 37:7929-37. [PMID: 26700672 DOI: 10.1007/s13277-015-4685-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 12/16/2015] [Indexed: 02/05/2023] Open
Abstract
The aim of our study was to assess the correlation between the tobacco exposure and NAT2 gene (rs1041983 C/T, rs1801280 T/C, rs1799930 G/A) polymorphisms in association with breast cancer development. We wanted to determine the prognostic clinical importance of these polymorphisms in association with smoking and breast cancer. For the detection of possible association between smoking, NAT2 gene polymorphisms, and the risk of breast cancer, we designed a case-controlled study with 198 patients enrolled, 98 breast cancer patients and 100 healthy controls. Ten milliliters of peripheral blood from the cubital vein was withdrawn from every patient. The HRM (high resolution melting) analysis was used for the detection of three abovementioned NAT2 gene polymorphisms. When comparing a group of women smoking more than 5 cigarettes a day with the patients smoking fewer than 5 cigarettes a day, we found out that if women were the carriers of aberrant AA genotype for rs1799930, the first group of women had higher risk of breast carcinoma than the second group. If patients were the carriers of aberrant TT genotype for rs1041983, for rs1801280CC genotype, and rs1799930AA genotype and they smoked more than 5 cigarettes a day, they had higher risk of malignant breast disease than never-smoking women. Our results confirm the hypothesis that NAT2 gene polymorphisms (rs1041983 C/T, rs1801280 T/C, and rs1799930 G/A) in association with long-period active smoking could be the possible individual risk-predicting factors for breast cancer development in the population of Slovak women.
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Affiliation(s)
- Petra Kasajova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
| | - Veronika Holubekova
- Biomedical Center Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Andrea Mendelova
- Biomedical Center Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Zora Lasabova
- Biomedical Center Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Pavol Zubor
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Erik Kudela
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Kristina Biskupska-Bodova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Jan Danko
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
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8
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Wang H, Iwasaki M, Haiman CA, Kono S, Wilkens LR, Keku TO, Berndt SI, Tsugane S, Le Marchand L. Interaction between Red Meat Intake and NAT2 Genotype in Increasing the Risk of Colorectal Cancer in Japanese and African Americans. PLoS One 2015; 10:e0144955. [PMID: 26683305 PMCID: PMC4684304 DOI: 10.1371/journal.pone.0144955] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 11/25/2015] [Indexed: 01/28/2023] Open
Abstract
Heterocyclic aromatic amines formed in cooked meat may be an underlying mechanism for the red meat-colorectal cancer (CRC) association. These compounds require bioactivaction by N-acetyltransferase 2 (NAT2). An interaction effect between red meat consumption and NAT2 in increasing CRC risk has been inconsistently reported in whites. We investigated this interaction in two populations in which the high-activity rapid NAT2 phenotype is 10- and 2-fold more common than in whites. We meta-analyzed four studies of Japanese (2,217 cases, 3,788 controls) and three studies of African Americans (527 cases, 4,527 controls). NAT2 phenotype was inferred from an optimized seven-SNP genotyping panel. Processed and total red meat intakes were associated with an increased CRC risk in Japanese and in both ethnic groups combined (P’s ≤ 0.002). We observed an interaction between processed meat intake and NAT2 in Japanese (P = 0.04), African Americans (P = 0.02), and in both groups combined (P = 0.006). The association of processed meat with CRC was strongest among individuals with the rapid NAT2 phenotype (combined analysis, OR for highest vs. lowest quartile: 1.62, 95% CI: 1.28–2.05; Ptrend = 8.0×10−5), intermediate among those with the intermediate NAT2 phenotype (1.29, 95% CI: 1.05–1.59; Ptrend = 0.05) and null among those with the slow phenotype (Ptrend = 0.45). A similar interaction was found for NAT2 and total red meat (Pinteraction = 0.03). Our findings support a role for NAT2 in modifying the association between red meat consumption and CRC in Japanese and African Americans.
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Affiliation(s)
- Hansong Wang
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
| | - Motoki Iwasaki
- Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Suminori Kono
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Lynne R. Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
| | - Temitope O. Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Shoichiro Tsugane
- Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
- * E-mail:
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9
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Ma G, Cheng N, Su H, Liu Y. Exploring the substrate-assisted acetylation mechanism by UDP-linked sugar N-acetyltransferase from QM/MM calculations: the role of residue Asn84 and the effects of starting geometries. RSC Adv 2015. [DOI: 10.1039/c4ra13278e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Based on the QM/MM calculation, we revised the proposed mechanism ofN-acetyltransferase and explore the role of Asn84 and the effects of starting geometries.
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Affiliation(s)
- Guangcai Ma
- School of Chemistry and Chemical Engineering
- Shandong University
- Jinan
- China
| | - Na Cheng
- School of Chemistry and Chemical Engineering
- Shandong University
- Jinan
- China
| | - Hao Su
- School of Chemistry and Chemical Engineering
- Shandong University
- Jinan
- China
| | - Yongjun Liu
- School of Chemistry and Chemical Engineering
- Shandong University
- Jinan
- China
- Key Laboratory of Tibetan Medicine Research
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Abstract
The report by Aldred Scott Warthin in 1913 of a cancer family history and expanded on by Henry T. Lynch demonstrated one of the most enduring traits observed in patients with Lynch syndrome. The recognition of a variety of malignancies occurring at differing ages within a single family suggested the role of genetic variance on disease expression in an autosomal dominantly inherited genetic condition. With the identification of the genetic basis of Lynch syndrome and the subsequent collection of families and their medical records it has become possible to identify subtle genetic effects that influence the age at which disease onset occurs in this cancer predisposition. Knowledge about genetic modifiers influencing disease expression has the potential to be used to personalise prophylactic screening measures to maximise the benefits for family members and their carers.
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11
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NAT2 slow acetylation genotypes contribute to asthma risk among Caucasians: evidence from 946 cases and 1,091 controls. Mol Biol Rep 2014; 41:1849-55. [PMID: 24442317 DOI: 10.1007/s11033-014-3034-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 01/03/2014] [Indexed: 10/25/2022]
Abstract
NAT2 plays a critical role in external chemical detoxification. Thus, polymorphism of NAT2 has been suggested to associate with several disorders. A number of studies have been devoted to the relationship between NAT2 polymorphism and asthma risk. However, the results were inconclusive. In this study we aimed to derive a more precise estimation of the association. A literature search in the common databases was conducted and then meta-analyses evaluating the association of NAT2 polymorphism and asthma risk were performed. Eligible studies were identified for the period up to May 2013. A total of five case-control studies containing 946 cases and 1,091 controls were lastly included for analysis. The overall data showed that slow acetylators of NAT2 might have an association with increased asthma risk (OR 2.20; 95% CI 1.31-3.72). The pooled data suggest that slow acetylators of NAT2 might contribute to asthma risk among Caucasians. Future studies are needed to confirm this conclusion.
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12
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Theodoratou E, Montazeri Z, Hawken S, Allum GC, Gong J, Tait V, Kirac I, Tazari M, Farrington SM, Demarsh A, Zgaga L, Landry D, Benson HE, Read SH, Rudan I, Tenesa A, Dunlop MG, Campbell H, Little J. Systematic Meta-Analyses and Field Synopsis of Genetic Association Studies in Colorectal Cancer. J Natl Cancer Inst 2012; 104:1433-57. [DOI: 10.1093/jnci/djs369] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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13
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Zhuo W, Zhang L, Qiu Z, Cai L, Zhu B, Chen Z. Association of NAT2 polymorphisms with risk of colorectal adenomas: Evidence from 3,197 cases and 4,681 controls. Exp Ther Med 2012; 4:895-900. [PMID: 23226745 PMCID: PMC3493788 DOI: 10.3892/etm.2012.695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 08/29/2012] [Indexed: 12/14/2022] Open
Abstract
Previous studies have implicated NAT2 polymorphisms as risk factors for various types of cancer. Colorectal adenomas are recognized as a pre-neoplastic lesion. A growing body of research documenting the association of NAT2 polymorphisms with the risk of colorectal adenomas has yielded conflicting results. The aim of the present study was to derive a more precise estimation of this association. Meta-analyses assessing the association of NAT2 variants with colorectal adenomas were conducted and subgroup analyses on smoking status and the source of the controls were also performed. Eligible studies were identified for the period before March 2012. A total of seven case-control studies, including 3,197 cases and 4,681 controls, were selected following extensive searching and screening. In the overall data, no associations between NAT2 polymorphisms and colorectal adenomas were observed [odds ratio (OR), 1.04; 95% confidence interval (CI), 0.90-1.21]. However, in the subgroup analysis concerning smoking status, slow acetylator variants were revealed to be correlated with increased colorectal adenoma risk in individuals who have smoked (OR, 1.31; 95% CI, 1.04-1.64). In conclusion, the data of the present study suggested that NAT2 polymorphisms may be a risk factor for colorectal adenomas in individuals who have a history of smoking.
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Affiliation(s)
- Wenlei Zhuo
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University
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14
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Liu J, Ding D, Wang X, Chen Y, Li R, Zhang Y, Luo R. N-acetyltransferase polymorphism and risk of colorectal adenoma and cancer: a pooled analysis of variations from 59 studies. PLoS One 2012; 7:e42797. [PMID: 22905173 PMCID: PMC3419224 DOI: 10.1371/journal.pone.0042797] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Accepted: 07/11/2012] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship. METHODS/PRINCIPAL FINDINGS A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk (OR 0.99, 95% CI 0.91-1.07). We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC (OR 1.07, 95% CI 1.01-1.13). There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk (NAT1: OR 1.14, 95% CI 0.99-1.29; NAT2: OR 0.94, 95% CI 0.86-1.03). CONCLUSION This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk.
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Affiliation(s)
- Jinxin Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, GuangZhou, China
- Department of Oncology, Longgang District Central Hospital of ShenZhen, ShenZhen, China
| | - Dapeng Ding
- Institute of Genetic Engineering, Southern Medical University, Guangzhou, China
| | - Xiaoxue Wang
- Department of Proctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yizhi Chen
- Department of Health Records, Longgang District Central Hospital of ShenZhen, ShenZhen, China
| | - Rong Li
- Department of Oncology, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Ying Zhang
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Rongcheng Luo
- Department of Oncology, Nanfang Hospital, Southern Medical University, GuangZhou, China
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Zhuo XL, Ling JJ, Zhou Y, Zhao HY, Song YF, Tan YH. NAT2 polymorphisms with oral carcinoma susceptibility: a meta-analysis. Mol Biol Rep 2012; 39:8813-9. [PMID: 22722991 DOI: 10.1007/s11033-012-1744-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 06/07/2012] [Indexed: 12/18/2022]
Abstract
Published data have implicated NAT2 polymorphisms as risk factors for various cancers. A number of studies have focused on the association of NAT2 polymorphisms with susceptibility to oral carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship. We first carried out a deliberate search in the databases without a language limitation, covering all papers published up to Dec 2011. A total of seven case-control studies including 1,379 cases and 1,868 controls were selected and the relevant data were extracted for systematic meta-analyses. No significant association was found for the overall data (OR: 1.04, 95 % CI: 0.79-1.39). In subgroup analyses according to ethnicity, slow acetylators might increase oral cancer risk among Asians (OR: 1.38, 95 % CI: 1.04-1.82) but not Caucasians or Mixed races. The data suggested that NAT2 polymorphisms might be a low-penetrant risk factor for oral carcinoma in Asians.
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Affiliation(s)
- Xian-Lu Zhuo
- Department of Stomatology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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Jonas DE, Wilt TJ, Taylor BC, Wilkins TM, Matchar DB. Chapter 11: challenges in and principles for conducting systematic reviews of genetic tests used as predictive indicators. J Gen Intern Med 2012; 27 Suppl 1:S83-93. [PMID: 22648679 PMCID: PMC3364361 DOI: 10.1007/s11606-011-1898-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In this paper, we discuss common challenges in and principles for conducting systematic reviews of genetic tests. The types of genetic tests discussed are those used to 1). determine risk or susceptibility in asymptomatic individuals; 2). reveal prognostic information to guide clinical management in those with a condition; or 3). predict response to treatments or environmental factors. This paper is not intended to provide comprehensive guidance on evaluating all genetic tests. Rather, it focuses on issues that have been of particular concern to analysts and stakeholders and on areas that are of particular relevance for the evaluation of studies of genetic tests. The key points include: The general principles that apply in evaluating genetic tests are similar to those for other prognostic or predictive tests, but there are differences in how the principles need to be applied or the degree to which certain issues are relevant. A clear definition of the clinical scenario and an analytic framework is important when evaluating any test, including genetic tests. Organizing frameworks and analytic frameworks are useful constructs for approaching the evaluation of genetic tests. In constructing an analytic framework for evaluating a genetic test, analysts should consider preanalytic, analytic, and postanalytic factors; such factors are useful when assessing analytic validity. Predictive genetic tests are generally characterized by a delayed time between testing and clinically important events. Finding published information on the analytic validity of some genetic tests may be difficult. Web sites (FDA or diagnostic companies) and gray literature may be important sources. In situations where clinical factors associated with risk are well characterized, comparative effectiveness reviews should assess the added value of using genetic testing along with known factors compared with using the known factors alone. For genome-wide association studies, reviewers should determine whether the association has been validated in multiple studies to minimize both potential confounding and publication bias. In addition, reviewers should note whether appropriate adjustments for multiple comparisons were used.
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Affiliation(s)
- Daniel E Jonas
- Department of Medicine, Cecil G. Sheps Center for Health Services Research, and Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599, USA.
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Millner LM, Doll MA, Stepp MW, States JC, Hein DW. Functional analysis of arylamine N-acetyltransferase 1 (NAT1) NAT1*10 haplotypes in a complete NATb mRNA construct. Carcinogenesis 2011; 33:348-55. [PMID: 22114069 DOI: 10.1093/carcin/bgr273] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
N-acetyltransferase 1 (NAT1) catalyzes N-acetylation of arylamines as well as the O-acetylation of N-hydroxylated arylamines. O-acetylation leads to the formation of electrophilic intermediates that result in DNA adducts and mutations. NAT1*10 is the most common variant haplotype and is associated with increased risk for numerous cancers. NAT1 is transcribed from a major promoter, NATb, and an alternative promoter, NATa, resulting in messenger RNAs (mRNAs) with distinct 5'-untranslated regions (UTRs). To best mimic in vivo metabolism and the effect of NAT1*10 polymorphisms on polyadenylation usage, pcDNA5/Flp recombination target plasmid constructs were prepared for transfection of full-length human mRNAs including the 5'-UTR derived from NATb, the open reading frame and 888 nucleotides of the 3'-UTR. Following stable transfection of NAT1*4, NAT1*10 and an additional NAT1*10 variant (termed NAT1*10B) into nucleotide excision repair-deficient Chinese hamster ovary cells, N- and O-acetyltransferase activity (in vitro and in situ), mRNA and protein expression were higher in cells transfected with NAT1*10 and NAT1*10B than in cells transfected with NAT1*4 (P < 0.05). Consistent with NAT1 expression and activity, cytotoxicity and hypoxanthine phosphoribosyl transferase mutants following 4-aminobiphenyl exposures were higher in NAT1*10 than in NAT1*4 transfected cells. Ribonuclease protection assays showed no difference between NAT1*4 and NAT1*10. However, protection of one probe by NAT1*10B was not observed with NAT1*4 or NAT1*10, suggesting additional mechanisms that regulate NAT1*10B. The higher mutants in cells transfected with NAT1*10 and NAT1*10B are consistent with an increased cancer risk for individuals possessing NAT1*10 haplotypes.
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Affiliation(s)
- Lori M Millner
- Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville, Louisville, KY 40202, USA
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18
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Ying XJ, Dong P, Shen B, Wang J, Wang S, Wang G. Possible association of NAT2 polymorphism with laryngeal cancer risk: an evidence-based meta-analysis. J Cancer Res Clin Oncol 2011; 137:1661-7. [PMID: 21877196 DOI: 10.1007/s00432-011-1045-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Accepted: 08/15/2011] [Indexed: 11/30/2022]
Abstract
PURPOSE N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of various potential carcinogens, which can be subdivided into rapid and slow acetylation phenotype according to the different genotypes. A number of studies have been devoted to the association of NAT2 polymorphism with susceptibility to laryngeal carcinoma; however, the results were inconsistent and inconclusive. The aim of the present study was to conduct a meta-analysis assessing the possible association of NAT2 polymorphism with laryngeal cancer risk. METHODS The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure until February 2011 and selected on the basis of the established inclusion criteria for publications, and then a meta-analysis was performed to quantitatively summarize the association of NAT2 polymorphism with laryngeal cancer susceptibility. RESULTS Seven studies were included in the present meta-analysis, which described a total of 980 laryngeal cancer cases and 1,487 controls. The overall odds ratio (OR) for NAT2 slow and rapid acetylators was 0.99 (95% CI = 0.71-1.38) and 1.01 (95% CI = 0.72-1.40), respectively. When stratifying for race, the pooled ORs for NAT2 slow acetylator were 1.99 (95% CI = 1.10-3.63) in Asians and 0.85 (95% CI = 0.62-1.15) in Caucasians, and the pooled ORs for NAT2 rapid acetylator were 0.50 (95% CI = 0.28-0.91) in Asians and 1.18 (95% CI = 0.87-1.60) in Caucasians. CONCLUSIONS This meta-analysis suggested that there was overall lack of association between NAT2 polymorphism and laryngeal cancer risk; however, NAT2 slow acetylation may contribute to a risk factor for laryngeal cancer in Asians but not in Caucasians.
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Affiliation(s)
- Xin-Jiang Ying
- Department of Otolaryngology-Head and Neck Surgery, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China.
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Mortensen HM, Froment A, Lema G, Bodo JM, Ibrahim M, Nyambo TB, Omar SA, Tishkoff SA. Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations. Pharmacogenomics 2011; 12:1545-58. [PMID: 21995608 DOI: 10.2217/pgs.11.88] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
UNLABELLED Functional variability at the arylamine N-acetyltransferase genes is associated with drug response in humans and may have been adaptive in the past owing to selection pressure from diet and exposure to toxins during human evolution. AIMS We have characterized nucleotide variation at the NAT1 and NAT2 genes, and at the NATP1 pseudogene in global human populations, including many previously under-represented African populations, in order to identify potential functional variants and to understand the role that natural selection has played in shaping variation at these loci in globally diverse populations. MATERIALS & METHODS We have resequenced approximately 2800 bp for each of the NAT1 and NAT2 gene regions, as well as the pseudogene NATP1, in 197 African and 132 nonAfrican individuals. RESULTS & CONCLUSION We observe a signature of balancing selection maintaining variation in the 3'-UTR of NAT1, suggesting that these variants may play a functional role that is currently undefined. In addition, we observed high levels of nonsynonymous functional variation at the NAT2 locus that differs amongst ethnically diverse populations.
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Affiliation(s)
- Holly M Mortensen
- Department of Biology, University of Maryland, College Park, MD, USA
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Rajasekaran M, Abirami S, Chen C. Effects of single nucleotide polymorphisms on human N-acetyltransferase 2 structure and dynamics by molecular dynamics simulation. PLoS One 2011; 6:e25801. [PMID: 21980537 PMCID: PMC3183086 DOI: 10.1371/journal.pone.0025801] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 09/11/2011] [Indexed: 11/22/2022] Open
Abstract
Background Arylamine N-acetyltransferase 2 (NAT2) is an important catalytic enzyme that metabolizes the carcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E, are classified as slow acetylators, whereas the wild-type NAT2 is classified as a fast acetylator. The slow acetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutations have previously been characterized, but the structural basis behind the reduced catalytic activity and reduced protein level is not clear. Methodology/Principal Findings We performed multiple molecular dynamics simulations of these mutants as well as NAT2 to investigate the structural and dynamical effects throughout the protein structure, specifically the catalytic triad, cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confined to the inter-domain, domain 3 and 17-residue insert region, where the flexibility was significantly reduced relative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conformation, cofactor binding site, substrate binding pocket size/shape and electrostatic potential. Conclusions/Significance Our results showed that the dynamical properties of all the mutant structures, especially in inter-domain, domain 3 and 17-residue insert region were affected in the same manner. Similarly, the electrostatic potential of all the mutants were altered and also the functionally important regions such as catalytic triad, cofactor binding site, and substrate binding pocket adopted different orientation and/or conformation relative to the wild-type that may affect the functions of the mutants. Overall, our study may provide the structural basis for reduced catalytic activity and protein level, as was experimentally observed for these polymorphisms.
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Affiliation(s)
- M. Rajasekaran
- Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
- Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China
- Chemical Biology and Molecular Biophysics, Institute of Biological Chemistry, Taiwan International Graduate Program, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
| | - Santhanam Abirami
- Chemical Biology and Molecular Biophysics, Institute of Biological Chemistry, Taiwan International Graduate Program, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
- Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
- Institute of Biochemical Sciences, College of Life Sciences, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Chinpan Chen
- Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China
- * E-mail:
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Turesky RJ, Le Marchand L. Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: lessons learned from aromatic amines. Chem Res Toxicol 2011; 24:1169-214. [PMID: 21688801 PMCID: PMC3156293 DOI: 10.1021/tx200135s] [Citation(s) in RCA: 222] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct, and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels, and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs, and thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and emerging biomarkers of HAAs that may be implemented in molecular epidemiology studies are discussed.
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Affiliation(s)
- Robert J Turesky
- Division of Environmental Health Sciences, Wadsworth Center , Albany, New York 12201, United States.
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Silva TDD, Felipe AV, Lima JMD, Oshima CTF, Forones NM. N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer. World J Gastroenterol 2011; 17:760-5. [PMID: 21390146 PMCID: PMC3042654 DOI: 10.3748/wjg.v17.i6.760] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 11/02/2010] [Accepted: 11/09/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the possible association between meat intake, cigarette smoking and N-acetyltransferase 2 (NAT2) genetic polymorphisms on colorectal cancer (CRC) risk.
METHODS: Patients with CRC were matched for gender and age to healthy controls. Meat intake and cigarette smoking were assessed using a specific frequency questionnaire. DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by polymerase chain reaction-restriction fragment length polymorphism. Five NAT2 alleles were studied (WT, M1, M2, M3 and M4) using specific digestion enzymes.
RESULTS: A total of 147 patients with colorectal cancer (76 women and 90 men with colon cancer) and 212 controls were studied. The mean age of the two groups was 62 years. More than half the subjects (59.8% in the case group and 51.9% in the control group) were NAT2 slow acetylators. The odds ratio for colorectal cancer was 1.38 (95% CI: 0.90-2.12) in slow acetylators. Although the number of women was small (n = 76 in the case group), the cancer risk was found to be lower in intermediate (W/Mx) acetylators [odds ratio (OR): 0.55, 95% confidence interval (95% CI): 0.29-1.02]. This difference was not observed in men (OR: 0.56, 95% CI: 0.16-2.00). Among NAT2 fast acetylators (W/W or W/Mx), meat consumption more than 3 times a week increased the risk of colorectal cancer (OR: 2.05, 95% CI: 1.01-4.16). In contrast, cigarette smoking increased the risk of CRC among slow acetylators (OR: 1.97, 95% CI: 1.02-3.79).
CONCLUSION: The risk of CRC was higher among fast acetylators who reported a higher meat intake. Slow NAT2 acetylation was associated with an increased risk of CRC.
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Khelil M, Zenati A, Makrelouf M, Otmane A, Tayebi B. Polymorphisms in NAT2 gene and atherosclerosis in an Algerian population. Arch Med Res 2010; 41:215-20. [PMID: 20682180 DOI: 10.1016/j.arcmed.2010.03.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 03/19/2010] [Indexed: 01/23/2023]
Abstract
BACKGROUND AND AIMS The etiology of atherosclerosis is multifactorial. Genetic and environmental factors are involved in the development of atherosclerosis. Human arylamine N-acetyltransferase 2 (NAT2) is an important metabolizing enzyme that exhibits genetic polymorphisms and modifies individual response and/or toxicity to many xenobiotics. We undertook this study to investigate the NAT2 polymorphisms in patients with atherosclerosis. METHODS Genotyping for NAT2 alleles was performed using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) in 285 Algerian patients with atherosclerosis and 286 controls. RESULTS There was no association between NAT2 polymorphisms and atherosclerosis risk. However, the haplotype NAT2(*)5F decreased susceptibility to the disease (p = 0.005, OR = 0.55, 95% CI = 0.37-0.84). The frequency of the slow acetylator phenotype was approximately 50% in both cases and controls. CONCLUSIONS These results suggest that NAT2 polymorphisms may not be involved in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Malika Khelil
- Département de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari, Boumediène, Alger, Algérie.
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Zhong X, Hui C, Xiao-Ling W, Yan L, Na L. NAT2 polymorphism and gastric cancer susceptibility: a meta-analysis. Arch Med Res 2010; 41:275-80. [PMID: 20637371 DOI: 10.1016/j.arcmed.2010.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Accepted: 06/02/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS N-acetyltransferase 2 (NAT2) is a polymorphic enzyme that plays an important role in the metabolism of various potential carcinogens. NAT2 can be subdivided into rapid and slow acetylation phenotype according to the different genotypes. Studies investigating the association between NAT2 polymorphisms and gastric cancer risk in humans showed conflicting results. The aim of this study was to conduct a meta-analysis assessing the association of NAT2 acetylation phenotype with risk of gastric cancer. METHODS Relevant studies were identified through a search of Embase, ISI Web of Knowledge, Medline and Chinese Biomedicine Database until January 2010. A meta-analysis was conducted to quantitatively summarize association of NAT2 acetylation phenotype with GC susceptibility. RESULTS Thirteen studies were included in the present meta-analysis, which described a total of 2,391 gastric cancer cases and 3,237 controls. The combined ORs for NAT2 slow or rapid acetylator and gastric cancer risk were 1.05 (95% CI 0.810-1.35) and 0.96 (95% CI 0.74-1.23), respectively. When stratifying for race and Lauren's classification, results also showed no significant association in genotype distribution between gastric cancer and control. CONCLUSIONS No association is found between NAT2 acetylation status and gastric cancer risk in this meta-analysis.
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Affiliation(s)
- Xu Zhong
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Gra O, Mityaeva O, Berdichevets I, Kozhekbaeva Z, Fesenko D, Kurbatova O, Goldenkova-Pavlova I, Nasedkina T. Microarray-Based Detection ofCYP1A1,CYP2C9,CYP2C19,CYP2D6,GSTT1,GSTM1,MTHFR,MTRR,NQO1,NAT2,HLA-DQA1, andAB0Allele Frequencies in Native Russians. Genet Test Mol Biomarkers 2010; 14:329-42. [DOI: 10.1089/gtmb.2009.0158] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Olga Gra
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russian Federation
| | - Olga Mityaeva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Iryna Berdichevets
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russian Federation
| | - Zhanna Kozhekbaeva
- Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
| | - Denis Fesenko
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Olga Kurbatova
- Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russian Federation
| | | | - Tatyana Nasedkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
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Association between dietary heterocyclic amine levels, genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 and risk of stomach cancer: a hospital-based case-control study in Japan. Gastric Cancer 2010; 12:198-205. [PMID: 20047124 DOI: 10.1007/s10120-009-0523-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 09/01/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the associations between grilled (broiled) or barbecued meats or fish intake and stomach cancer risk have been investigated, the evidence implicating heterocyclic amine (HCA) intake as a cause of stomach cancer is limited. We conducted a case-control study to investigate the association between HCA intake and stomach cancer risk. We also investigated the possible effect of genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on stomach cancer. METHODS HCA exposure data were assessed using a self-administered food-frequency questionnaire, and estimated HCA intake was verified by measuring 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) values in human hair. A total of 149 cases and 296 controls were included in the analyses. Odds ratios (ORs) were calculated, using conditional logistic regression analysis, to compare intake levels between the first and third tertiles. RESULTS Results showed no statistically significant increase in the risk of stomach cancer with respect to total HCA intake (OR, 1.11; 95% confidence interval [CI], 0.36, 3.49), or with respect to the intake of individual HCAs; namely, PhIP, 2-amino-3, 4-dimethylimidazo[4,5-f]quinoline (MeIQ), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 did not influence the association of HCA intake with stomach cancer. CONCLUSION In the present study, with a limited sample size of subjects with low HCA exposure, no association was found between HCA intake and stomach cancer, nor was there any evidence of any influence by genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on the risk of stomach cancer.
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Kobayashi M, Otani T, Iwasaki M, Natsukawa S, Shaura K, Koizumi Y, Kasuga Y, Sakamoto H, Yoshida T, Tsugane S. Association between dietary heterocyclic amine levels, genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 and risk of colorectal cancer: a hospital-based case-control study in Japan. Scand J Gastroenterol 2010; 44:952-9. [PMID: 19452301 DOI: 10.1080/00365520902964721] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Although associations between dietary HCA intake and colorectal cancer risk have been investigated, results have been suggestive but inconsistent. The aim of this hospital-based case-control study was to examine the impact of heterocyclic amine (HCA) intake on colorectal cancer risk. A further objective was to investigate the possible effect of genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 on colorectal cancer. MATERIAL AND METHODS HCA exposure data were assessed using a self-administered food frequency questionnaire, and estimated HCA intake was verified by measuring the PhIP value in human hair. A total of 117 cases and 238 controls were included in these analyses. Odds ratios (ORs) were calculated using conditional logistic regression analysis to compare intake levels between the first and third tertiles. RESULTS No statistically significant increase in the risk of colorectal cancer with respect to total HCA intake was shown by analysis (OR = 0.99, 95% CI = 0.21-4.81). Furthermore, no association with risk was seen for individual HCAs, including PhIP, MeIQ, and MeIQx. Although variant alleles of CYP1A2 were associated with colorectal cancer (OR = 0.27; 95% CI = 0.07-0.99), genetic polymorphisms of NAT2, CYP1A1, and CYP1A2 did not influence the association of HCA intake with colorectal cancer. CONCLUSIONS In the present study in subjects with low HCA exposure and with a limited sample size, no association was found between HCA intake and colorectal cancer, or any evidence of influence by genetic polymorphisms of NAT2, CYP1A1, and CYP1A2.
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Affiliation(s)
- Minatsu Kobayashi
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.
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Benedetti MS, Whomsley R, Poggesi I, Cawello W, Mathy FX, Delporte ML, Papeleu P, Watelet JB. Drug metabolism and pharmacokinetics. Drug Metab Rev 2009; 41:344-90. [PMID: 19601718 DOI: 10.1080/10837450902891295] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs. Drug-metabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. Finally, a new and promising methodology, microdosing, has been presented, although it has not yet been applied to drugs used in the treatment of allergic diseases.
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Mignone LI, Giovannucci E, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Hampton JM, Orav EJ, Willett WC, Egan KM. Meat consumption, heterocyclic amines, NAT2, and the risk of breast cancer. Nutr Cancer 2009; 61:36-46. [PMID: 19116874 DOI: 10.1080/01635580802348658] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Meat consumption and heterocyclic amine (HCA) intake have been inconsistently associated with breast cancer risk in epidemiologic studies. Genetic variation in N-acetyltransferase2 (NAT2) has been suggested to modify the association of meat intake with breast cancer through its influence on metabolism of HCAs. We examined associations between meat intake, HCA exposure, acetylator genotype, and breast cancer risk in a case-control study of 2,686 case women and 3,508 controls. Women were asked to report their usual intake, cooking method, and preferred doneness of specific meats. We observed no association between total meat, red meat, or chicken with breast cancer risk. Women who consumed 5 or more servings of meat per week had no increased risk of breast cancer compared to women consuming fewer than 2 servings per week (OR = 0.99, 95% CI 0.84-1.15). No statistically significant associations with breast cancer were found for individual HCAs or for total estimated mutagenic activity of meat. Results varied modestly according to menopausal status. There were no statistically significant interactions with NAT2 genotype. Results do not support an important association of HCAs with breast cancer risk, although potential biases in case-control studies should be considered.
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Affiliation(s)
- Laura I Mignone
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
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Kuznetsov IB, McDuffie M, Moslehi R. A web server for inferring the human N-acetyltransferase-2 (NAT2) enzymatic phenotype from NAT2 genotype. Bioinformatics 2009; 25:1185-6. [PMID: 19261719 PMCID: PMC2672629 DOI: 10.1093/bioinformatics/btp121] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Summary:N-acetyltransferase-2 (NAT2) is an important enzyme that catalyzes the acetylation of aromatic and heterocyclic amine carcinogens. Individuals in human populations are divided into three NAT2 acetylator phenotypes: slow, rapid and intermediate. NAT2PRED is a web server that implements a supervised pattern recognition method to infer NAT2 phenotype from SNPs found in NAT2 gene positions 282, 341, 481, 590, 803 and 857. The web server can be used for a fast determination of NAT2 phenotypes in genetic screens. Availability:Freely available at http://nat2pred.rit.albany.edu Contact:ikuznetsov@albany.edu; rmoslehi@albany.edu Supplementary information:Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Igor B Kuznetsov
- Gen*NY*Sis Center for Excellence in Cancer Genomics, Department of Epidemiology and Biostatistics, University at Albany, One Discovery Drive, Rensselaer, NY 12144, USA.
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Huang CC, Chien WP, Wong RH, Cheng YW, Chen MC, Lee H. NAT2 fast acetylator genotype and MGMT promoter methylation may contribute to gender difference in K-RAS mutation occurrence in Taiwanese colorectal cancer. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2009; 50:127-133. [PMID: 19107910 DOI: 10.1002/em.20444] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
A recent study conducted by our group showed that the NAT2 fast acetylator genotype is associated with an increasing risk for the development of colorectal cancer (CRC), especially for females. We therefore examined whether a higher risk of CRC in females with the NAT2 fast acetylator genotype was associated with the occurrence of K-RAS mutation, and to further verify whether MGMT promoter methylation was linked to the occurrence of K-RAS mutation in patients with the NAT2 fast acetylator genotype. Herein, 151 CRC cases were examined for NAT2 genetic polymorphisms and MGMT promoter methylation by PCR-RFLP and methylation-specific PCR (MSP). The results of this study show that the NAT2 fast acetylator genotype is associated with the occurrence of K-RAS mutation in female cases (OR = 4.820, 95% CI = 1.113-20.873), but not associated with MGMT promoter methylation. Surprisingly, MGMT promoter methylation significantly deepens the impact of NAT2 fast acetylation on K-RAS mutation in the female cases (OR = 5.129, 95% CI = 1.092-24.105). In conclusion, Taiwanese women with the NAT2 fast acetylator genotype may exhibit a higher risk of CRC with increased occurrence of K-RAS mutation. Detection of NAT2 genotypes and MGMT promoter methylation may be useful in the risk assessment for CRC in Taiwanese women.
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Affiliation(s)
- Chi-Chou Huang
- Colorectal Division, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
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Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2009; 12:440-472. [PMID: 20183529 DOI: 10.1080/10937400903158383] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.
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Affiliation(s)
- Katy Walker
- Clark University, Center for Technology, Environment, and Development, Worcester, Massachusetts, USA
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Gates MA, Tworoger SS, Terry KL, Titus-Ernstoff L, Rosner B, De Vivo I, Cramer DW, Hankinson SE. Talc use, variants of the GSTM1, GSTT1, and NAT2 genes, and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2008; 17:2436-44. [PMID: 18768514 DOI: 10.1158/1055-9965.epi-08-0399] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epidemiologic evidence suggests a possible association between genital use of talcum powder and risk of epithelial ovarian cancer; however, the biological basis for this association is not clear. We analyzed interactions between talc use and genes in detoxification pathways [glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and N-acetyltransferase 2 (NAT2)] to assess whether the talc/ovarian cancer association is modified by variants of genes potentially involved in the response to talc. Our analysis included 1,175 cases and 1,202 controls from a New England-based case-control study and 210 cases and 600 controls from the prospective Nurses' Health Study. We genotyped participants for the GSTM1 and GSTT1 gene deletions and three NAT2 polymorphisms. We used logistic regression to analyze the main effect of talc use, genotype, and gene-talc interactions in each population and pooled the estimates using a random-effects model. Regular talc use was associated with increased ovarian cancer risk in the combined study population (RR, 1.36; 95% CI, 1.14-1.63; P(trend) < 0.001). Independent of talc, the genes examined were not clearly associated with risk. However, the talc/ovarian cancer association varied by GSTT1 genotype and combined GSTM1/GSTT1 genotype. In the pooled analysis, the association with talc was stronger among women with the GSTT1-null genotype (P(interaction) = 0.03), particularly in combination with the GSTM1-present genotype (P(interaction) = 0.03). There was no clear evidence of an interaction with GSTM1 alone or NAT2. These results suggest that women with certain genetic variants may have a higher risk of ovarian cancer associated with genital talc use. Additional research is needed on these interactions and the underlying biological mechanisms.
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Affiliation(s)
- Margaret A Gates
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Slattery ML, Wolff RK, Curtin K, Fitzpatrick F, Herrick J, Potter JD, Caan BJ, Samowitz WS. Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res 2008; 660:12-21. [PMID: 18992263 DOI: 10.1016/j.mrfmmm.2008.10.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2008] [Revised: 10/03/2008] [Accepted: 10/03/2008] [Indexed: 10/21/2022]
Abstract
Variation in genes associated with serum levels of proteins may be useful for examining specific disease pathways. Using data from a large study of colon cancer, we examine genetic variants in insulin, inflammation, estrogen, metabolizing enzymes, and energy homeostasis genes to explore associations with microsatellite instability (MSI), CpG Island methylator phenotype (CIMP), mutations of p53 in exons 5 through 8, and mutations in codons 12 and 13 of Ki-ras. Insulin-related genes were associated with CIMP-positive and MSI tumors, with the strongest associations among aspirin users. The Fok1 vitamin D receptor (VDR) polymorphism was associated with CIMP-positive/Ki-ras-mutated tumors; the Poly A and CDX2 VDR polymorphisms were associated only with Ki-ras-mutated tumors. NAT2 was associated with CIMP-positive/Ki-ras-mutated tumors but not with MSI tumors. The TCF7L2 rs7903146 polymorphism was associated with p53 mutated tumors. Most associations varied by recent aspirin/NSAID use: IL6 rs1800796 and rs1800795 polymorphisms were associated inversely with tumor mutations in the presence of aspirin/NSAIDs; POMC significantly reduced risk of Ki-ras-mutated tumors when aspirin/NSAIDs were not used; the TCF7L2 rs7903146 was associated with reduced risk of Ki-ras-mutated tumors in the presence of aspirin and increased risk in the absence of aspirin. These data, although exploratory, identify specific tumor subsets that may be associated with specific exposures/polymorphism combinations. The important modifying effects of aspirin/NSAIDs on associations with genetic polymorphisms reinforce the underlying role of inflammation in the etiology of colon cancer.
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Affiliation(s)
- Martha L Slattery
- Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA.
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35
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Shin A, Shrubsole MJ, Rice JM, Cai Q, Doll MA, Long J, Smalley WE, Shyr Y, Sinha R, Ness RM, Hein DW, Zheng W. Meat intake, heterocyclic amine exposure, and metabolizing enzyme polymorphisms in relation to colorectal polyp risk. Cancer Epidemiol Biomarkers Prev 2008; 17:320-9. [PMID: 18268115 DOI: 10.1158/1055-9965.epi-07-0615] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk.
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Affiliation(s)
- Aesun Shin
- Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, 8th Floor, 2525 West End Avenue, Nashville, TN 37203, USA
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Erickson RP, McQueen CA, Chau B, Gokhale V, Uchiyama M, Toyoda A, Ejima F, Maho N, Sakaki Y, Gondo Y. An N-ethyl-N-nitrosourea-induced mutation in N-acetyltransferase 1 in mice. Biochem Biophys Res Commun 2008; 370:285-8. [DOI: 10.1016/j.bbrc.2008.03.085] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 03/18/2008] [Indexed: 11/16/2022]
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Prospective study of NAT1 and NAT2 polymorphisms, tobacco smoking and meat consumption and risk of colorectal cancer. Cancer Lett 2008; 266:186-93. [PMID: 18372103 DOI: 10.1016/j.canlet.2008.02.046] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Revised: 02/19/2008] [Accepted: 02/20/2008] [Indexed: 11/21/2022]
Abstract
Heterocyclic amines in tobacco smoke and fried meat are activated or detoxified by N-acetyltransferases (NAT1 and NAT2). We identified 379 cases with colorectal cancer (CRC) and 769 sub-cohort members among a cohort of 57,000 members. There were no statistically significant associations between tobacco smoking, consumption of meat (red, processed and fried) and CRC risk. Preference for brown-dark pan-fried meat increased the CRC risk. NAT1 fast acetylators had a significantly higher risk of CRC than NAT1 slow acetylators, whereas NAT2 acetylator status did not affect the CRC risk. There were no statistically significant interactions between tobacco smoking and either NAT1 or NAT2 acetylator status in relation to CRC risk. However, smoking intensity increased CRC risk among carriers of both NAT1 and NAT2 fast. This indicates that N-acetylator status affects the relationship between smoking and CRC risk.
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Butler LM, Millikan RC, Sinha R, Keku TO, Winkel S, Harlan B, Eaton A, Gammon MD, Sandler RS. Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study. Mutat Res 2008; 638:162-74. [PMID: 18022202 PMCID: PMC2234436 DOI: 10.1016/j.mrfmmm.2007.10.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2007] [Revised: 10/03/2007] [Accepted: 10/04/2007] [Indexed: 05/25/2023]
Abstract
OBJECTIVE Colorectal cancer incidence is greater among African Americans, compared to whites in the U.S., and may be due in part to differences in diet, genetic variation at metabolic loci, and/or the joint effect of diet and genetic susceptibility. We examined whether our previously reported associations between meat-derived heterocyclic amine (HCA) intake and colon cancer were modified by N-acetyltransferase 1 (NAT1) or 2 (NAT2) genotypes and whether there were differences by race. METHODS In a population-based, case-control study of colon cancer, exposure to HCAs was assessed using a food-frequency questionnaire with a meat-cooking and doneness module, among African Americans (217 cases and 315 controls) and whites (290 cases and 534 controls). RESULTS There was no association with NAT1*10 versus NAT1-non*10 genotypes for colon cancer. Among whites, there was a positive association for NAT2-"rapid/intermediate" genotype [odds ratio (OR)=1.4; 95% confidence interval (CI)=1.0, 1.8], compared to the NAT2-"slow" that was not observed among African Americans. Colon cancer associations with HCA intake were modified by NAT1, but not NAT2, regardless of race. However, the "at-risk" NAT1 genotype differed by race. For example, among African Americans, the positive association with 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) was confined to those with NAT1*10 genotype (OR=1.8; 95% CI=1.0, 3.3; P for interaction=0.02, comparing highest to lowest intake), but among whites, an association with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was confined to those with NAT1-non*10 genotype (OR=1.9; 95% CI=1.1, 3.1; P for interaction=0.03). CONCLUSIONS Our data indicate modification by NAT1 for HCA and colon cancer associations, regardless of race. Although the at-risk NAT1 genotype differs by race, the magnitude of the individual HCA-related associations in both race groups are similar. Therefore, our data do not support the hypothesis that NAT1 by HCA interactions contribute to differences in colorectal cancer incidence between African Americans and whites.
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Affiliation(s)
- Lesley M Butler
- University of California-Davis, Department of Public Health Sciences, Division of Epidemiology, Davis, CA 95616, USA.
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Methods for meta-analysis in genetic association studies: a review of their potential and pitfalls. Hum Genet 2007; 123:1-14. [PMID: 18026754 DOI: 10.1007/s00439-007-0445-9] [Citation(s) in RCA: 154] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2007] [Accepted: 10/29/2007] [Indexed: 12/14/2022]
Abstract
Meta-analysis offers the opportunity to combine evidence from retrospectively accumulated or prospectively generated data. Meta-analyses may provide summary estimates and can help in detecting and addressing potential inconsistency between the combined datasets. Application of meta-analysis in genetic associations presents considerable potential and several pitfalls. In this review, we present basic principles of meta-analytic methods, adapted for human genome epidemiology. We describe issues that arise in the retrospective or the prospective collection of relevant data through various sources, common traps to consider in the appraisal of evidence and potential biases that may interfere. We describe the relative merits and caveats for common methods used to trace inconsistency across studies along with possible reasons for non-replication of proposed associations. Different statistical models may be employed to combine data and some common misconceptions may arise in the process. Several meta-analysis diagnostics are often applied or misapplied in the literature, and we comment on their use and limitations. An alternative to overcome limitations arising from retrospective combination of data from published studies is to create networks of research teams working in the same field and perform collaborative meta-analyses of individual participant data, ideally on a prospective basis. We discuss the advantages and the challenges inherent in such collaborative approaches. Meta-analysis can be a useful tool in dissecting the genetics of complex diseases and traits, provided its methods are properly applied and interpreted.
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Ochs-Balcom HM, Wiesner G, Elston RC. A meta-analysis of the association of N-acetyltransferase 2 gene (NAT2) variants with breast cancer. Am J Epidemiol 2007; 166:246-54. [PMID: 17535831 DOI: 10.1093/aje/kwm066] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation and detoxification pathways. Therefore, NAT2 variants may represent underlying susceptibility to breast cancer. Because a number of studies of the association of NAT2 with breast cancer have been published, the authors performed a meta-analysis. They extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. They summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. The authors identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. They found no evidence for heterogeneity (Cochran's Q statistic p=0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio=1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.
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Affiliation(s)
- Heather M Ochs-Balcom
- Department of Epidemiology and Biostatistics, Case Western Reserve University, and Ireland Comprehensive Cancer Center at University Hospitals of Cleveland, OH 44106-7281, USA
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Huang CC, Chien WP, Wong RH, Cheng YW, Chen MC, Chou MC, Lee H. NAT2 fast acetylator genotype is associated with an increased risk of colorectal cancer in Taiwan. Dis Colon Rectum 2007; 50:981-9. [PMID: 17525862 DOI: 10.1007/s10350-007-0230-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In Taiwan, colorectal cancer has one of the highest rates of increased incidence in the past two decades. Heterocyclic amines from dietary cooked meats are metabolically activated by NAT2 (N-acetyltransferase 2), which are associated with colorectal cancer incidence. Thus, the NAT2 fast acetylator genotype may be associated with colorectal cancer risk. However, the association between the NAT2 genotype and colorectal cancer risk is not clearly understood. We conducted a study with 244 primary colorectal cancer cases and 299 cancer-free healthy control subjects to verify the association of NAT2 polymorphisms with the risk of Taiwanese colorectal cancer. Our data showed that subjects with the NAT2 W/W homozygous genotype had a 1.63-fold increased risk of colorectal cancer compared with those with the Mx/Mx slow acetylator genotype (95 percent confidence interval, 1.03-2.58); however, no risk was found in the W/Mx heterozygous and Mx/W+W/W fast acetylator genotypes. Being stratified by gender factors, the colorectal cancer risk in females with homozygous W/W or Mx/W+W/W fast acetylators increased 2.47-fold and 2.13-fold compared with those with the Mx/Mx slow acetylator genotype (95 percent confidence interval, 1.27-4.82 for W/W genotype; 95 percent confidence interval, 1.17-3.89 for Mx/W+W/W genotype); however, the risk of the NAT2 genotype and colorectal cancer was not observed in males. Collectively, patients with the NAT2 fast acetylator genotype were more prone to colorectal cancer and reflected the possibility that exposure to heterocyclic amines may contribute to colorectal cancer development in Taiwan, especially in Taiwanese females.
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Affiliation(s)
- Chi-Chou Huang
- Colorectal Division, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
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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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Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ. Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients. Cancer Epidemiol Biomarkers Prev 2007; 15:2307-10. [PMID: 17119063 DOI: 10.1158/1055-9965.epi-06-0040] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germ-line mutations in DNA mismatch repair genes. There is considerable variation in disease expression that cannot be explained by genotype/phenotype correlation, which is likely to be the result of polymorphic modifier genes. One candidate group of modifiers is the xenobiotic clearance enzyme genes that encode CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. Alterations in these xenobiotic clearance genes can potentially influence the host response to carcinogen exposure and thereby alter cancer risk. We have investigated eight polymorphisms in xenobiotic clearance genes to assess the effect on the risk of disease in mutation positive HNPCC patients. METHODS DNA samples from 220 mutation-positive HNPCC participants (86 Australian and 134 Polish) were genotyped for single nucleotide polymorphisms (SNP) in CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. The association between the SNPs and disease characteristics, disease expression and age of diagnosis of colorectal cancer (CRC), was tested with Pearson's chi(2) and Kaplan-Meier survival analysis. RESULTS The HNPCC population displays a significant difference in the genotype frequency distribution between CRC patients and unaffected mismatch repair gene mutation carriers for the CYP1A1 SNP where the CRC patients harbor more of the mutant genotype. CONCLUSIONS Evidence from this study is not conclusive, but our data suggest that the CYP1A1 influences disease expression in individuals with HNPCC.
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Affiliation(s)
- Bente A Talseth
- Discipline of Medical Genetic, Faculty of Health, University of Newcastle and the Hunter Medical Research Institute, Newcastle, New South Wales, Australia
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Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. THE PHARMACOGENOMICS JOURNAL 2007; 8:4-15. [PMID: 17549068 DOI: 10.1038/sj.tpj.6500462] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
For most drug-metabolizing enzymes (DMEs), the functional consequences of genetic polymorphisms have been examined. Variants leading to reduced or increased enzymatic activity as compared to the wild-type alleles have been identified. This review tries to define potential fields in the therapy of major medical conditions where genotyping (or phenotyping) of genetically polymorphic DMEs might be beneficial for drug safety or therapeutic outcome. The possible application of genotyping is discussed for depression, cardiovascular diseases and thromboembolic disorders, gastric ulcer, malignant diseases and tuberculosis. Some drugs used for relief of these ailments are metabolized with participation of genetically polymorphic DMEs including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase and N-acetyltransferase type 2. Current evidence suggests that taking genetically determined metabolic capacities of DMEs into account has the potential to improve individual risk/benefit relationship. However, more prospective studies with clinical endpoints are needed before the paradigm of 'personalized medicine' based on DME variants can be established.
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Affiliation(s)
- D Tomalik-Scharte
- Department of Pharmacology, Clinical Pharmacology, University of Cologne, Köln, Germany.
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Abstract
Arylamine N-acetyltransferases (NATs), known as drug- and carcinogen-metabolising enzymes, have had historic roles in cellular metabolism, carcinogenesis and pharmacogenetics, including epidemiological studies of disease susceptibility. NAT research in the past 5 years builds on that history and additionally paves the way for establishing the following new concepts in biology and opportunities in drug discovery: i) NAT polymorphisms can be used as tools in molecular anthropology to study human evolution; ii) tracing NAT protein synthesis and degradation within cells is providing insight into protein folding in cell biology; iii) studies on control of NAT gene expression may help to understand the increase in the human NAT isoenzyme, NAT1, in breast cancer; iv) a NAT homologue in mycobacteria plays an essential role in cell-wall synthesis and mycobacterial survival inside host macrophage, thus identifying a novel biochemical pathway; v) transgenic mice, with genetic modifications of all Nat genes, provide in vivo tools for drug metabolism; and vi) structures of NAT isoenzymes provide essential in silico tools for drug discovery.
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Affiliation(s)
- Edith Sim
- University of Oxford, Department of Pharmacology, Mansfield Road, Oxford, UK.
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Ognjanovic S, Yamamoto J, Maskarinec G, Le Marchand L. NAT2, meat consumption and colorectal cancer incidence: an ecological study among 27 countries. Cancer Causes Control 2007; 17:1175-82. [PMID: 17006723 DOI: 10.1007/s10552-006-0061-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2005] [Accepted: 07/05/2006] [Indexed: 11/26/2022]
Abstract
The polymorphic gene NAT2 is a major determinant of N-acetyltransferase activity and, thus, may be responsible for differences in one's ability to bioactivate heterocyclic amines, a class of procarcinogens in cooked meat. An unusually marked geographic variation in enzyme activity has been described for NAT2. The present study re-examines the international direct correlation reported for meat intake and colorectal cancer (CRC) incidence, and evaluates the potential modifying effects of NAT2 phenotype and other lifestyle factors on this correlation. Country-specific CRC incidence data, per capita consumption data for meat and other dietary factors, prevalence of the rapid/intermediate NAT2 phenotype, and prevalence of smoking for 27 countries were used. Multiple linear regression models were fit and partial correlation coefficients (PCCs) were computed for men and women separately. Inclusion of the rapid/intermediate NAT2 phenotype with meat consumption improved the fit of the regression model for CRC incidence in both sexes (males-R (2) = 0.78, compared to 0.70 for meat alone; p for difference in model fit-0.009; females-R (2) = 0.76 compared to 0.69 for meat alone; p = 0.02). Vegetable consumption (inversely and in both sexes) and fish consumption (directly and in men only) were also weakly correlated with CRC, whereas smoking prevalence and alcohol consumption had no effects on the models. The PCC between NAT2 and CRC incidence was 0.46 in males and 0.48 in females when meat consumption was included in the model, compared to 0.14 and 0.15, respectively, when it was not. These data suggest that, in combination with meat intake, some proportion of the international variability in CRC incidence may be attributable to genetic susceptibility to heterocyclic amines, as determined by NAT2 genotype.
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Affiliation(s)
- Simona Ognjanovic
- Epidemiology Program, Cancer Research Center of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, HI 96813, USA.
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Stanisławska-Sachadyn A, Jensen LE, Kealey C, Woodside JV, Young IS, Scott JM, Murray L, Boreham CA, McNulty H, Strain JJ, Whitehead AS. Association between the NAT1 1095C > A polymorphism and homocysteine concentration. Am J Med Genet A 2007; 140:2374-7. [PMID: 17036310 DOI: 10.1002/ajmg.a.31475] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Anna Stanisławska-Sachadyn
- Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA
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Hecht JT, Ester A, Scott A, Wise CA, Iovannisci DM, Lammer EJ, Langlois PH, Blanton SH. NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet A 2007; 143A:2285-91. [PMID: 17726690 DOI: 10.1002/ajmg.a.31927] [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] [Indexed: 11/07/2022]
Abstract
Idiopathic talipes equinovarus (ITEV), or isolated clubfoot, is a common developmental anomaly that is characterized by a rigid foot, adducted forefoot, cavus midfoot, equinovarus of the hindfoot, and hypoplastic calf musculature. The etiology of this common birth defect is largely unknown, but genetic factors have been implicated in population and family studies and maternal smoking during pregnancy has been identified as an environmental risk factor. The biotransformation of exogenous substances, such as tobacco smoke, is modulated by numerous genes including N-acetylation genes, NAT1 and NAT2. Functional variants of these genes exist and can be distinguished by genotyping. We hypothesized that variation in NAT1 and NAT2 genes might be associated with ITEV. To test this hypothesis, NAT1 and NAT2 were genotyped in a sample of 56 multiplex ITEV families, 57 trios with a positive family history and 160 simplex trios with ITEV. The results detected a slight decrease in the expected number of homozygotes for the NAT2 normal allele in the Hispanic simplex trios. In addition, in a pilot case-control study of ITEV, there were significantly more slow NAT2 acetylators among the cases. This suggests that slow acetylation may be a risk factor for ITEV. This study is the first to find evidence suggesting a role for a biotransformation candidate gene in the etiology of ITEV and provides a scientific foundation to further explore the contributions of other tobacco metabolism genes in the etiology of clubfoot.
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Affiliation(s)
- Jacqueline T Hecht
- Department of Pediatrics, University of Texas Medical School, Houston, Texas 77225, USA.
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Carmichael SL, Shaw GM, Yang W, Iovannisci DM, Lammer E. Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. Am J Med Genet A 2006; 140:1915-22. [PMID: 16906563 DOI: 10.1002/ajmg.a.31402] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.
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Affiliation(s)
- Suzan L Carmichael
- March of Dimes Birth Defect Foundation/California Department of Health Services, California Birth Defects Monitoring Program, Berkeley, California 94710, USA.
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Moslehi R, Chatterjee N, Church TR, Chen J, Yeager M, Weissfeld J, Hein DW, Hayes RB. Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma. Pharmacogenomics 2006; 7:819-29. [PMID: 16981843 DOI: 10.2217/14622416.7.6.819] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransferases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. Our interest is in the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco–colorectal tumor relationship by impacting on the metabolic activation and detoxification of tobacco smoke-derived carcinogens. Methods: In the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, we compared NAT1 and NAT2 gene variant distributions for 772 cases with left-sided advanced adenoma and 777 gender and age-matched controls. Individual NAT1 and NAT2 diplotypes were assigned and NAT2 acetylator phenotypes were derived. Results: Risks for advanced colorectal adenoma were significantly increased among recent smokers (current smokers or those who quit less than 10 years ago) (odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.7–3.1) and among those who smoked more than 20 cigarettes per day (OR = 1.7, 95% CI: 1.3–2.2), compared with nonsmokers. Risk decreased with increasing NAT2 phenotypic activity (0: slow, 1: intermediate, and 2: rapid) (OR trend: 0.8; 95% CI: 0.7–1.0, p-trend = 0.04) overall. When stratified by smoking status, significant phenotype-associated trends were observed among recent smokers (OR trend = 0.4, 95% CI: 0.3–0.7, p trend <0.001) (p-interaction = 0.02), but not among past or nonsmokers. Diplotypes most strongly associated with lower risks in smokers were NAT2*4/*5B (OR = 0.3, 95% CI: 0.1–0.8, p = 0.01) and NAT2*4/*4 (OR = 0.2, 95% CI: 0.04–0.7, p = 0.02), categorized as intermediate and rapid acetylators, respectively. One NAT1 diplotype, NAT1*4/*10 (OR = 0.5, 95% CI: 0.3–0.9, p = 0.03), was also associated with a decreased risk in smokers. Conclusions: Our study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco smoking with respect to adenoma risk, providing leads for disease prevention.
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Affiliation(s)
- Roxana Moslehi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Blvd., EPS 8047, Rockville, MD 20852 USA.
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