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Wang Y, Huo L, Yang C, He X. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility: an updated meta-analysis. Biosci Rep 2023; 43:BSR20222553. [PMID: 36896928 PMCID: PMC10116338 DOI: 10.1042/bsr20222553] [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: 12/21/2022] [Revised: 02/24/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Widely regarded as one of the most prevalent malignancies worldwide, gastric cancer (GC) is a common clinical condition of the digestive system. Reviewing 14 meta-analyses that evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and GC risk, we observed inconsistent results, and the credibility of the significant correlation between the statistical results was ignored. With the aim of further exploring the association between MTHFR C677T and A1298C and the risk of GC, we searched electronic databases, pooling 43 relevant studies and calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for each of the five genetic models. Subgroup and regression analyses were performed to look for sources of heterogeneity and publication bias was assessed by funnel plots. To assess the plausibility of statistically significant associations, we used the FPRP test and the Venice criteria. Overall data analysis showed that MTHFR C677T polymorphism was significantly associated with GC risk, especially in Asians, while MTHFR A1298C polymorphism was not associated with GC risk. However, in subgroup analysis by hospital-based controls, we found that MTHFR A1298C might be a protective factor for GC. After credibility assessment, the statistical association between MTHFR C677T and GC susceptibility study was classified as 'less credible positive result', while the result of MTHFR A1298C was considered unreliable. In summary, the present study strongly suggests that MTHFR C677T and A1298C polymorphisms are not significantly associated with the GC risk.
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Affiliation(s)
- Yuwei Wang
- Department of Digestive internal medicine, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi 046000, China
| | - Lili Huo
- Department of Digestive internal medicine, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi 046000, China
| | - Changqing Yang
- Department of Digestive internal medicine, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi 046000, China
| | - Xiaofeng He
- Department of Epidemiology, School of Public Health, Southern Medical University, Guang-dong, Guangzhou 510515, China
- Institute of Evidence-Based Medicine, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi 046000, China
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Investigation of the relationship between MTRR A66G, MTR A2756G gene variations and cell anomalies in early diagnosis and progression of bladder cancer. Mol Biol Rep 2022; 49:7719-7729. [PMID: 35715601 DOI: 10.1007/s11033-022-07597-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/08/2022] [Accepted: 05/11/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND The aim of this study is to investigate the relationship between MTRR A66G, MTRA2756G gene variations and cell anomalies in the early diagnosis and progression of bladder cancer. METHODS PCR and RFLP methods were used to determine the genotype distributions of MTRR A66G and MTR A2756G gene variations. Peripheral smear preparations prepared from blood samples were fixed with methanol fixative and stained histochemically. Cellular morphological evaluations were made under the light microscope. RESULTS In our study, AA-GG haplotype was observed significantly more in the patient group than control group (OR: 3.304, 95% CI: 1.023-10.665, p = 0.046). The significant increase was determined in terms of histological damage parameters in the patient group compared to the control group (p < 0.05). For multiple vacuoles damage parameter (mild score), AA genotype of MTR A2756G gene variation was significantly different compared to AA genotype of MTRR A66G gene variation (OR: 0.211, 0.049-0.912, p = 0.037). AA genotype of MTR A2756G gene variation was observed more than AA homozygous genotype of MTR A66G gene variation for giant platelets with different sizes damage parameter (mild score) (OR: 0.062, 0.017-0.228, p < 0.001). CONCLUSIONS In conclusion, in Thrace population, AA genotype of the MTR A2756G gene variation was significantly higher than the AA homozygous genotype of the MTR A66G gene variation as a genetic risk factor for the multiple vacuoles damage parameter. In addition, AA genotype of MTR A2756G gene variation was determined as a genetic risk factor for giant platelets with different sizes damage parameter.
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Zhong G, Luo X, Li J, Liao Y, Gui G, Sheng J. MTRR rs1532268 polymorphism and gastric cancer risk: evidence from a meta-analysis. J Int Med Res 2022; 50:3000605221097486. [PMID: 35579185 PMCID: PMC9127855 DOI: 10.1177/03000605221097486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 04/11/2022] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE The methionine synthase reductase (MTRR) gene encodes the MTRR enzyme involved in the metabolic pathway of homocysteine. Several studies investigated the effect of the MTRR rs1532268 gene polymorphism on the risk of gastric cancer (GC), but the results have been inconsistent. METHODS We performed a comprehensive and systematic search of PubMed, Google Scholar, MEDLINE, Science Direct, Scopus, CNKI, and Web of Science. Five studies were included in this meta-analysis to determine whether MTRR rs1532268 polymorphism contributes to the risk of GC. RESULTS Pooled data indicated that the MTRR rs1532268 polymorphism significantly increased GC risk under the allele comparison model (odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.01-1.29) and dominant model (OR = 1.14, 95% CI = 1.00-1.30). In the analysis stratified by ethnicity, no relationship was found in Whites or Asians. CONCLUSION Our meta-analysis suggests a positive correlation between MTRR rs1532268 polymorphism and GC development.
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Affiliation(s)
- Guping Zhong
- Department of Gastroenterology, The People’s Hospital of Yichun City, Jiangxi, China
| | - Xiaojin Luo
- Department of Urology, The People’s Hospital of Yichun City, Jiangxi, China
| | - Ji Li
- Department of Gastroenterology, The People’s Hospital of Yichun City, Jiangxi, China
| | - Yuanhang Liao
- Department of Gastroenterology, The People’s Hospital of Yichun City, Jiangxi, China
| | - Guan Gui
- Department of Gastroenterology, The People’s Hospital of Yichun City, Jiangxi, China
| | - Jianwen Sheng
- Department of Gastroenterology, The People’s Hospital of Yichun City, Jiangxi, China
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Rodriguez FD, Coveñas R. Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers. Cancers (Basel) 2021; 13:cancers13143548. [PMID: 34298760 PMCID: PMC8306032 DOI: 10.3390/cancers13143548] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Of all yearly deaths attributable to alcohol consumption globally, approximately 12% are due to cancers, representing approximately 0.4 million deceased individuals. Ethanol metabolism disturbs cell biochemistry by targeting the structure and function of essential biomolecules (proteins, nucleic acids, and lipids) and by provoking alterations in cell programming that lead to cancer development and cancer malignancy. A better understanding of the metabolic and cell signaling realm affected by ethanol is paramount to designing effective treatments and preventive actions tailored to specific neoplasias. Abstract The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
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Affiliation(s)
- Francisco D. Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Correspondence: ; Tel.: +34-677-510-030
| | - Rafael Coveñas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, University of Salamanca, 37007 Salamanca, Spain
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Riboflavin intake, MTRR genetic polymorphism (rs1532268) and gastric cancer risk in a Korean population: a case-control study. Br J Nutr 2021; 127:1026-1033. [PMID: 34078503 DOI: 10.1017/s0007114521001811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The vitamin B group, including riboflavin, plays paramount roles in one-carbon metabolism (OCM), and disorders related to this pathway have been linked to cancer development. The variants of genes encoding OCM enzymes and the insufficiency of B vitamins could contribute to carcinogenesis. Very few observational studies have revealed a relationship between riboflavin and gastric cancer (GC), especially under conditions of modified genetic factors. We carried out a study examining the association of riboflavin intake and its interaction with MTRR (rs1532268) genetic variants with GC risk among 756 controls and 377 cases. The OR and 95 % CI were evaluated using unconditional logistic regression models. We observed protective effects of riboflavin intake against GC, particularly in the female subgroup (OR = 0·52, 95 % CI 0·28, 0·97, Ptrend = 0·031). In the MTRR (rs1532268) genotypes analysis, the dominant model showed that the effects of riboflavin differed between the CC and CT + TT genotypes. Compared with CC carriers, low riboflavin intake in T+ carriers was significantly associated with a 93 % higher GC risk (OR = 1·93, 95 % CI 1·09, 3·42, Pinteraction = 0·037). In general, higher riboflavin intake might help reduce the risk of GC in both CC and TC + TT carriers, particularly the T+ carriers, with marginal significance (OR = 0·54, 95 % CI 0·28, 1·02, Pinteraction = 0·037). Our study indicates a protective effect of riboflavin intake against GC. Those who carry at least one minor allele and have low riboflavin intake could modify this association to increase GC risk in the Korean population.
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Hasan T, Arora R, Bansal AK, Bhattacharya R, Sharma GS, Singh LR. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 2019; 51:1-13. [PMID: 30804341 PMCID: PMC6389897 DOI: 10.1038/s12276-019-0216-4] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 11/30/2022] Open
Abstract
Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5–15 μmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 μmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed. Cancer can be added to the wide range of diseases known to be associated with elevated blood levels of the small amino acid homocysteine. Abnormally high levels of this compound are already known to contribute to conditions including cardiovascular problems, neurodegenerative diseases, neural tube defects, Down’s syndrome, diabetes and megaloblastic anemia. This review, by Laishram R. Singh and colleagues at the University of Delhi, India, concludes that disturbed homocysteine metabolism is associated with many forms of human cancer. The authors discuss a range of genetic, epigenetic and environmental factors that may be involved in the cause and effect relationships between homocysteine metabolism and cancer. It is particularly interesting that low folate (vitamin B9) levels result in high homocysteine levels, and vice versa. Further research may yield insights leading to new forms of cancer treatment and diagnosis.
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Affiliation(s)
- Tauheed Hasan
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Reetika Arora
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Aniket Kumar Bansal
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Reshmee Bhattacharya
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Gurumayum Suraj Sharma
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
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Wang C, Lu D, Ling Q, Chen J, Liu Z, Guo H, Xu X, Zheng S. Donor one‑carbon metabolism gene single nucleotide polymorphisms predict the susceptibility of cancer recurrence after liver transplantation. Gene 2018; 689:97-101. [PMID: 30529095 DOI: 10.1016/j.gene.2018.11.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND Many enzymes involved in one‑carbon metabolism (OCM) are considered to have important roles in carcinogenesis, especially in hepatocellular carcinoma (HCC). However, the influence of polymorphisms in OCM genes on recurrence in HCC patients with liver transplantation has yet not been reported. The aim of this study was to explore the impact of donor liver graft OCM gene polymorphism on the prognosis of liver transplant recipients with HCC. METHODS This study enrolled 100 liver transplantation patients from a Chinese Han population to detect the association between donor OCM genes polymorphisms and post-transplant HCC recurrence. Nine SNPs from seven OCM genes (MTHFD1, MTR, MTRR, DHFR, ALDH1L1, SHMT1, and CBS) were evaluated by Chi-square test and Kaplan-Meier survival analysis. RESULT None of the nine SNPs were significantly associated with cancer recurrence after liver transplantation. However, tumor-free survival for recipients with the AA genotype of rs1801394 polymorphism was significantly shorter than patients with AG/GG genotype (1097 ± 155 vs. 1657 ± 173 days, P < 0.05) among patients with alpha-fetoprotein < 400 ng/ml. Kaplan-Meier survival curves showed that recipients with donor rs1127717 homozygous TT had a significantly longer tumor-free survival and overall survival than heterozygous CT/CC recipients (tumor-free survival 1395 ± 128 vs. 671 ± 233 days, P < 0.05; overall survival 1540 ± 114 vs. 925 ± 242 days, P < 0.05) in the patient subgroup with well or moderately differentiated HCC. CONCLUSION This is the first genetic study to examine the relation between donor liver graft OCM gene polymorphisms and the risk of HCC recurrence after liver transplantation. Our findings support the hypothesis that polymorphisms of donor genes related to OCM play important roles in post-transplant HCC recurrence. Furthermore, donor rs1801394 and rs1127717 polymorphism may serve as promising prognostic biomarkers for HCC recurrence in liver transplant recipients.
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Affiliation(s)
- Chao Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Di Lu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Qi Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Jun Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Zhikun Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Haijun Guo
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
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Wang P, Li S, Wang M, He J, Xi S. Association of MTRR A66G polymorphism with cancer susceptibility: Evidence from 85 studies. J Cancer 2017; 8:266-277. [PMID: 28243331 PMCID: PMC5327376 DOI: 10.7150/jca.17379] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 11/14/2016] [Indexed: 02/07/2023] Open
Abstract
Methionine synthase reductase (MTRR) is a key regulatory enzyme involved in the folate metabolic pathway. Previous studies investigating the association of MTRR A66G polymorphism with cancer susceptibility reported inconclusive results. We performed the current meta-analysis to obtain a more precise estimation of the possible association. Published literatures were identified from PubMed, Embase and CBM databases up to October 2016. The strength of the association between the MTRR A66G polymorphism and cancer susceptibility was assessed using odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Eighty five published studies with 32,272 cases and 37,427 controls were included in this meta-analysis. Pooled results indicated that the MTRR A66G polymorphism was associated with an increased overall cancer risk (homozygous model: OR = 1.08, 95% CI = 1.02-1.15, P = 0.009; recessive model: OR = 1.06, 95% CI = 1.00-1.12, P < 0.001 and allele comparison: OR = 1.03, 95% CI = 1.00-1.06, P < 0.001). Stratification analysis further indicated significant associations in head and neck cancer, Caucasians, Africans, and high quality studies. However, to avoid the "false-positive report", the significant findings were assessed by the false-positive report probability (FPRP) test. Interestingly, the results of FPRP test revealed that the increased risk for MTRR A66G polymorphism among Africans need further validation due to the high probabilities of false-positive results. This meta-analysis suggests that the MTRR A66G polymorphism is associated with significantly increased cancer risk, a finding that needs to be confirmed in single large studies.
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Affiliation(s)
- Ping Wang
- The Key Laboratory of Pharmacology and Medical Molecular Biology, Medical College, Henan University of Science and Technology, Luoyang 471023, Henan, China
| | - Sanqiang Li
- The Molecular Medicine Key Laboratory of Liver Injury and Repair, Medical College, Henan University of Science and Technology, Luoyang 471023, Henan, China
| | - Meilin Wang
- The Key Laboratory of Pharmacology and Medical Molecular Biology, Medical College, Henan University of Science and Technology, Luoyang 471023, Henan, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
- ✉ Corresponding authors: Shoumin Xi, The Key Laboratory of Pharmacology and Medical Molecular Biology, Medical College, Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luoyang 471023, Henan, China, Tel.: (+86-379) 64830346, Fax: (+86-379) 64830345, E-mail: ; or Jing He, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, China, Tel./Fax: (+86-20) 38076560, E-mail:
| | - Shoumin Xi
- The Key Laboratory of Pharmacology and Medical Molecular Biology, Medical College, Henan University of Science and Technology, Luoyang 471023, Henan, China
- ✉ Corresponding authors: Shoumin Xi, The Key Laboratory of Pharmacology and Medical Molecular Biology, Medical College, Henan University of Science and Technology, No. 263 Kaiyuan Avenue, Luoyang 471023, Henan, China, Tel.: (+86-379) 64830346, Fax: (+86-379) 64830345, E-mail: ; or Jing He, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou 510623, Guangdong, China, Tel./Fax: (+86-20) 38076560, E-mail:
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Xu W, Cheng Y, Zhu H. Evaluation of an Association of Blood Homocysteine Levels With Gastric Cancer Risk From 27 Case-Control Studies. Medicine (Baltimore) 2016; 95:e3700. [PMID: 27196483 PMCID: PMC4902425 DOI: 10.1097/md.0000000000003700] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
High blood homocysteine levels may risk gastric cancer. However, observational studies have been plagued by chance, bias, confounding, or reverse causality. In this study, we assessed the relationship between blood homocysteine levels and gastric cancer by using a Mendelian randomization method, which is independent of nongenetic confounding.We took 2 steps to perform Mendelian randomization analysis. First, we evaluated the methylenetetrahydrofolate reductase (MTHFR) C677T association with gastric cancer by a meta-analysis of case-control studies including 7566 patients with gastric cancer and 10 640 control subjects from 27 Case-Control studies. Second, MTHFR C677T polymorphism, which affects the blood homocysteine levels, was used as an instrumental variable to calculate the risk and estimate the association of gastric cancer with this single nucleotide polymorphism (SNP). We obtained an estimate to the association of blood total homocysteine levels with this SNP from a meta-analysis of Genome-Wide Association Studies (GWAS), which comprises a total of 44 147 individuals.In our Mendelian randomization analysis, we demonstrated a significant effect of the blood homocysteine levels on gastric cancer risk, representing an OR of 2.56 (95% CI = 2.41-2.72; P = 5.0×10) for gastric cancer per 1-SD increase in the natural log-transformed blood total homocysteine levels.We proved that there is a causal relationship between blood total homocysteine and risk of gastric cancer, and this study will add insight into the treatment and pathology research of gastric cancer.
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Affiliation(s)
- Wei Xu
- From the Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kim W, Woo HD, Lee J, Choi IJ, Kim YW, Sung J, Kim J. Dietary folate, one-carbon metabolism-related genes, and gastric cancer risk in Korea. Mol Nutr Food Res 2015; 60:337-45. [PMID: 26833750 DOI: 10.1002/mnfr.201500384] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/24/2015] [Accepted: 09/18/2015] [Indexed: 12/12/2022]
Abstract
SCOPE We evaluated the interactions between polymorphisms involved in one-carbon metabolism-related genes and dietary folate intake in gastric cancer risk within the Korean population through a hospital-based case-control study. METHODS AND RESULTS A total of 542 controls and 271 cases were included. Genotype data were selected from data produced by the Affymetrix Axiom(®) Exome 319 Array. We considered seven single nucleotide polymorphisms (SNPs) of five genes whose SNPs are located in the coding region with a minor allele frequency > 5%: MTHFR (G1793A, A1298C, C677T), MTR A2756G, MTRR A66G, SHMT1 C1420T, and SLC19A1 G80A. Our study found that MTR A2756G was associated with a decreased gastric cancer risk. MTHFR G1793A showed a statistically significant interaction between dietary folate intake and gastric cancer. CONCLUSION Our results suggest that MTR A2756G is significantly associated with gastric cancer risk, and that MTHFR G1793A statistically interacts with dietary folate intake. Our findings indicate that gene-folate interactions may contribute to gastric cancer risk.
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Affiliation(s)
- Woori Kim
- Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Korea
| | - Hae Dong Woo
- Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Korea
| | - Jeonghee Lee
- Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Korea
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, Korea
| | - Young Woo Kim
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang, Korea
| | - Joohon Sung
- Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, Korea
| | - Jeongseon Kim
- Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Korea
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Chen L, Lu N, Zhang BH, Weng LI, Lu J. Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls. Oncol Lett 2015; 10:1159-1165. [PMID: 26622644 DOI: 10.3892/ol.2015.3356] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 03/26/2015] [Indexed: 12/16/2022] Open
Abstract
Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta-analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.20-1.62; heterozygous model: OR, 1.18; 95% CI, 1.05-1.32; dominant model: OR, 1.23; 95% CI, 1.10-1.38; recessive model: OR, 1.26; 95% CI, 1.12-1.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.43-1.90; heterozygous model: OR, 1.30; 95% CI, 1.16-1.45; dominant model: OR, 1.39; 95% CI, 1.25-1.54; recessive model: OR, 1.41; 95% CI, 1.25-1.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.89-1.48; heterozygous model: OR, 1.03; 95% CI, 0.84-1.25; dominant model: OR, 1.05; 95% CI, 0.86-1.28; recessive model: OR, 1.09; 95% CI, 0.91-1.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations.
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Affiliation(s)
- Long Chen
- Department of Oncology, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Ning Lu
- Department of Oncology, Urumqi Military Command General Hospital of the People's Liberation Army, Urumqi, Xinjiang 830000, P.R. China
| | - Bai-Hong Zhang
- Department of Oncology, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - L I Weng
- Department of Oncology, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Jun Lu
- Department of Oncology, Lanzhou Military Command General Hospital of the People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
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Long ZW, Yu HM, Wang YN, Liu D, Chen YZ, Zhao YX, Bai L. Association of IL-17 polymorphisms with gastric cancer risk in Asian populations. World J Gastroenterol 2015; 21:5707-5718. [PMID: 25987798 PMCID: PMC4427697 DOI: 10.3748/wjg.v21.i18.5707] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 11/05/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate associations between the IL-17 rs2275913 G>A and rs763780 T>C polymorphisms and susceptibility to gastric cancer in Asian populations.
METHODS: We reviewed studies published up to 2014 on IL-17 polymorphisms with gastric cancer susceptibility systematically. Relevant articles were identified in the MEDLINE, Science Citation Index, Cochrane Library, PubMed, EMBASE, CINAHL and Current Contents Index databases. We used version 12.0 STATA statistical software to evaluate the statistical data. Two reviewers abstracted the data independently. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated.
RESULTS: Seven independent, case-control studies were chosen for the meta-analysis, which included 3210 gastric cancer patients and 3889 healthy controls. The overall estimation showed a positive association between the IL-17 rs2275913 G>A polymorphism and the occurrence of gastric cancer for five genetic models (all P < 0.05) and similar results were observed for the IL-17 rs763780 T>C variation with four genetic models (all P < 0.05), but not for the dominant model (P > 0.05). Subgroup analysis by country revealed that the rs2275913 G>A and rs763780 T>C polymorphisms may be the main risk factor for gastric cancer in Chinese and Japanese populations.
CONCLUSION: The IL-17 gene may be significantly correlated with gastric cancer risk in Asian populations, especially those carrying the rs2275913 G>A and rs763780 T>C polymorphisms.
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Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet 2014; 58:1-10. [PMID: 25449138 DOI: 10.1016/j.ejmg.2014.10.004] [Citation(s) in RCA: 269] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 10/26/2014] [Indexed: 02/06/2023]
Abstract
The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally.
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Chang SC, Chang PY, Butler B, Goldstein BY, Mu L, Cai L, You NCY, Baecker A, Yu SZ, Heber D, Lu QY, Li L, Greenland S, Zhang ZF. Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population. PLoS One 2014; 9:e109235. [PMID: 25337902 PMCID: PMC4206280 DOI: 10.1371/journal.pone.0109235] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022] Open
Abstract
One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.
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Affiliation(s)
- Shen-Chih Chang
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Po-Yin Chang
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Brendan Butler
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Binh Y. Goldstein
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Lina Mu
- Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY, United States of America
| | - Lin Cai
- Department of Epidemiology, Fujian Medical University, Fuzhou, Fujian, China
| | - Nai-Chieh Y. You
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Aileen Baecker
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
| | - Shun-Zhang Yu
- Department of Epidemiology, Fudan University School of Public Health, Shanghai, China
| | - David Heber
- Center for Human Nutrition, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States of America
| | - Qing-Yi Lu
- Center for Human Nutrition, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States of America
| | - Liming Li
- Department of Epidemiology, Peking University School of Public Health, Beijing, China
| | - Sander Greenland
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
- Department of Statistics, University of California Los Angeles College of Letters and Science, Los Angeles, CA, United States of America
| | - Zuo-Feng Zhang
- Department of Epidemiology, University of California Los Angeles Fielding School of Public Health, Los Angeles, CA, United States of America
- * E-mail:
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Xia LZ, Liu Y, Xu XZ, Jiang PC, Ma G, Bu XF, Zhang YJ, Yu F, Xu KS, Li H. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility. World J Gastroenterol 2014; 20:11429-11438. [PMID: 25170232 PMCID: PMC4145786 DOI: 10.3748/wjg.v20.i32.11429] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 03/04/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility.
METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.
RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04).
CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations.
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Kim J, Cho YA, Choi WJ, Jeong SH. Gene-diet interactions in gastric cancer risk: A systematic review. World J Gastroenterol 2014; 20:9600-9610. [PMID: 25071358 PMCID: PMC4110595 DOI: 10.3748/wjg.v20.i28.9600] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/17/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To conduct a systematic review of the published epidemiological studies investigating the association of the interactions between gene variants and dietary intake with gastric cancer risk.
METHODS: A literature search was conducted in PubMed, EMBASE, and MEDLINE for articles published between January 2000 and July 2013, and 38 studies were identified. Previous studies included various dietary factors (e.g., fruits and vegetables, soybean products, salt, meat, and alcohol) and genetic variants that are involved in various metabolic pathways.
RESULTS: Studies suggest that individuals who carry high-risk genetic variants and demonstrate particular dietary habits may have an increased risk of gastric cancer compared with those who do not carry high-risk genetic variants. Distinctive dietary patterns and variations in the frequency of genetic variants may explain the higher incidence of gastric cancer in a particular region. However, most previous studies have limitations, such as a small sample size and a retrospective case-control design. In addition, past studies have been unable to elucidate the specific mechanism in gene-diet interaction associated with gastric carcinogenesis.
CONCLUSION: Additional large prospective epidemiological and experimental studies are required to identify the gene-diet metabolic pathways related to gastric cancer susceptibility.
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Zinck JWR, MacFarlane AJ. Approaches for the identification of genetic modifiers of nutrient dependent phenotypes: examples from folate. Front Nutr 2014; 1:8. [PMID: 25988111 PMCID: PMC4428393 DOI: 10.3389/fnut.2014.00008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/25/2014] [Indexed: 01/14/2023] Open
Abstract
By combining the sciences of nutrition, bioinformatics, genomics, population genetics, and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene–nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome-wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene–nutrient interaction studies, the association of genetic polymorphisms with disease expression, and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focused on specific examples from investigations of the interactions of folate, B-vitamin consumption, and polymorphisms in the genes of B-vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status.
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Affiliation(s)
- John W R Zinck
- Science Integration Division, Public Health Agency of Canada , Ottawa, ON , Canada
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Yan S, Xu D, Wang P, Wang P, Liu C, Hua C, Jiang T, Zhang B, Li Z, Lu L, Liu X, Wang B, Zhang D, Zhang R, He S, Sun B, Wang X. MTHFR C677T polymorphism contributes to the risk for gastric cancer. Tumour Biol 2014; 35:2123-32. [PMID: 24122207 DOI: 10.1007/s13277-013-1282-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 09/27/2013] [Indexed: 02/06/2023] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR) has been demonstrated to be involved in carcinogenesis. Increasing individual studies have investigated the role of MTHFR C677T polymorphism in gastric cancer pathogenesis, but with inconsistent findings. The aim of this study was to clarify the potential association of the MTHFR C677T polymorphism with gastric cancer risk by pooling all available data from published case-control studies. We searched the PubMed, Embase, Web of Science, and Wanfang databases for all relevant publications to date. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95% CI) was calculated. Stratified analysis and sensitivity analysis were also carried out to estimate the strength of this association. A total of 25 case-control studies with 6,572 cases and 9,584 controls were retrieved. Overall, the ORs under five contrast models indicated that the MTHFR C677T variant was positively associated with gastric cancer risk (ORT vs. C = 1.21, 95% CI 1.10–1.34, P(OR) < 0.001; OR(TT vs. CC) = 1.47, 95% CI 1.22–1.76, P(OR) < 0.001; OR(TC vs. CC) = 1.20, 95% CI 1.03-1.40, P(OR) = 0.022; OR(TT + TC vs. CC) = 1.27, 95% CI 1.10-1.47, P(OR) = 0.001; OR(TT vs. CC + TC) = 1.29, 95% CI 1.15-1.46, P(OR) < 0.001). Stratified analyses according to ethnicity and source of controls further confirmed the significant correlations. The current meta-analysis provides strong evidence that the MTHFR C677T polymorphism may be a risk factor for gastric cancer among Asians and Caucasians.
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Association between TLR2, MTR, MTRR, XPC, TP73, TP53 genetic polymorphisms and gastric cancer: a meta-analysis. Clin Res Hepatol Gastroenterol 2014; 38:346-59. [PMID: 24534481 DOI: 10.1016/j.clinre.2013.12.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/06/2013] [Accepted: 12/24/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The aim of our meta-analyses is to test the association between six genetic polymorphisms and gastric cancer. METHODS A systematic search was performed for all the available candidate genes and gastric cancer among several online databases including PubMed, Embase, Web of Science, the Cochrane Library, CNKI and Wanfang online libraries. After a comprehensive screening, a total of six genes were harvested for the current meta-analyses. These genes include TLR2 (-196 to -174 ins>del), MTR (rs1805087), MTRR (rs1801394), XPC (rs2228001), TP73 (G4C14-A4T14), and TP53 (rs1042522). RESULTS Altogether 49 comparative studies among 11 776 cases and 18 633 controls were involved in our meta-analyses. TP53 rs1042522 polymorphism was shown to be associated with gastric cancer risk under the dominant model (P=0.02, OR=1.03, 95% CI=1.00-1.05). A subgroup meta-analysis indicated a significant association under dominant model between TP53 rs1042522 and gastric cancer in the Eastern Asians (P=0.03, OR=1.17, 95%=1.02-1.34). CONCLUSIONS These results suggest that TP53 rs1042522 polymorphism might contribute to the susceptibility of gastric cancer under the dominant model, especially in Eastern Asians.
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Nazki FH, Sameer AS, Ganaie BA. Folate: Metabolism, genes, polymorphisms and the associated diseases. Gene 2014; 533:11-20. [DOI: 10.1016/j.gene.2013.09.063] [Citation(s) in RCA: 206] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 08/19/2013] [Accepted: 09/17/2013] [Indexed: 12/22/2022]
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Rai V, Yadav U, Kumar P, Yadav SK. Analysis of methionine synthase reductase polymorphism (A66G) in Indian Muslim population. INDIAN JOURNAL OF HUMAN GENETICS 2013; 19:183-7. [PMID: 24019620 PMCID: PMC3758725 DOI: 10.4103/0971-6866.116123] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND OBJECTIVES: Methionine synthase reductase (MTRR) is a vital enzyme of homocysteine/methionine metabolic pathway and is required for the conversion of inactive form of methionine synthase (MTR) to its active form. A clinically important allelic variant of MTRR A66G, with less enzymatic activity is reported with worldwide prevalence rate of ~ 30%. The present study was designed to determine the frequency of MTRR A66G polymorphism in rural Sunni Muslim population of Eastern Uttar Pradesh. MATERIALS AND METHODS: Total 56 subjects were analyzed for MTRR A66G polymorphism. A66G mutation analysis was carried out according to the polymerase chain reaction-restriction fragment length polymorphism method of Wilson et al.
[1] amplification with MTRR specific primers followed by amplicon digestion with NdeI enzyme was used for the identification of different MTRR genotypes in subjects. RESULTS AND DISCUSSION: The AA genotype was found in 5 subjects, AG in 23 subjects, and GG genotype in 28 subjects. Genotype frequencies of AA, AG, and GG were 0.089, 0.41, and 0.5 respectively. The allele frequency of A allele was found to be 0.298 and G allele was 0.705. CONCLUSION: It is evident from the present study that the percentage of homozygous genotype GG and frequency of G allele is high in the target Muslim population.
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Affiliation(s)
- Vandana Rai
- Human Molecular Genetics Laboratory, Department of Biotechnology, VBS Purvanchal University, Jaunpur, Uttar Pradesh, India
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Lv L, Wang P, Sun B, Chen G. The polymorphism of methylenetetrahydrofolate reductase C677T but not A1298C contributes to gastric cancer. Tumour Biol 2013; 35:227-37. [PMID: 23897558 DOI: 10.1007/s13277-013-1028-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Accepted: 07/15/2013] [Indexed: 02/07/2023] Open
Abstract
Increasing epidemiological studies have revealed the important role of methylenetetrahydrofolate reductase (MTHFR) in carcinogenesis. The association of MTHFR A1298C and MTHFR C677T polymorphisms with the risk for gastric cancer remains obscure due to inconsistent findings in independent studies among diverse ethnicities. A meta-analysis based on all available publications on this genetic association was performed. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the effect of MTHFR variants on gastric carcinogenesis. Totally, 25 eligible case-control studies were included into the meta-analysis according to the inclusion criteria. The MTHFR C677T polymorphism was demonstrated to significantly increase the susceptibility to gastric cancer (OR(T vs. C) = 1.21, 95% CI 1.10-1.34; OR(TT vs. CC )= 1.47, 95% CI 1.22-1.76; OR(TC vs. CC )= 1.20, 95% CI 1.03-1.40; OR(TT + TC vs. CC) = 1.27, 95% CI 1.10-1.47; OR(TT vs. CC + TC )= 1.29, 95% CI 1.15-1.46), whereas no significant correlation was observed when assessing the MTHFR A1298C polymorphism (OR(C vs. A )= 1.00, 95% CI 0.90-1.10; OR(CC vs. AA) = 0.99, 95% CI 0.75-1.31; OR(CA vs. AA )= 1.01, 95% CI 0.89-1.14; OR(CC + CA vs. AA) = 1.00, 95% CI 0.89-1.13; OR(CC vs. AA + CA) = 0.97, 95% CI 0.74-1.27). Subgroup analyses by ethnicity and source of controls further confirmed the findings in overall analysis. The meta-analysis suggests that the polymorphism of MTHFR C677T but not MTHFR A1298C confers a risk effect on the development of gastric cancer among Asians and Caucasians, which provides a new insight into the gastric cancer pathogenesis.
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Affiliation(s)
- Long Lv
- Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
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Saberi S, Zendehdel K, Jahangiri S, Talebkhan Y, Abdirad A, Mohajerani N, Bababeik M, Karami N, Esmaili M, Oghalaie A, Hassanpour P, Amini N, Mohagheghi MA, Eshagh Hossieni M, Mohammadi M. Impact of methylenetetrahydrofolate reductase C677T polymorphism on the risk of gastric cancer and its interaction with Helicobacter pylori infection. IRANIAN BIOMEDICAL JOURNAL 2013. [PMID: 23183616 DOI: 10.6091/ibj.1102.2012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Attempts for early detection of gastric cancer have recently focused on host's genetic susceptibility factors and gene-environment interactions. We have, herein, studied the association of MTHFR C677T single nucleotide polymorphism (SNP) and its interaction with Helicobacter pylori infection, smoking, age and gender on the risk of gastric cancer among an Iranian population. METHODS Gastric cancer patients (n = 450) and cancer-free controls (n = 780) were studied for serum H. pylori-specific IgG antibodies by ELISA and MTHFR C677T polymorphism (SNP) by PCR-RFLP. Demographic and life style data were collected through patient interviews. Unconditional logistic regression model estimated odds ratio (OR) and the corresponding 95% confidence intervals (CI). RESULTS The interactions of MTHFR genotype with H. pylori infection (P = 0.03), age (P = 0.049) and gender (P = 0.007) were statistically significant. Accordingly, MTHFR C677T carriers who were also positive for H. pylori infection exhibited 80% (OR = 1.8, 95% CI = 1.0-2.9) significant excess risk of non-cardia gastric cancer. Furthermore, subjects over the age of 50 or female subjects carrying MTHFR C677T SNP showed 40 (OR = 1.4, 95% CI = 1.0-2.0) and 100 (OR = 2.0, 95% CI = 1.2-3.2) percent increased risk of gastric cancer, respectively. CONCLUSION MTHFR C677T SNP seems to increase the risk of gastric cancer and the effect is significantly inflated by interactions with H. pylori infection, age and gender.
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Affiliation(s)
- Samaneh Saberi
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Kazem Zendehdel
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Sahar Jahangiri
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Yeganeh Talebkhan
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Afshin Abdirad
- Dept. of Pathology, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mohajerani
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Bababeik
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Najmeh Karami
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Esmaili
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Akbar Oghalaie
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Parisa Hassanpour
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Neda Amini
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Mohagheghi
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Marjan Mohammadi
- HPGC Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Lack of association between methionine synthase A2756G polymorphism and digestive system cancer risk: evidence from 3,9327 subjects. PLoS One 2013; 8:e61511. [PMID: 23613867 PMCID: PMC3629058 DOI: 10.1371/journal.pone.0061511] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 03/10/2013] [Indexed: 12/14/2022] Open
Abstract
Background Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of digestive system cancer. Methionine synthase (MTR) plays a central role in folate metabolism, thereby affecting DNA methylation. The association between A2756G polymorphism (rs1805087) in MTR and digestive system cancer susceptibility was inconsistent in previous studies. To investigate this inconsistency, we performed this meta-analysis. Methods Databases including Pubmed, EMBASE, ISI Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression. Results A total of 29 articles with 15,368 patients and 23,959 controls were included. We found no association between MTR A2756G polymorphism and digestive system cancer in overall population (G allele: OR = 1.03, 95% CI = 0.98–1.09, P = 0.25; dominant model: OR = 1.03, 95% CI = 0.97–1.10, P = 0.33; recessive model: OR = 1.02, 95% CI = 0.89–1.17, P = 0.79). In the stratified analyses according to cancer type, sample size and genotyping method, no evidence of any gene-disease association was obtained in almost all genetic models. However, marginal significant associations were found for East Asians and hospital-based studies. Conclusions This meta-analysis suggests that there is no significant association between the MTR A2756G polymorphism and digestive system cancer risk.
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Izmirli M. A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk. Mol Biol Rep 2012; 40:625-37. [PMID: 23076526 DOI: 10.1007/s11033-012-2101-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 10/03/2012] [Indexed: 12/18/2022]
Abstract
5,10-Methlenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism. This enzyme is mapped on chromosome 1, which is located at the end of the short arm (1p36.3). The C677T and A1298C are MTHFR polymorphisms that decrease in vitro MTHFR enzyme activity. Folate metabolism plays a key role in cell metabolism. These reactions are associated with purine-pyrimidine synthesis: DNA, RNA, and protein methylation. Polymorphism is also a factor in biodiversity, and be affected by ethnic heritage and geographic locale. In the case of unknown outcomes, not only should all geographical regions be investigated to ascertain biodiversity, but all populations as well to fully understand the variations in the effect. PUBMED was searched from January 2006 to December 2011 to develop an investigatory pursuit strategy. MTHFR, cancer, C677T, A1298C, and polymorphisms were key words used to focus the search. The literature review included all published relevant cancer types and MTHFR polymorphisms for that 5 years period. All selected polymorphisms data for cancer types was listed in tables for easy access and retrieval.
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Affiliation(s)
- Muzeyyen Izmirli
- Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, 34093 Istanbul, Turkey.
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26
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Metayer C, Scélo G, Chokkalingam AP, Barcellos LF, Aldrich MC, Chang JS, Guha N, Urayama KY, Hansen HM, Block G, Kiley V, Wiencke JK, Wiemels JL, Buffler PA. Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control 2011; 22:1243-58. [PMID: 21748308 DOI: 10.1007/s10552-011-9795-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 06/08/2011] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair, and methylation of DNA. We examined whether child's germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk. METHODS Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS), were genotyped in 377 ALL cases and 448 controls. Log-additive associations between genotypes and ALL risk were adjusted for age, sex, Hispanic ethnicity (when appropriate), and maternal race. RESULTS Single and haplotype SNPs analyses showed statistically significant associations between SNPs located in (or adjacent to) CBS, MTRR, TYMS/ENOFS, and childhood ALL. Many regions of CBS were associated with childhood ALL in Hispanics and non-Hispanics (p < 0.01). Levels of maternal folate intake modified associations with SNPs in CBS, MTRR, and TYMS. CONCLUSION Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.
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Affiliation(s)
- Catherine Metayer
- School of Public Health, University of California, Berkeley, 1995 University Avenue, Suite 460, Berkeley, CA 94704-7392, USA.
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Han D, Shen C, Meng X, Bai J, Chen F, Yu Y, Jin Y, Fu S. Methionine synthase reductase A66G polymorphism contributes to tumor susceptibility: evidence from 35 case-control studies. Mol Biol Rep 2011; 39:805-16. [PMID: 21547363 DOI: 10.1007/s11033-011-0802-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2010] [Accepted: 04/29/2011] [Indexed: 12/17/2022]
Abstract
Methionine synthase reductase (MTRR) gene is involved in tumorigenesis by regulating DNA methylation through activation of methionine synthase (MTR). MTRR is polymorphic at nucleotide 66 (A-to-G) and the resulting variant enzyme has a lower affinity for MTR. The reported associations of MTRR A66G polymorphism with cancer risk are contradictory. Therefore, we performed a meta-analysis to better assess the associations, including 18,661 cases and 27,678 controls from 35 studies. Crude ORs with 95% CIs were used to assess the strength of association between the MTRR A66G polymorphism and cancer risk. The pooled ORs were performed for homozygote model (GG vs. AA), heterozygote model (GG vs. GA), recessive genetic model (GG vs. GA + AA), and dominant genetic model (GG + GA vs. AA), respectively. Overall, results indicated that the G allele and GG variant genotypes were associated with a significantly increased cancer risk (G vs. A: OR, 1.039; 95% CI, 1.009-1.078; homozygote model: OR, 1.094; 95% CI, 1.006-1.191). In subgroup analysis by ethnicity, significant increased risks were found among Asians with G allele (G vs. A: OR, 1.063; 95% CI, 1.011-1.119; homozygote model: OR, 1.189; 95% CI, 1.055-1.341; recessive model: OR, 1.197; 95% CI, 1.068-1.341). For stratification analysis, the cancer types with fewer than three studies were categorized into "other cancers", and the results indicated that there was a significant elevated cancer risk in "other cancers" in all genetic models, not in colorectal cancer, lymphoid leukemia or breast cancer. In summary, our study suggests that the MTRR A66G polymorphism is a potential biomarker for cancer risk.
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Affiliation(s)
- Dong Han
- Laboratory of Medical Genetics, Harbin Medical University, Baojian Road 157, Nangang District, Harbin 150081, China
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Ibiebele TI, Hughes MC, Pandeya N, Zhao Z, Montgomery G, Hayward N, Green AC, Whiteman DC, Webb PM. High intake of folate from food sources is associated with reduced risk of esophageal cancer in an Australian population. J Nutr 2011; 141:274-83. [PMID: 21178085 PMCID: PMC3021447 DOI: 10.3945/jn.110.131235] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Folate plays a key role in DNA synthesis and methylation. Limited evidence suggests high intake may reduce risks of esophageal cancer overall; however, associations with esophageal cancer subtypes and Barrett's esophagus (BE), a precancerous lesion, remain unexplored. We evaluated the relation between intake of folate, B vitamins, and methyl-group donors (methionine, choline, betaine) from foods and supplements, polymorphisms in key folate-metabolizing genes, and risk of BE, esophageal adenocarcinoma (EAC), and esophageal squamous cell carcinoma (ESCC) in 2 population-based case-control studies in Australia. BE patients without (n = 266) or with (n = 101) dysplasia were compared with population controls (n = 577); similarly, EAC (n = 636) or ESCC (n = 245) patients were compared with population controls (n = 1507) using multivariable adjusted logistic regression. Increasing intake of folate from foods was associated with reduced EAC risk (P-trend = 0.01) and mitigated the increased risks of ESCC associated with smoking and alcohol consumption. In contrast, high intake of folic acid from supplements was associated with a significantly elevated risk of BE with dysplasia. High intakes of riboflavin and methionine from food were associated with increased EAC risk, whereas increasing betaine intake was associated with reduced risks of BE without (P-trend = 0.004) or with dysplasia (P-trend = 0.02). Supplemental thiamin, riboflavin, niacin, and vitamin B-12 were associated with increased EAC risk. There were no consistent associations between genetic polymorphisms studied and BE or EAC risk. High intake of folate-containing foods may reduce risk of EAC, but our data raise the possibility that folic acid supplementation may increase risks of BE with dysplasia and EAC.
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Hou L, Wang H, Sartori S, Gawron A, Lissowska J, Bollati V, Tarantini L, Zhang FF, Zatonski W, Chow WH, Baccarelli A. Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population. Int J Cancer 2010; 127:1866-74. [PMID: 20099281 DOI: 10.1002/ijc.25190] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Global hypomethylation has been shown to increase genome instability potentially leading to increased cancer risk. We determined whether global methylation in blood leukocyte DNA was associated with gastric cancer in a population-based study on 302 gastric cancer cases and 421 age- and sex-matched controls in Warsaw, Poland, between 1994 and 1996. Using PCR-pyrosequencing, we analyzed methylation levels of Alu and LINE-1, 2 CG-rich repetitive elements, to measure global methylation levels. Gastric cancer risk was highest among those with lowest level of methylation in either Alu (OR = 1.3, 95% CI = 0.9-1.9) or LINE-1 (OR = 1.4, 95% CI = 0.9-2.0) relative to those with the highest levels, although the trends were not statistically significant. For Alu, the association was stronger among those aged 70 or older (OR = 2.6, 95% CI = 1.3-5.5, p for interaction = 0.02). We did not observe meaningful differences in the associations by other risk factors and polymorphisms examined. For LINE-1, the association tended to be stronger among individuals with a family history of cancer (OR = 3.1, 95% CI = 1.4-7.0, p for interaction = 0.01), current alcohol drinkers (OR = 1.9, 95% CI = 1.0-3.6, p for interaction = 0.05), current smokers (OR = 2.3, 95% CI = 1.1-4.6, p for interaction = 0.02), those who rarely or never consumed fruit (OR = 3.1, 95% CI = 1.2-8.1, p for interaction = 0.03), CC carriers for the MTRR Ex5+123C>T polymorphism (OR = 2.3, 95% CI = 1.2-4.4, p for interaction = 0.01) and TT carriers for the MTRR Ex15+572T>C polymorphism (OR = 1.7, 95% CI = 1.0-2.8, p for interaction = 0.06). The association was not different by sex, Helicobacter pylori infection, intake of folate, vitamin B6 and total protein and the remaining polymorphisms examined. Our results indicate that interactions between blood leukocyte DNA hypomethylation and host characteristics may determine gastric cancer risk.
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Affiliation(s)
- Lifang Hou
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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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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31
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Cui LH, Shin MH, Kweon SS, Kim HN, Song HR, Piao JM, Choi JS, Shim HJ, Hwang JE, Kim HR, Park YK, Kim SH. Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population. BMC Cancer 2010; 10:236. [PMID: 20504332 PMCID: PMC2893109 DOI: 10.1186/1471-2407-10-236] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 05/26/2010] [Indexed: 12/17/2022] Open
Abstract
Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.
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Affiliation(s)
- Lian-Hua Cui
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
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Galbiatti ALS, Ruiz MT, Biselli-Chicote PM, Chicote-Biselli PM, Raposo LS, Maniglia JV, Pavarino-Bertelli EC, Goloni-Bertollo EM. 5-Methyltetrahydrofolate-homocysteine methyltransferase gene polymorphism (MTR) and risk of head and neck cancer. Braz J Med Biol Res 2010; 43:445-50. [PMID: 20490431 DOI: 10.1590/s0100-879x2010007500034] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Accepted: 04/12/2010] [Indexed: 12/11/2022] Open
Abstract
The functional effect of the A>G transition at position 2756 on the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase), involved in folate metabolism, may be a risk factor for head and neck squamous cell carcinoma (HNSCC). The frequency of MTR A2756G (rs1805087) polymorphism was compared between HNSCC patients and individuals without history of neoplasias. The association of this polymorphism with clinical histopathological parameters was evaluated. A total of 705 individuals were included in the study. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype the polymorphism. For statistical analysis, the chi-square test (univariate analysis) was used for comparisons between groups and multiple logistic regression (multivariate analysis) was used for interactions between the polymorphism and risk factors and clinical histopathological parameters. Using univariate analysis, the results did not show significant differences in allelic or genotypic distributions. Multivariable analysis showed that tobacco and alcohol consumption (P < 0.05), AG genotype (P = 0.019) and G allele (P = 0.028) may be predictors of the disease and a higher frequency of the G polymorphic allele was detected in men with HNSCC compared to male controls (P = 0.008). The analysis of polymorphism regarding clinical histopathological parameters did not show any association with the primary site, aggressiveness, lymph node involvement or extension of the tumor. In conclusion, our data provide evidence that supports an association between the polymorphism and the risk of HNSCC.
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Affiliation(s)
- A L S Galbiatti
- Unidade de Pesquisa em Genética e Biologia Molecular, Faculdade de Medicina de São José do Rio Preto, Brasil
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Dong X, Wu J, Liang P, Li J, Yuan L, Liu X. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer: a meta-analysis. Arch Med Res 2010; 41:125-33. [PMID: 20470942 DOI: 10.1016/j.arcmed.2010.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2009] [Accepted: 12/16/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Case/control studies that investigated the association between gastric cancer and the MTHFR C677T and A1298C polymorphisms so far have provided controversial results. To clarify the effect of MTHFR polymorphisms on the risk of gastric cancer, a meta-analysis was performed. METHODS We performed a computerized search of the PubMed database for relevant reports before September 2009. No language restrictions were added. The associated literature was acquired through a deliberate retrieval strategy and selected based on the established inclusion criteria for publications. RESULTS The studies provided 4070/6462 cases/controls for C677T and 1923/3561 cases/controls for A1298C. There was significant heterogeneity (p = 0.015, I(2) = 44.0%) among the 22 studies, and the RE model showed that the C677T allele T was associated with a 17.3% increased risk of gastric cancer compared with the allele C (RE OR = 1.173 [1.051-1.274]). Results from the subgroup analysis showed an increased risk in Asians (fixed-effect, FE OR 1.277 [1.179-1.382]), but not in Caucasians (random-effect, RE OR 1.194 [0.866-1.646]). The contrast of homozygotes (TT vs. CC) produced significant results in Asians (FE OR 1.611 [1.366-1.901]), whereas, in Caucasians, it was not significant (RE OR 1.385 [0.754-2.544]). In regard to the A1298C polymorphism, there was no heterogeneity among the 11 studies comparing the C vs. the A allele (p = 0.352, I(2) = 9.7%), but no significant association was detected. CONCLUSIONS The evidence from our meta-analysis supports that TT genotype of MTHFR C677T polymorphism contributes to susceptibility to gastric cancer, but no significant association was detected for CC genotype of MTHFR A1298C.
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Affiliation(s)
- Xingli Dong
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, China
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Eussen SJPM, Vollset SE, Hustad S, Midttun Ø, Meyer K, Fredriksen A, Ueland PM, Jenab M, Slimani N, Ferrari P, Agudo A, Sala N, Capellá G, Del Giudice G, Palli D, Boeing H, Weikert C, Bueno-de-Mesquita HB, Büchner FL, Carneiro F, Berrino F, Vineis P, Tumino R, Panico S, Berglund G, Manjer J, Stenling R, Hallmans G, Martínez C, Arrizola L, Barricarte A, Navarro C, Rodriguez L, Bingham S, Linseisen J, Kaaks R, Overvad K, Tjønneland A, Peeters PHM, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Trichopoulou A, Lund E, Plebani M, Riboli E, González CA. Vitamins B2 and B6 and genetic polymorphisms related to one-carbon metabolism as risk factors for gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 2010; 19:28-38. [PMID: 20056620 DOI: 10.1158/1055-9965.epi-08-1096] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.
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Affiliation(s)
- Simone J P M Eussen
- LOCUS for homocysteine and related vitamins, Department of Pharmacology, Institute of Medicine, University of Bergen, and Haukeland University Hospital, Bergen, Norway.
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Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Maruyama N, Kamano T, Kamiya Y, Fujita H, Nakagawa Y, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I, Arisawa T. MTHFR 677T carrier influences the methylation status of H. pylori-infected gastric mucosa in older subjects. Dig Dis Sci 2009; 54:2391-8. [PMID: 19082889 DOI: 10.1007/s10620-008-0624-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2008] [Accepted: 11/03/2008] [Indexed: 12/29/2022]
Abstract
DNA methylation is one of the major events in the early process of gastric carcinogenesis and it also occurs in non-neoplastic gastric mucosa. MTHFR plays a central role in biotransformation of folate to form S-adenosylmethionine, the universal methyl donor in cells and affects DNA methylation status. We investigated the association between common functional polymorphism of MTHFR C677T and DNA methylation status in H. pylori-infected non-neoplastic gastric mucosa. For 99 gastric mucosa samples from H. pylori positive non-cancer subjects, we assessed the association between MTHFR C677T genetic polymorphism and promoter methylation status of the four candidate promoters (p14, p16, DAP-kinase, and CDH1). In most all of the subjects, weak correlation was found between the p16 promoter methylation and MTHFR 677T carriers (age, sex-adjusted OR = 2.57, P = 0.053). When subjects were divided into two groups according to age, the MTHFR T carrier held a significantly higher risk of p16 promoter methylation, especially in 66 years or older generation (sex-adjusted OR = 14.28, P = 0.02). In addition, mean number of methylated CpG cites were significantly higher in T carrier than CC genotype in the same generation (P = 0.0418). Our data suggest that MTHFR 677T carrier influences the risk of DNA methylation in gastric mucosa in the long-term outcome of the H. pylori infection.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
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Hou L, Savage SA, Blaser MJ, Perez-Perez G, Hoxha M, Dioni L, Pegoraro V, Dong LM, Zatonski W, Lissowska J, Chow WH, Baccarelli A. Telomere length in peripheral leukocyte DNA and gastric cancer risk. Cancer Epidemiol Biomarkers Prev 2009; 18:3103-9. [PMID: 19861514 DOI: 10.1158/1055-9965.epi-09-0347] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Telomere length reflects lifetime cumulative oxidative stress from environmental exposures, such as cigarette smoking and chronic inflammation. Shortened telomere length is thought to cause genomic instability and has been associated with several cancers. We examined the association of telomere length in peripheral leukocyte DNA with gastric cancer risk as well as potential confounding factors and risk modifiers for telomere length-related risk. In a population-based study of gastric cancer conducted in a high-risk population in Warsaw, Poland, between 1994 and 1996, we measured relative telomere length in 300 cases and 416 age- and gender-matched controls using quantitative real-time PCR. Among controls, telomeres were significantly shorter in association with aging (P < 0.001), increasing pack-years of cigarette smoking (P = 0.02), decreasing fruit intake (P = 0.04), and Helicobacter pylori positivity (P = 0.03). Gastric cancer cases had significantly shorter telomere length (mean +/- SD relative telomere length, 1.25 +/- 0.34) than controls (1.34 +/- 0.35; P = 0.0008). Gastric cancer risk doubled [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.33-3.13] among subjects in the shortest compared with the highest quartile of telomere length (P(trend) < 0.001). Telomere length-associated risks were higher among individuals with the lowest risk profile, those H. pylori-negative (OR, 5.45; 95% CI, 2.10-14.1), nonsmokers (OR, 3.07; 95% CI, 1.71-5.51), and individuals with high intake of fruits (OR, 2.43; 95% CI, 1.46-4.05) or vegetables (OR, 2.39; 95% CI, 1.51-3.81). Our results suggest that telomere length in peripheral leukocyte DNA was associated with H. pylori positivity, cigarette smoking, and dietary fruit intake. Shortened telomeres increased gastric cancer risk in this high-risk Polish population.
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Affiliation(s)
- Lifang Hou
- Department of Preventive Medicine, Feinberg School of Medicine, and The Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
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Abstract
Polymorphisms in methionine synthase (MTR) gene may be involved in carcinogenesis by affecting DNA methylation. However, association studies on MTR A2756G polymorphism in cancers have reported conflicting results. Therefore we performed a meta-analysis to better assess the associations. A total of 24 896 cancer patients and 33 862 controls from 52 articles for MTR A2756G were investigated. Overall, individuals carrying MTR 2756GG genotype had a subtly reduced cancer risk under a recessive genetic model (odds ratio (OR), 0.92; P=0.053; 95% confidence interval (95% CI), 0.84-1.00; I(2)=0.0%; P(heterogeneity)=0.61). In the subgroup analyses by ethnicity, 2756GG was associated with a significantly reduced cancer risk in European populations (OR, 0.83; P=0.001; 95% CI, 0.74-0.93; I(2)=0.0%; P(heterogeneity)=0.99). However, in Asian populations, a significantly elevated association between 2756GG genotype and cancer risk was observed (OR, 1.33; P=0.012; 95% CI, 1.06-1.65; I(2)=0.0%; P(heterogeneity)=0.50). In studies stratified by tumor site, there was a significantly reduced risk of acute lymphoblastic leukemia (ALL) (OR, 0.54; P=0.049; 95% CI, 0.29-1.00; I(2)=10.7%; P(heterogeneity)=0.33) and colorectal cancer (OR, 0.63; P=0.004; 95% CI, 0.47-0.87; I(2)=0.0%; P(heterogeneity)=0.73) in European populations. Our study indicates that MTR A2756G polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors. Large-scale, well-designed, and population-based studies are required to further investigate gene-gene and gene-environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population.
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The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women. Cancer Causes Control 2009; 21:23-30. [DOI: 10.1007/s10552-009-9430-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Accepted: 09/08/2009] [Indexed: 10/20/2022]
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Methylenetetrahydrofolate reductase polymorphisms and susceptibility to gastric cancer in Chinese populations: a meta-analysis. Eur J Cancer Prev 2008; 17:446-52. [PMID: 18714187 DOI: 10.1097/cej.0b013e328305a140] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are thought to have significant effects on folate metabolism and, thus, on cancer risk, but the reported results are not always consistent. In this meta-analysis including 2165 patients and 3279 controls, we assessed reported studies of associations between polymorphisms of MTHFR and susceptibility to gastric cancer in Chinese populations. An increased risk was found for MTHFR C677T in the meta-analysis [odds ratio (OR): 1.42; 95% confidence interval (CI): 1.24-1.62]. No association resulted for MTHFR A1298C (OR: 0.95; 95% CI: 0.78-1.17). Results from the subgroup analyses showed an increased risk for individuals with low (OR: 1.50; 95% CI: 1.18-1.91) versus high (OR: 1.21; 95% CI: 0.98-1.51) folate levels. The sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. Overall, these findings support the hypothesis that folate plays a role in gastric carcinogenesis. Regarding cardia or noncardia gastric cancer, more studies are required for definite conclusions, as the number of studies is relatively small.
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Vollset SE, Igland J, Jenab M, Fredriksen A, Meyer K, Eussen S, Gjessing HK, Ueland PM, Pera G, Sala N, Agudo A, Capella G, Del Giudice G, Palli D, Boeing H, Weikert C, Bueno-de-Mesquita HB, Carneiro F, Pala V, Vineis P, Tumino R, Panico S, Berglund G, Manjer J, Stenling R, Hallmans G, Martínez C, Dorronsoro M, Barricarte A, Navarro C, Quirós JR, Allen N, Key TJ, Bingham S, Linseisen J, Kaaks R, Overvad K, Tjønneland A, Büchner FL, Peeters PHM, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Lund E, Slimani N, Ferrari P, Riboli E, González CA. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 2008; 16:2416-24. [PMID: 18006931 DOI: 10.1158/1055-9965.epi-07-0256] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n=247) and controls (n=631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P=0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C-->T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A-->C polymorphism (odds ratio, 1.47 for CC versus AA; P=0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer.
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Affiliation(s)
- Stein Emil Vollset
- LOCUS for Homocysteine and Related Vitamins, Institute of Medicine, University of Bergen, Bergen, Norway.
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