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Ye M, Xu G, Zhang L, Kong Z, Qiu Z. Meta Analysis of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism and its association with folate and colorectal cancer. BMC Cancer 2025; 25:169. [PMID: 39875876 PMCID: PMC11776141 DOI: 10.1186/s12885-025-13546-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/16/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND DNA hypomethylation and uracil misincorporation into DNA, both of which have a very important correlation with colorectal carcinogenesis. Folate plays a crucial role in DNA synthesis, acting as a coenzyme in one-carbon metabolism, which involves the synthesis of purines, pyrimidines, and methyl groups. MTHFR, a key enzyme in folate metabolism, has been widely studied in relation to neural tube defects and hypertension, but its role in colorectal cancer remains underexplored. Therefore, understanding the role of folate and MTHFR genes in colorectal cancer may be helpful for potential preventive or therapeutic interventions. In this meta-analysis, the effects of MTHFR genotype and folate intake on colorectal cancer incidence were analyzed. METHODS We searched PubMed,Embase, Web of Science, and CNKI database to identify relevant studies up to January 2024. We included a series of studies on the association of MTHFR C677T genotype and folate intake with colorectal cancer incidence. The meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). It included 100 studies (39702 cases and 55718 controls),that investigated the association between the MTHFR C677T polymorphism and colorectal cancer (CRC). Additionally, the analysis incorporated further stratification by ethnic population and geographical region. Furthermore, Six of the studies which clarified high amount of folate might be a protective factor for CRC in all three MTHFR C677T genotype, especially in TT genotype. RESULTS MTHFR 677TT genotype was negatively associated with CRC incidence compared with CC genotype (OR = 0.89; 95% CI: 0.85-0.93; P < 0.00001; Z = 5.17). MTHFR 677CT genotype was not significantly associated with colorectal cancer incidence (OR = 1.00; 95% CI: 0.98,1.03). A negative correlation between TT genotype and CRC was observed in ethnics of Asians (OR = 0.83, 95% CI: 0.76, 0.91), Caucasians (OR = 0.93, 95% CI: 0.88, 0.99) and the region of USA (OR = 0.77, 95% CI: 0.71, 0.85), Asia (OR = 0.93, 95% CI: 0.86, 1.00) and Europe (OR = 0.93, 95% CI:0.87, 1.00),but not in Indian (TT: OR = 1.67, 95% CI: 1.06, 2.63; CT: OR = 1.31, 95% CI: 1.00, 1.73)). Amount folate intakes might reduce the morbidity of CRC for people in MTHFR 677TT genotype (OR = 0.68; 95% CI: 0.48,0.96; P = 0.03). CONCLUSION The analysis showed that the incidence of colorectal cancer was reduced among individuals with TT genotype. The individuals with TT genotype and amount folate intake may collectively improve the incidence of colorectal cancer. While the MTHFR 677TT genotype is associated with a reduced risk of CRC, especially in certain populations, these findings should be interpreted with caution due to the limitations of retrospective studies.
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Affiliation(s)
- Meng Ye
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Guojie Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P.R. China
| | - Liming Zhang
- The First Clinical Medical College, Guangdong Medical University, Zhanjiang, 524023, P.R. China
| | - Zhihui Kong
- Department of Laboratory Medicine, Jingshan People's Hospital, Jingshan, 431800, P.R. China.
| | - Zhenhua Qiu
- Department of Laboratory Medicine, Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming, 525200, P.R. China.
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Chu V, Fascetti AJ, Larsen JA, Montano M, Giulivi C. Factors influencing vitamin B6 status in domestic cats: age, disease, and body condition score. Sci Rep 2024; 14:2037. [PMID: 38263201 PMCID: PMC10806207 DOI: 10.1038/s41598-024-52367-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 01/17/2024] [Indexed: 01/25/2024] Open
Abstract
Limited studies are available on vitamin B6 status in domestic cats. To this end, we evaluated glutamate-oxaloacetate transaminase (GOT) activity in hemolysates with and without pyridoxal 5'-phosphate addition in two feline populations: a cohort of 60 healthy, domestic (sexually intact and specific pathogen-free) cats maintained under strictly controlled conditions with appropriate diets housed at the Feline Nutrition and Pet Care Center, and a cohort of 57 cats randomly selected between December 2022 to January 2023 that visited the Veterinary Medicine Teaching Hospital to seek care under different circumstances. The GOT activity expressed as the ratio with and without pyridoxal 5'-phosphate addition (primary activation ratio; PAR) decreased significantly with age in the healthy cohort. The PAR values normalized to age established a cut-off for vitamin B6 deficiency in both cohorts, identifying 17 of 101 animals as vitamin B6 deficient. Using machine learning, a partition-based model (decision tree) was built to identify the most important factors that predicted vitamin B6 deficiency while using the resulting tree to make predictions for new observations. This analysis, performed with all 101 cats, revealed that the diagnosis of an infectious, chronic or acute condition (0.55) was the main contributor, followed by age (0.26), and body condition score (optimal-overweight; 0.19). Thus, our study supports that vitamin B6 supplementation may be indicated in junior to adult animals diagnosed with an infectious, chronic, or acute conditions or healthy cats with body weight ranging from optimal to overweight. In older cats, even if healthy, underweight to optimal cats appear to be at risk of vitamin B6 deficiency.
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Affiliation(s)
- Vy Chu
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Andrea J Fascetti
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Jennifer A Larsen
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Maria Montano
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA
| | - Cecilia Giulivi
- Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA.
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA, USA.
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Alsaeedi A, Welham S, Rose P. Impact of lifestyle factors on dietary vitamin B 6 intake and plasma pyridoxal 5'-phosphate level in UK adults: National Diet and Nutrition Survey Rolling Programme (NDNS) (2008-2017). Br J Nutr 2023; 130:1403-1415. [PMID: 36789783 PMCID: PMC10511679 DOI: 10.1017/s0007114523000417] [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: 06/29/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/16/2023]
Abstract
Reduction in dietary vitamin B6 intake is associated with an increased relative risk of diseases such as cancer, atherosclerosis and cognitive dysfunction. The current research has assessed vitamin B6 intakes and PLP concentrations as a marker of vitamin B6 status among the UK adult (≥ 19 years) population. This study was carried out using a cross-sectional analysis of the National Diet and Nutrition Survey Rolling Programme (NDNS) (2008-2017). The impacts of lifestyle factors, including type of diet, smoking, alcohol consumption, and commonly used medications grouped by therapeutic usage, were determined, and data were analysed using IBM SPSS®. Results are expressed as medians (25th-75th percentiles), with P values ≤ 0·05 considered statistically significant. Among UK adults, the median intakes of total population of dietary vitamin B6 met the reference nutrient intake and median plasma PLP concentrations were above the cut-off of vitamin B6 deficiency; however, we found an association between reduction in vitamin B6 intake and plasma PLP concentration and age group (P < 0·001). Smokers had significantly lower plasma PLP concentrations than non-smokers (P < 0·001). Moreover, regression analysis showed some commonly used medications were associated with plasma PLP levels reduction (P < 0·05). Taken together, we report on a tendency for dietary vitamin B6 intake and plasma PLP concentrations to decrease with age and lifestyle factors such as smoking and medication usage. This information could have important implications for smokers and in the elderly population using multiple medications (polypharmacy).
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Affiliation(s)
- Asrar Alsaeedi
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Loughborough, LeicestershireLE12 5RD, UK
| | - Simon Welham
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Loughborough, LeicestershireLE12 5RD, UK
| | - Peter Rose
- Division of Food, Nutrition and Dietetics, School of Biosciences, University of Nottingham, Loughborough, LeicestershireLE12 5RD, UK
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Franco CN, Seabrook LJ, Nguyen ST, Yang Y, Campos M, Fan Q, Cicchetto AC, Kong M, Christofk HR, Albrecht LV. Vitamin B 6 is governed by the local compartmentalization of metabolic enzymes during growth. SCIENCE ADVANCES 2023; 9:eadi2232. [PMID: 37682999 PMCID: PMC10491294 DOI: 10.1126/sciadv.adi2232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/08/2023] [Indexed: 09/10/2023]
Abstract
Vitamin B6 is a vital micronutrient across cell types and tissues, and dysregulated B6 levels contribute to human disease. Despite its importance, how B6 vitamer levels are regulated is not well understood. Here, we provide evidence that B6 dynamics are rapidly tuned by precise compartmentation of pyridoxal kinase (PDXK), the rate-limiting B6 enzyme. We show that canonical Wnt rapidly led to the accumulation of inactive B6 by shunting cytosolic PDXK into lysosomes. PDXK was modified with methyl-arginine Degron (MrDegron), a protein tag for lysosomes, which enabled delivery via microautophagy. Hyperactive lysosomes resulted in the continuous degradation of PDXK and B6 deficiency that promoted proliferation in Wnt-driven colorectal cancer (CRC) cells. Pharmacological or genetic disruption of the coordinated MrDegron proteolytic pathway was sufficient to reduce CRC survival in cells and organoid models. In sum, this work contributes to the repertoire of micronutrient-regulated processes that enable cancer cell growth and provides insight into the functional impact of B6 deficiencies for survival.
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Affiliation(s)
- Carolina N. Franco
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Laurence J. Seabrook
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Steven T. Nguyen
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Ying Yang
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Melissa Campos
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Qi Fan
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Andrew C. Cicchetto
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mei Kong
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Heather R. Christofk
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lauren V. Albrecht
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
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Yang RJ, Wang N, Ma X, Gong MD, Wang YR, Meng SY, Liu ZY, Tang Q. A Novel Two-Dimensional Liquid Chromatography Combined with Ultraviolet Detection Method for Quantitative Determination of Pyridoxal 5'-Phosphate, 4-Pyridoxine Acid and Pyridoxal in Animal Plasma. Animals (Basel) 2023; 13:ani13081333. [PMID: 37106896 PMCID: PMC10135266 DOI: 10.3390/ani13081333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/17/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Vitamin B6 is an indispensable micronutrient in organisms and is widely distributed in blood, tissues, and organs. Changes in the content and ratio of vitamin B6 can affect the entire physiological condition of the body, so it becomes particularly important to reveal the relationship between changes in its content and disease by monitoring vitamin B6 levels in the organism. In this study, a two-dimensional liquid chromatography-UV detector (2D-LC-UV) was used to establish a method for the simultaneous detection of PLP, PA, and PL for the first time. First, PLP, PA, and PL were extracted with plasma: 0.6 M TCA: ultrapure water = 1:2:3 (v/v/v) and then derivatized. Enrichment and preliminary separation were performed on a one-dimensional column and automatically entered into a two-dimensional column for further separation. This method exhibited good selectivity, and the correlation coefficients for the analyte calibration curves were >0.99. The detection limits for PLP, PA, and PL were 0.1, 0.2, and 4 nmol/L, respectively. The results showed that the system has high loading capacity, excellent resolution, and a good peak shape. This method is expected to provide applicability for the determination of PLP, PA, and PL in pharmacological, pharmaceutical, and clinical research.
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Affiliation(s)
- Rong-Ju Yang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Na Wang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Xiao Ma
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Meng-Die Gong
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Yi-Rong Wang
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Si-Yu Meng
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Zhao-Ying Liu
- College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
- Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China
| | - Qi Tang
- College of Horticulture, Hunan Agricultural University, Changsha 410128, China
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Khoziainova S, Rozenberg G, Levy M. Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer. DNA Cell Biol 2022; 41:1007-1011. [PMID: 36454261 PMCID: PMC10162116 DOI: 10.1089/dna.2022.0486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 12/05/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Although certain genetic predispositions may contribute to one's risk for developing CRC, dietary and lifestyle factors may play an important role as well. In a recent study in Nature, Dmitrieva-Posocco et al, reveal a potential protective role of the ketogenic diet in colorectal cancer growth and progression. Administration of a ketogenic diet to CRC-bearing mice demonstrated a tumor-suppressive effect. Specifically, the ketone body β-hydroxybutyrate (BHB) exhibited the ability to suppress epithelial cell proliferation and inhibit tumor growth. BHB acts on cancer cells through regulation of homeodomain-only protein Hopx, known regulator of CRC. Furthermore, BHB requires a surface receptor Hcar to induce Hopx expression and suppress proliferation of intestinal epithelial cells. Taken together, these results describe a new therapeutic approach of using dietary intervention for the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Svetlana Khoziainova
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Galina Rozenberg
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Maayan Levy
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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7
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Holowatyj AN, Ose J, Gigic B, Lin T, Ulvik A, Geijsen AJMR, Brezina S, Kiblawi R, van Roekel EH, Baierl A, Böhm J, Bours MJL, Brenner H, Breukink SO, Chang-Claude J, de Wilt JHW, Grady WM, Grünberger T, Gumpenberger T, Herpel E, Hoffmeister M, Keulen ETP, Kok DE, Koole JL, Kosma K, Kouwenhoven EA, Kvalheim G, Li CI, Schirmacher P, Schrotz-King P, Singer MC, van Duijnhoven FJB, van Halteren HK, Vickers K, Vogelaar FJ, Warby CA, Wesselink E, Ueland PM, Ulrich AB, Schneider M, Habermann N, Kampman E, Weijenberg MP, Gsur A, Ulrich CM. Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer. Am J Clin Nutr 2022; 116:303-313. [PMID: 35394006 PMCID: PMC9348990 DOI: 10.1093/ajcn/nqac090] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 04/04/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. OBJECTIVES We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. METHODS A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. RESULTS After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). CONCLUSION Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.
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Affiliation(s)
- Andreana N Holowatyj
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA,Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Biljana Gigic
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Tengda Lin
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | | | - Anne J M R Geijsen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Stefanie Brezina
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
| | - Rama Kiblawi
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA,Medical Faculty, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
| | - Eline H van Roekel
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Andreas Baierl
- Department of Statistics and Operations Research, University of Vienna, Austria
| | - Jürgen Böhm
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Martijn J L Bours
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Hermann Brenner
- Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stéphanie O Breukink
- Department of Surgery, GROW School for Oncology and Development Biology, Maastricht University, The Netherlands
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg Germany
| | - Johannes H W de Wilt
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Radboud University Medical Center, The Netherlands
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - Tanja Gumpenberger
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
| | - Esther Herpel
- Institute of Pathology, University of Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Eric T P Keulen
- Department of Internal Medicine and Gastroenterology, Zuyderland Medical Center, Sittard, The Netherlands
| | - Dieuwertje E Kok
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Janna L Koole
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Katharina Kosma
- Department of Surgery, Kaiser Franz Josef Hospital, Vienna, Austria
| | | | | | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - Petra Schrotz-King
- Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany
| | - Marie C Singer
- Department of Surgery, Kaiser Franz Josef Hospital, Vienna, Austria
| | | | - Henk K van Halteren
- Department of Internal Medicine, Admiraal de Ruyter Hospital, Goes, The Netherlands
| | - Kathy Vickers
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - F Jeroen Vogelaar
- Department of Surgery, VieCuri Medical Center, Venlo, The Netherlands
| | - Christy A Warby
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | | | - Alexis B Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Nina Habermann
- Genome Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Ellen Kampman
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
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Fedota O, Sadovnychenko I, Chorna L, Roshcheniuk L, Vorontsov V, Ryzhko P, Haybonyuk I, Belyaev S, Belozorov I, Makukh H. The Effects of Polymorphisms in One-carbon Metabolism Genes on Manifestation of Ichthyosis Vulgaris. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris.
AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris.
METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay.
RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002).
CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.
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Yang T, Li X, Farrington SM, Dunlop MG, Campbell H, Timofeeva M, Theodoratou E. A Systematic Analysis of Interactions between Environmental Risk Factors and Genetic Variation in Susceptibility to Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:1145-1153. [PMID: 32238408 PMCID: PMC7311198 DOI: 10.1158/1055-9965.epi-19-1328] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/15/2020] [Accepted: 03/24/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The underlying etiology of colorectal cancer includes both genetic variation and environmental exposures. The main aim of this study was to search for interaction effects between well-established environmental risk factors and published common genetic variants exerting main effects on colorectal cancer risk. METHODS We used a two-phase approach: (i) discovery phase (2,652 incident colorectal cancer cases and 10,608 controls from UK Biobank) and (ii) validation phase (1,656 cases and 2,497 controls from the Study of Colorectal Cancer in Scotland). Interactions with nominal P < 0.05 in phase I were taken forward for validation in phase II. Furthermore, we constructed a weighted genetic risk score (GRS) of colorectal cancer risk for each individual and studied interactions between the GRS and the environmental risk factors. RESULTS Seventy of the 1,500 tested interactions were nominally significant in phase I. After testing these 70 interactions in phase II, an interaction between rs11903757 (2q32.3) and body mass index (BMI) was nominally significant (P = 0.02) with the same direction of effect. The rs11903757*BMI interaction was also significant (ratio of ORs = 1.26; 95% confidence interval, 1.10-1.44; P interaction = 6.03 × 10-4; P heterogeneity = 0.63) in a meta-analysis combining results from both phases. No interactions were significant in phase II after accounting for multiple testing. No interactions involving the GRS were found with statistical significance. CONCLUSIONS Limited evidence of gene-environment interactions in colorectal cancer risk was observed. There are potential modifications of the rs11903757 effect by BMI on colorectal cancer risk. IMPACT Our findings might contribute to identifying subpopulations with different susceptibility to the effect of BMI on colorectal cancer risk.
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Affiliation(s)
- Tian Yang
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
| | - Xue Li
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Susan M Farrington
- Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
- Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
- Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
| | - Harry Campbell
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom.
- Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
- Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
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10
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Yang T, Li X, Montazeri Z, Little J, Farrington SM, Ioannidis JP, Dunlop MG, Campbell H, Timofeeva M, Theodoratou E. Gene-environment interactions and colorectal cancer risk: An umbrella review of systematic reviews and meta-analyses of observational studies. Int J Cancer 2019; 145:2315-2329. [PMID: 30536881 PMCID: PMC6767750 DOI: 10.1002/ijc.32057] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 12/14/2022]
Abstract
The cause of colorectal cancer (CRC) is multifactorial, involving both genetic variants and environmental risk factors. We systematically searched the MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases from inception to December 2016, to identify systematic reviews and meta-analyses of observational studies that investigated gene-environment (G×E) interactions in CRC risk. Then, we critically evaluated the cumulative evidence for the G×E interactions using an extension of the Human Genome Epidemiology Network's Venice criteria. Overall, 15 articles reporting systematic reviews of observational studies on 89 G×E interactions, 20 articles reporting meta-analyses of candidate gene- or single-nucleotide polymorphism-based studies on 521 G×E interactions, and 8 articles reporting 33 genome-wide G×E interaction analyses were identified. On the basis of prior and observed scores, only the interaction between rs6983267 (8q24) and aspirin use was found to have a moderate overall credibility score as well as main genetic and environmental effects. Though 5 other interactions were also found to have moderate evidence, these interaction effects were tenuous due to the lack of main genetic effects and/or environmental effects. We did not find highly convincing evidence for any interactions, but several associations were found to have moderate strength of evidence. Our conclusions are based on application of the Venice criteria which were designed to provide a conservative assessment of G×E interactions and thus do not include an evaluation of biological plausibility of an observed joint effect.
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Affiliation(s)
- Tian Yang
- Centre for Global Health Research, Usher Institute of Population Health Sciences and InformaticsThe University of EdinburghEdinburghUnited Kingdom
| | - Xue Li
- Centre for Global Health Research, Usher Institute of Population Health Sciences and InformaticsThe University of EdinburghEdinburghUnited Kingdom
| | - Zahra Montazeri
- School of Epidemiology and Public HealthUniversity of OttawaOttawaOntarioCanada
| | - Julian Little
- School of Epidemiology and Public HealthUniversity of OttawaOttawaOntarioCanada
| | - Susan M. Farrington
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
| | - John P.A. Ioannidis
- Stanford Prevention Research Center, Departments of Medicine, of Health Research and Policy, and of Biomedical Data Science, Stanford University School of Medicine, and Department of StatisticsStanford University School of Humanities and SciencesStanfordCaliforniaUSA
- Meta‐Research Innovation Center at Stanford (METRICS)Stanford UniversityStanfordCaliforniaUSA
| | - Malcolm G. Dunlop
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
| | - Harry Campbell
- Centre for Global Health Research, Usher Institute of Population Health Sciences and InformaticsThe University of EdinburghEdinburghUnited Kingdom
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
| | - Evropi Theodoratou
- Centre for Global Health Research, Usher Institute of Population Health Sciences and InformaticsThe University of EdinburghEdinburghUnited Kingdom
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics & Molecular MedicineWestern General Hospital, The University of EdinburghEdinburghUnited Kingdom
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11
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Hosseinzadeh P, Javanbakht M, Alemrajabi M, Gholami A, Amirkalali B, Sohrabi M, Zamani F. The Association of Dietary Intake of Calcium and Vitamin D to Colorectal Cancer Risk among Iranian Population. Asian Pac J Cancer Prev 2019; 20:2825-2830. [PMID: 31554383 PMCID: PMC6976838 DOI: 10.31557/apjcp.2019.20.9.2825] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Indexed: 02/06/2023] Open
Abstract
Background: Vitamin D and Calcium have a possible protective impact versus rectal neoplasm. Vitamin D, an important nutrient, is vital to regulate the absorption of calcium and bone mineralization; nevertheless, in a case-control study in Iran, we investigated the relationship among the dietary intake of vitamin D and calcium with the hazard of rectal neoplasm. Methods: 363 subjects (162 cases and 201 controls) participated in the case- control Study from March 2017 to November 2018. Dietary intake of Calcium and Vitamin D was calculated using a 148-items food-frequency questionnaire. Results: Since altering the strong confounding agents, the multivariate risk proportion within the dietary vitamin D intake was OR=0.2, 95%CI 0.1-0.5, P-value <0.001 among cases. There was no association in case of calcium and rectal cancer. Conclusions: Taken together, a possible reduction in the hazard of rectal neoplasm with dietary intake of Vitamin D within Iranian patients was observed.
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Affiliation(s)
- Payam Hosseinzadeh
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdi Alemrajabi
- Firoozgar Hospital, FCRDC, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Gholami
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.,Department of Epidemiology and Biostatistics, School of Public Health, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Bahare Amirkalali
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Masoudreza Sohrabi
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center (GILDRC), Iran University of Medical Sciences (IUMS), Tehran, Iran.
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12
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Law PJ, Timofeeva M, Fernandez-Rozadilla C, Broderick P, Studd J, Fernandez-Tajes J, Farrington S, Svinti V, Palles C, Orlando G, Sud A, Holroyd A, Penegar S, Theodoratou E, Vaughan-Shaw P, Campbell H, Zgaga L, Hayward C, Campbell A, Harris S, Deary IJ, Starr J, Gatcombe L, Pinna M, Briggs S, Martin L, Jaeger E, Sharma-Oates A, East J, Leedham S, Arnold R, Johnstone E, Wang H, Kerr D, Kerr R, Maughan T, Kaplan R, Al-Tassan N, Palin K, Hänninen UA, Cajuso T, Tanskanen T, Kondelin J, Kaasinen E, Sarin AP, Eriksson JG, Rissanen H, Knekt P, Pukkala E, Jousilahti P, Salomaa V, Ripatti S, Palotie A, Renkonen-Sinisalo L, Lepistö A, Böhm J, Mecklin JP, Buchanan DD, Win AK, Hopper J, Jenkins ME, Lindor NM, Newcomb PA, Gallinger S, Duggan D, Casey G, Hoffmann P, Nöthen MM, Jöckel KH, Easton DF, Pharoah PDP, Peto J, Canzian F, Swerdlow A, Eeles RA, Kote-Jarai Z, Muir K, Pashayan N, Harkin A, Allan K, McQueen J, Paul J, Iveson T, Saunders M, Butterbach K, Chang-Claude J, Hoffmeister M, Brenner H, Kirac I, Matošević P, Hofer P, Brezina S, Gsur A, Cheadle JP, Aaltonen LA, Tomlinson I, Houlston RS, Dunlop MG. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat Commun 2019; 10:2154. [PMID: 31089142 PMCID: PMC6517433 DOI: 10.1038/s41467-019-09775-w] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 03/29/2019] [Indexed: 02/02/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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Affiliation(s)
- Philip J Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Ceres Fernandez-Rozadilla
- Grupo de Medicina Xenómica, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación de Santiago, Santiago de Compostela, 15706, Spain
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Peter Broderick
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - James Studd
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Juan Fernandez-Tajes
- Wellcome Centre for Human Genetics, McCarthy Group, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Susan Farrington
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Victoria Svinti
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Claire Palles
- Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Giulia Orlando
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Amy Holroyd
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Steven Penegar
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Evropi Theodoratou
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Peter Vaughan-Shaw
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Harry Campbell
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Lina Zgaga
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Department of Public Health and Primary Care, Institute of Population Health, Trinity College Dublin, University of Dublin, Dublin, D02 PN40, Ireland
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Archie Campbell
- Generation Scotland, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Sarah Harris
- Generation Scotland, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Ian J Deary
- Generation Scotland, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - John Starr
- Generation Scotland, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Laura Gatcombe
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Maria Pinna
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Sarah Briggs
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Lynn Martin
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Emma Jaeger
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Archana Sharma-Oates
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - James East
- Translational Gastroenterology Unit, Nuffield Department. of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK
| | - Simon Leedham
- Wellcome Centre for Human Genetics, McCarthy Group, Roosevelt Drive, Oxford, OX3 7BN, UK
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Roland Arnold
- Cancer Bioinfomatics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Elaine Johnstone
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7LE, UK
| | - Haitao Wang
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7LE, UK
| | - David Kerr
- Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Rachel Kerr
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7LE, UK
| | - Tim Maughan
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7LE, UK
| | - Richard Kaplan
- Medical Research Council Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Nada Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia
| | - Kimmo Palin
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Ulrika A Hänninen
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Tatiana Cajuso
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Tomas Tanskanen
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Johanna Kondelin
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Eevi Kaasinen
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Antti-Pekka Sarin
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland
| | - Johan G Eriksson
- Folkhälsan Research Centre, 00250, Helsinki, Finland
- Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland
| | - Harri Rissanen
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Paul Knekt
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Eero Pukkala
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland, and Faculty of Social Sciences, University of Tampere, Tampere, 33014, Finland
- Faculty of Social Sciences, University of Tampere, Tampere, 33014, Finland
| | - Pekka Jousilahti
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, 00271, Finland
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland
- Department of Public Health, University of Helsinki, Helsinki, 00014, Finland
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00014, Finland
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Laura Renkonen-Sinisalo
- Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, 00029, Finland
| | - Anna Lepistö
- Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, 00029, Finland
| | - Jan Böhm
- Department of Pathology, Central Finland Central Hospital, Jyväskylä, 40620, Finland
| | - Jukka-Pekka Mecklin
- Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, 40620, Finland
- Department of Health Sciences, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, 40014, Finland
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia
- Victorian Comprehensive Cancer Centre, University of Melbourne, Centre for Cancer Research, Parkville, Victoria, 3010, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3010, Australia
| | - Aung-Ko Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - John Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Mark E Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Noralane M Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Polly A Newcomb
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Steven Gallinger
- Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada
| | - David Duggan
- Translational Genomics Research Institute (TGen), An Affiliate of City of Hope, Phoenix, AZ, 85004, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Virginia, VA, 22903, USA
| | - Per Hoffmann
- Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, 4031, Switzerland
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
| | - Markus M Nöthen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
- Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, 53127, Germany
| | - Karl-Heinz Jöckel
- Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
| | - Douglas F Easton
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Paul D P Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Julian Peto
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
| | - Anthony Swerdlow
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
- Division of Breast Cancer Research, The Institute of Cancer Research, London, SW3 6JB, UK
| | - Rosalind A Eeles
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
- Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK
| | - Zsofia Kote-Jarai
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Kenneth Muir
- Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, M13 9PL, UK
- Warwick Medical School, University of Warwick, Coventry, CV4 7HL, UK
| | - Nora Pashayan
- Department of Applied Health Research, University College London, London, WC1E 7HB, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK
| | - Andrea Harkin
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK
| | - Karen Allan
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK
| | - John McQueen
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK
| | - James Paul
- Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK
| | - Timothy Iveson
- University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Mark Saunders
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Katja Butterbach
- Division of Clinical Epidemiology and Aging Research, Deutsches Krebsforschungszentrum, 69120, Heidelberg, Germany
| | - Jenny Chang-Claude
- Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
- University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, 20251, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, Deutsches Krebsforschungszentrum, 69120, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, Deutsches Krebsforschungszentrum, 69120, Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany
| | - Iva Kirac
- Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre, Zagreb, 10000, Croatia
| | - Petar Matošević
- Department of Surgery, University Hospital Center Zagreb, 10000, Zagreb, Croatia
| | - Philipp Hofer
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria
| | - Stefanie Brezina
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria
| | - Andrea Gsur
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Medicum and Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland
| | - Ian Tomlinson
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK
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Synthesis of [ 13C₃]-B6 Vitamers Labelled at Three Consecutive Positions Starting from [ 13C₃]-Propionic Acid. MOLECULES (BASEL, SWITZERLAND) 2018; 23:molecules23092117. [PMID: 30142892 PMCID: PMC6225105 DOI: 10.3390/molecules23092117] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/16/2018] [Accepted: 08/18/2018] [Indexed: 12/31/2022]
Abstract
[13C3]-labelled vitamers (PN, PL and PM) of the B6 group were prepared starting from [13C3]-propionic acid. [13C3]-PN was synthesized in ten linear steps with an overall yield of 17%. Hereby, higher alkyl homologues of involved esters showed a positive impact on the reaction outcome of the intermediates in the chosen synthetic route. Oxidation of [13C3]-PN to [13C3]-PL was undertaken using potassium permanganate and methylamine followed by acid hydrolysis of the imine derivative. [13C3]-PM could be prepared from the oxime derivative of [13C3]-PN by hydrogenation with palladium.
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14
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He Y, Timofeeva M, Farrington SM, Vaughan-Shaw P, Svinti V, Walker M, Zgaga L, Meng X, Li X, Spiliopoulou A, Jiang X, Hyppönen E, Kraft P, Kiel DP, Hayward C, Campbell A, Porteous D, Vucic K, Kirac I, Filipovic M, Harris SE, Deary IJ, Houlston R, Tomlinson IP, Campbell H, Theodoratou E, Dunlop MG. Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. BMC Med 2018; 16:142. [PMID: 30103784 PMCID: PMC6090711 DOI: 10.1186/s12916-018-1119-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/06/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.
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Affiliation(s)
- Yazhou He
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
- West China School of Medicine/West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Susan M Farrington
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Peter Vaughan-Shaw
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Victoria Svinti
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Marion Walker
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Lina Zgaga
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
- Department of Public Health and Primary Care, Institute of Population Health, Trinity College Dublin, University of Dublin, Dublin 24, D02 PN40, Ireland
| | - Xiangrui Meng
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Xue Li
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Athina Spiliopoulou
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Xia Jiang
- Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
- Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vagen 13, Stockholm, 17177, Sweden
| | - Elina Hyppönen
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, 5001, Australia
- Population, Policy and Practice, University College London, Great Ormond Street, Institute of Child Health, WC1E 6BT, London, UK
| | - Peter Kraft
- Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA
| | - Douglas P Kiel
- Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, 02142, USA
| | - Caroline Hayward
- MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK
| | - Archie Campbell
- Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - David Porteous
- Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Katarina Vucic
- Agency for Medicinal Products and Medical Devices, Department for Quality, Safety and Efficacy Assessment, Zagreb, Croatia
| | - Iva Kirac
- Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia
| | - Masa Filipovic
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sarah E Harris
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Ian J Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
- Department of Psychology, The University of Edinburgh, Edinburgh, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK
| | - Ian P Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Harry Campbell
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Evropi Theodoratou
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, EH8 9AG, UK.
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, EH4 2XU, UK.
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15
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Xu L, Qin Z, Wang F, Si S, Li L, Lin P, Han X, Cai X, Yang H, Gu Y. Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Biosci Rep 2017; 37:BSR20170917. [PMID: 29089462 PMCID: PMC5719002 DOI: 10.1042/bsr20170917] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 10/13/2017] [Accepted: 10/31/2017] [Indexed: 12/19/2022] Open
Abstract
The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer (CRC) susceptibility has been researched in numerous studies. However, the results of these studies were controversial. Therefore, the objective of this meta-analysis was to offer a more convincible conclusion about such association with more included studies. Eligible studies published till May 1, 2017 were searched from PubMed, Embase, Web of Science, and CNKI database about such association. Pooled odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated to evaluate such association. And the Begg's funnel plot and Egger's test were applied to assess the publication bias. This meta-analysis contained 37049 cases and 52444 controls from 87 publications with 91 eligible case-control studies. Because of lack of data for a particular genotype in several studies, all the included studies were analysed barely in the dominant model. Originally, there was no association between MTHFR C677T polymorphism and CRC susceptibility (OR =0.99, 95% CI =0.94-1.05). After excluding 13 studies according to their heterogeneity and publication bias, rs1801133 polymorphism was found to reduce the risks of CRC significantly (OR =0.96, 95% CI =0.94-0.99). In the subgroup analysis of ethnicity, there was a significant association in Asians (OR =0.94, 95% CI =0.89-1.00). Furthermore, when stratified by the source of controls and genotyping methods, the positive results were observed in population-based control group (OR =0.97, 95% CI =0.93-1.00) and PCR-restriction fragment length polymorphism (PCR-RFLP) method (OR =0.95, 95% CI =0.91-0.99. The results of the meta-analysis suggested that MTHFR C677T polymorphism was associated with CRC susceptibility, especially in Asian population.
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Affiliation(s)
- Lingyan Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhiqiang Qin
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Feng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Shuhui Si
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Lele Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Peinan Lin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiao Han
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiaomin Cai
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Haiwei Yang
- State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Heat-stabilised rice bran consumption by colorectal cancer survivors modulates stool metabolite profiles and metabolic networks: a randomised controlled trial. Br J Nutr 2017. [PMID: 28643618 PMCID: PMC5654571 DOI: 10.1017/s0007114517001106] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Rice bran (RB) consumption has been shown to reduce colorectal cancer (CRC) growth in mice and modify the human stool microbiome. Changes in host and microbial metabolism induced by RB consumption was hypothesised to modulate the stool metabolite profile in favour of promoting gut health and inhibiting CRC growth. The objective was to integrate gut microbial metabolite profiles and identify metabolic pathway networks for CRC chemoprevention using non-targeted metabolomics. In all, nineteen CRC survivors participated in a parallel randomised controlled dietary intervention trial that included daily consumption of study-provided foods with heat-stabilised RB (30 g/d) or no additional ingredient (control). Stool samples were collected at baseline and 4 weeks and analysed using GC-MS and ultra-performance liquid chromatography-MS. Stool metabolomics revealed 93 significantly different metabolites in individuals consuming RB. A 264-fold increase in β-hydroxyisovaleroylcarnitine and 18-fold increase in β-hydroxyisovalerate exemplified changes in leucine, isoleucine and valine metabolism in the RB group. A total of thirty-nine stool metabolites were significantly different between RB and control groups, including increased hesperidin (28-fold) and narirutin (14-fold). Metabolic pathways impacted in the RB group over time included advanced glycation end products, steroids and bile acids. Fatty acid, leucine/valine and vitamin B6 metabolic pathways were increased in RB compared with control. There were 453 metabolites identified in the RB food metabolome, thirty-nine of which were identified in stool from RB consumers. RB consumption favourably modulated the stool metabolome of CRC survivors and these findings suggest the need for continued dietary CRC chemoprevention efforts.
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17
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Haerian MS, Haerian BS, Molanaei S, Kosari F, Sabeti S, Bidari-Zerehpoosh F, Abdolali E. MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case-control study and meta-analysis. Pharmacogenomics 2017; 18:1075-1084. [PMID: 28691890 DOI: 10.2217/pgs-2017-0030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
AIM This study aims to evaluate the association between the MTRR rs1801394 alone or in interaction with the MTHFR rs1801133 and susceptibility to colorectal cancer (CRC) and its characteristics in Iranian population. Additionally, both a systematic review and meta-analysis were performed to derive a more precise assessment of this association. MATERIALS & METHODS Genomic DNA of 2332 subjects was genotyped for rs1801394. These data were pooled with 17 eligible studies for meta-analysis. RESULTS No significant association was found between the rs1801394 or rs1801394-rs1801133 and CRC risk. Meta-analysis results also demonstrated no significant relationship between the rs1801394 and CRC risk. CONCLUSION Results of this study showed that the rs1801394 alone or together with the rs1801133 is not a risk factor for CRC in Iranian population.
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Affiliation(s)
- Monir Sadat Haerian
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Bone & Joint Reconstruction Research Center, Shafa Yahyaeian Orthopedics Hospital, Iran University of Medical Science, Tehran, Iran
| | - Batoul Sadat Haerian
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Farid Kosari
- Department of Pathology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahram Sabeti
- Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farahnaz Bidari-Zerehpoosh
- Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebrahim Abdolali
- Department of Pathology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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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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Ueland PM, McCann A, Midttun Ø, Ulvik A. Inflammation, vitamin B6 and related pathways. Mol Aspects Med 2016; 53:10-27. [PMID: 27593095 DOI: 10.1016/j.mam.2016.08.001] [Citation(s) in RCA: 233] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/27/2016] [Indexed: 12/11/2022]
Abstract
The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers. Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies. Vitamin B6 intake and supplementation improve some immune functions in vitamin B6-deficient humans and experimental animals. A possible mechanism involved is mobilization of vitamin B6 to the sites of inflammation where it may serve as a co-factor in pathways producing metabolites with immunomodulating effects. Relevant vitamin B6-dependent inflammatory pathways include vitamin B6 catabolism, the kynurenine pathway, sphingosine 1-phosphate metabolism, the transsulfuration pathway, and serine and glycine metabolism.
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Affiliation(s)
- Per Magne Ueland
- Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Laboratory of Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway.
| | | | | | - Arve Ulvik
- Bevital A/S, Laboratoriebygget, 5021 Bergen, Norway
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20
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Pabalan N, Singian E, Tabangay L, Jarjanazi H, Singh N. Associations of the A66G Methionine Synthase Reductase Polymorphism in Colorectal Cancer: A Systematic Review and Meta-Analysis. BIOMARKERS IN CANCER 2015; 7:21-8. [PMID: 26549973 PMCID: PMC4627415 DOI: 10.4137/bic.s25251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 09/30/2015] [Accepted: 10/01/2015] [Indexed: 12/31/2022]
Abstract
Inconsistency in the reported associations between the A66G polymorphism in the methionine synthase reductase (MTRR) gene and colorectal cancer (CRC) prompted a meta-analysis, so that we could obtain a more precise estimate. Databases searches of the published literature yielded 20 case–control studies from 17 articles (8,371 cases and 12,574 controls). We calculated pooled odds ratios (ORs) and 95% confidence intervals in three genetic comparisons (A allele, G allele, and A/G genotype). We found no evidence of overall associations between MTRR A66G and CRC risk (OR 0.96–1.05, P = 0.12–0.44). This was materially unchanged when reanalyzed without the Hardy–Weinberg equilibrium (HWE)-deviating studies (OR 0.97–1.06, P = 0.11–0.65). In the A allele comparison, however, outlier treatment generated significant protection (OR 0.91, P = 0.01). Combined removal of the outliers and HWE-deviating studies reflected this summary effect (OR 0.90, P = 0.01) as did the pooled OR from high-quality studies (OR 0.90, P = 0.01). Only the Asian subgroup showed significant (both at P = 0.05) A allele (OR 1.13) and A/G genotype (OR 0.88) associations. In conclusion, post-outlier A allele effects were protective. Our study also suggests ethnic-specific associations with Asian susceptibility and protection in the A allele and A/G genotype comparisons, respectively. Folate status showed no association of this polymorphism with CRC.
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Affiliation(s)
- Noel Pabalan
- Center for Research and Development, Angeles University Foundation, Angeles City, Philippines
| | - Eloisa Singian
- College of Allied Medical Professions, Angeles University Foundation, Angeles City, Philippines
| | - Lani Tabangay
- Department of Biological Sciences, Angeles University Foundation, Angeles City, Philippines
| | - Hamdi Jarjanazi
- Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment and Climate Change, Toronto, ON, Canada
| | - Neetu Singh
- Genotoxicity Laboratory, Toxicology Division, Central Drug Research Institute, Lucknow, Uttar Pradesh, India
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21
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Mazzuca F, Borro M, Botticelli A, Aimati L, Gentile G, Capalbo C, Maddalena C, Mazzotti E, Simmaco M, Marchetti P. Effect of MTHFR Polymorphisms on Gastrointestinal Cancer Risk in Italy. World J Oncol 2015; 6:394-397. [PMID: 28983337 PMCID: PMC5624687 DOI: 10.14740/wjon930w] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The aim of the study was to assess the association of single nucleotide polymorphisms (SNPs) C677T and A1298C in the methylenetetrahydrofolate reductase gene with colorectal, esophageal/gastric and pancreatic cancer in a cohort of Italian patients. METHODS A total of 790 cancer patients and 202 healthy controls were genotyped and distributions in genotype and allele frequencies were compared by Chi-squared analysis and logistic regression analysis. RESULTS According to most of previous findings, we found an effect of the C677T variant, but no effect of the A1298C, in colorectal and esophageal/gastric, whereas no association was evidenced with pancreatic cancer. We found that only homozygous TT carriers of the C677T variant had an increased risk for onset of cancer. CONCLUSION This result could be related to dietary and behavioral habits of the analyzed population, which could mitigate the deleterious effect of the T allele in heterozygosity and it highlights the importance to validate genetic determinant of cancer risk in different population and geographical areas.
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Affiliation(s)
- Federica Mazzuca
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Marina Borro
- Department of Advanced Molecular Diagnosis Unit (DiMA), Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Andrea Botticelli
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Laura Aimati
- Department of Advanced Molecular Diagnosis Unit (DiMA), Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Giovanna Gentile
- Department of Advanced Molecular Diagnosis Unit (DiMA), Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Carlo Capalbo
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Chiara Maddalena
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Eva Mazzotti
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Maurizio Simmaco
- Department of Advanced Molecular Diagnosis Unit (DiMA), Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
| | - Paolo Marchetti
- Department of Clinical Oncology, Faculty of Medicine and Psychology, University of Rome "La Sapienza", Azienda Ospedaliera Sant'Andrea, Via di Grottarossa, 1035/39, 00189 Roma, Italy
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Quantitative assessment of the association between MS gene polymorphism and colorectal cancer risk. Cell Biochem Biophys 2015; 70:1943-9. [PMID: 25077679 DOI: 10.1007/s12013-014-0154-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Accumulating genetic association studies have investigated the risk of colorectal cancer (CRC) in relation to MS gene polymorphism with uncertain conclusions. In the current study, we sought to assess the association between MS gene and CRC. We performed an updated meta-analysis including 18 case-control studies with a total of 10, 303 CRC patients and 15, 389 CRC-free controls to estimate the strength of the association using odds ratios with the corresponding 95 % confidence intervals. Overall, no CRC risk associated with the genotypes of MS gene polymorphism was indicated in our meta-analysis. Similarly, the stratified analysis according to ethnicity and control source did not show any evident association either. The results of our updated meta-analysis suggest that MS gene polymorphism may not serve as a biomarker for the CRC risk. Future large-scale and well-designed studies are required to clarify the association identified in the present meta-analysis.
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Abstract
Measures of B6 status are categorized as direct biomarkers and as functional biomarkers. Direct biomarkers measure B6 vitamers in plasma/serum, urine and erythrocytes, and among these plasma pyridoxal 5'-phosphate (PLP) is most commonly used. Functional biomarkers include erythrocyte transaminase activities and, more recently, plasma levels of metabolites involved in PLP-dependent reactions, such as the kynurenine pathway, one-carbon metabolism, transsulfuration (cystathionine), and glycine decarboxylation (serine and glycine). Vitamin B6 status is best assessed by using a combination of biomarkers because of the influence of potential confounders, such as inflammation, alkaline phosphatase activity, low serum albumin, renal function, and inorganic phosphate. Ratios between substrate-products pairs have recently been investigated as a strategy to attenuate such influence. These efforts have provided promising new markers such as the PAr index, the 3-hydroxykynurenine:xanthurenic acid ratio, and the oxoglutarate:glutamate ratio. Targeted metabolic profiling or untargeted metabolomics based on mass spectrometry allow the simultaneous quantification of a large number of metabolites, which are currently evaluated as functional biomarkers, using data reduction statistics.
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Affiliation(s)
- Per Magne Ueland
- Department of Clinical Science, University of Bergen, and the Laboratory of Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway;
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Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in gastrointestinal diseases. World J Gastroenterol 2015; 21:5191-5209. [PMID: 25954093 PMCID: PMC4419060 DOI: 10.3748/wjg.v21.i17.5191] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases. For instance, most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials, however interventional trials failed to prove a clear beneficial preventive role. On the other hand, more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities. Examples for this include the therapeutic role of vitamin E in patients with non-alcoholic steatohepatitis, the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus, the role of vitamin C in reducing the risk of gallstones, the positive outcome with vitamin B12 in patients with aphthous stomatitis, and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease. Other potential uses are yet to be elaborated, like those on celiac disease, pancreatic cancer, pancreatitis, cholestasis and other potential fields. Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years. Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost, their use should be encouraged in the fields where positive data are available.
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Lo KK, Wong AH, Tam WW, Ho SC. Citation classics in the nutrition and dietetics literature: 50 frequently cited articles. Nutr Diet 2015. [DOI: 10.1111/1747-0080.12173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Kenneth K.H. Lo
- Jockey Club School of Public Health and Primary Care; Chinese University of Hong Kong; New Territories, Hong Kong China
| | - April H.C. Wong
- Jockey Club School of Public Health and Primary Care; Chinese University of Hong Kong; New Territories, Hong Kong China
| | - Wilson W.S. Tam
- Alice Lee Centre for Nursing Studies; Yong Loo Lin School of Medicine; National University of Singapore; Singapore
| | - Suzanne C. Ho
- Jockey Club School of Public Health and Primary Care; Chinese University of Hong Kong; New Territories, Hong Kong China
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Morita M, Yin G, Yoshimitsu SI, Ohnaka K, Toyomura K, Kono S, Ueki T, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Maekawa T, Yasunami Y, Takenaka K, Ichimiya H, Terasaka R. Folate-related nutrients, genetic polymorphisms, and colorectal cancer risk: the fukuoka colorectal cancer study. Asian Pac J Cancer Prev 2015; 14:6249-56. [PMID: 24377513 DOI: 10.7314/apjcp.2013.14.11.6249] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.
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Affiliation(s)
- Makiko Morita
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan E-mail :
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Abstract
Epidemiologic and laboratory animal studies have suggested that the availability of vitamin B6 modulates cancer risk. The means by which B6 mediates this effect is not known with any surety but it has been reported that high dietary vitamin B6 attenuates and low dietary vitamin B6 increases the risk of cancer. In fact vitamin B6 is widely distributed in foods and overt deficiency of this vitamin is not common. Nevertheless, marginal or secondary vitamin B6 deficiency, which might have an adverse effect on carcinogenesis, is rather common especially among old adults and alcoholics. This chapter addressed currently available information regarding the relationship between vitamin B6 and cancer.
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Zhang P, Suidasari S, Hasegawa T, Yanaka N, Kato N. Vitamin B₆ activates p53 and elevates p21 gene expression in cancer cells and the mouse colon. Oncol Rep 2014; 31:2371-6. [PMID: 24626782 DOI: 10.3892/or.2014.3073] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/10/2014] [Indexed: 11/06/2022] Open
Abstract
Increasing evidence indicates vitamin B6 acts as a protective factor against colon cancer. However, the mechanisms of the effect of vitamin B6 are poorly understood. The present preliminary study using DNA microarray and real-time PCR indicates p21 mRNA is upregulated in human colon carcinoma (HT29) cells exposed to pyridoxal (PL, 500 µM). A similar effect was observed in human epithelial colorectal adenocarcinoma (Caco2) cells, human colon adenocarcinoma (LoVo) cells, human embryonic kidney (HEK293T) cells, and human hepatoma (HepG2) cells. Adding other B6-vitamers such as pyridoxal 5'-phosphate (PLP), pyridoxine (PN), and pyridoxamine (PM) caused no such effect. In order to understand the mechanism of higher mRNA expression of p21 by PL, effect of PL on the p53 activation was examined (the upstream factor for p21 mRNA transcription) in HT29 cells, LoVo cells, and HepG2 cells. PL increased the phosphorylated p53 protein levels (active form) in whole-cell lysates and the nuclei of the cells. Noteworthy, the consumption of a vitamin B6-deficient diet for 5 weeks significantly reduced p21 mRNA levels and tended to reduce phosphorylated p53 protein levels (P=0.053) in the colons of mice compared to a diet with adequate vitamin B6. Thus, these results suggest vitamin B6 plays a role in increasing p21 gene expression via p53 activation in several cancer cells and the mouse colon.
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Affiliation(s)
- Peipei Zhang
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Sofya Suidasari
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Tomomi Hasegawa
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Noriyuki Yanaka
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Norihisa Kato
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
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Zhang P, Suidasari S, Hasegawa T, Yanaka N, Kato N. High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c‑Jun pathway. Mol Med Rep 2013; 8:973-8. [PMID: 23942851 DOI: 10.3892/mmr.2013.1629] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 08/08/2013] [Indexed: 11/05/2022] Open
Abstract
Increasing evidence suggests that dietary vitamin B6 is linked to the prevention of cancer and cardiovascular disease. However, the molecular mechanisms involved in this process are not yet understood. Preliminary results in the current study indicated, following DNA microarray analysis and quantitative PCR, that insulin‑like growth factor‑binding protein 1 (IGFBP1) mRNA is upregulated in HT29 colon carcinoma cells exposed to pyridoxal (PL, 500 µM). IGFBP1 is secreted from the liver and is hypothesized to exert a protective role in the development of cancer and cardiovascular disease. Thus, further experiments were performed to investigate the effect of PL on the expression of IGFBP1 in HepG2 hepatocellular carcinoma cells. The addition of PL (500 µM) markedly increased the expression of IGFBP1 mRNA in HepG2 cells at 6, 12 and 24 h (P<0.01), whereas other vitamers (500 µM), including pyridoxal 5'‑phosphate (PLP), pyridoxine (PN) and pyridoxamine (PM), caused no such effect. The expression of the IGFBP1 protein in the cell lysate and culture medium was elevated in the presence of PL. PL elevated expression of the active form of ERK1 protein, p‑ERK1, and the p‑c‑Jun protein, a downstream factor of ERK. Furthermore, IGFBP1 expression, elevated by PL, was suppressed by PD98059, an ERK inhibitor. Higher expression of IGFBP1 protein by PL was suppressed by cycloheximide. These results suggest that PL may induce the expression of IGFBP1 in hepatoma cells via a mechanism involving the ERK/c‑Jun pathway.
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Affiliation(s)
- Peipei Zhang
- Graduate School of Biosphere Science, Hiroshima University, Higashi‑Hiroshima, Hiroshima 739‑8528, Japan
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Zhao M, Li X, Xing C, Zhou B. Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis. Biomed Rep 2013; 1:781-791. [PMID: 24649029 DOI: 10.3892/br.2013.134] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 07/08/2013] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82-0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54-0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76-0.96) and the 1298CC (OR=0.82; 95% CI: 0.69-0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72-0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69-0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77-0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC.
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Affiliation(s)
- Mengmeng Zhao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
| | - Chengzhong Xing
- Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning 110001, P.R. China ; Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, Liaoning 110001, P.R. China
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31
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Okazaki Y, Utama Z, Suidasari S, Zhang P, Yanaka N, Tomotake H, Sakaguchi E, Kato N. Consumption of vitamin B(6) reduces fecal ratio of lithocholic acid to deoxycholic acid, a risk factor for colon cancer, in rats fed a high-fat diet. J Nutr Sci Vitaminol (Tokyo) 2013; 58:366-70. [PMID: 23327973 DOI: 10.3177/jnsv.58.366] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
To examine the effect of supplemental dietary vitamin B(6) on the colonic luminal environment, growing male rats were fed a high-fat diet containing 1, 7, or 35 mg pyridoxine HCl/kg diet for 6 wk. Food intake and growth were unaffected by the dietary treatment. Supplemental dietary vitamin B(6) significantly reduced the production of a fecal secondary bile acid, lithocholic acid (the most toxic secondary bile acid and a risk factor for colon cancer), and markedly reduced the ratio of lithocholic acid to deoxycholic acid (a less toxic secondary bile acid) in feces (p<0.05). Increasing dietary vitamin B(6) increased fecal mucin levels (a marker of intestinal barrier function) in a dose-dependent manner (p<0.05) but did not affect fecal immunoglobulin A levels (an index of intestinal immune function). Cecal levels of organic acids were not significantly affected by supplemental dietary vitamin B(6). These results suggest the possibility that dietary vitamin B(6) affects the colonic luminal environment by altering the production of secondary bile acids and mucins.
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Affiliation(s)
- Yukako Okazaki
- Faculty of Human Life Sciences, Fuji Women's University, Ishikari, Japan.
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Bassett JK, Severi G, Hodge AM, Baglietto L, Hopper JL, English DR, Giles GG. Dietary Intake of B Vitamins and Methionine and Colorectal Cancer Risk. Nutr Cancer 2013; 65:659-67. [DOI: 10.1080/01635581.2013.789114] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Nan H, Lee JE, Rimm EB, Fuchs CS, Giovannucci EL, Cho E. Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States. Ann Epidemiol 2013; 23:558-63. [PMID: 23726821 DOI: 10.1016/j.annepidem.2013.04.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 03/26/2013] [Accepted: 04/20/2013] [Indexed: 12/14/2022]
Abstract
PURPOSE To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. METHODS We evaluated the association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses' Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented. RESULTS Alcohol consumption was associated with an increased risk of colorectal cancer. Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for ≥30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval [95% CI], 1.09-1.70; P for trend, 0.02). The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS-1998) than in the postfortification period (1998-2008); the pooled multivariate relative risks for ≥30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00-1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69-1.65; P for trend, 0.67) in the postfortification period. CONCLUSIONS Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer.
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Affiliation(s)
- Hongmei Nan
- Division of Cancer Epidemiology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA
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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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Ding W, Zhou DL, Jiang X, Lu LS. Methionine synthase A2756G polymorphism and risk of colorectal adenoma and cancer: evidence based on 27 studies. PLoS One 2013; 8:e60508. [PMID: 23593229 PMCID: PMC3621882 DOI: 10.1371/journal.pone.0060508] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Accepted: 02/26/2013] [Indexed: 12/31/2022] Open
Abstract
Methionine synthase (MTR), which plays a central role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations, was thought to be involved in the development of colorectal cancer (CRC) and colorectal adenoma (CRA) by affecting DNA methylation. However, studies on the association between MTR A2756G polymorphism and CRC/CRA remain conflicting. We conducted a meta-analysis of 27 studies, including 13465 cases and 20430 controls for CRC, and 4844 cases and 11743 controls for CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio of G variant for CRC was 1.03 (95% CI: 0.96-1.09) and 1.05 (95% CI: 0.99-1.12) for CRA. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, source of controls, sample size, sex, and tumor site, no evidence of any gene-disease association was obtained. Results from the meta-analysis of four studies on MTR stratified according to smoking and alcohol drinking status showed an increased CRC risk in heavy smokers (OR = 2.06, 95% CI: 1.32-3.20) and heavy drinkers (OR = 2.00, 95% CI: 1.28-3.09) for G allele carriers. This meta-analysis suggests that the MTR A2756G polymorphism is not associated with CRC/CRA susceptibility and that gene-environment interaction may exist.
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Affiliation(s)
- Weixing Ding
- Department of Gastroenterology, The Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of China
- * E-mail: (WXD); (LSL)
| | - Dong-lei Zhou
- Department of Gastroenterology, The Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of China
| | - Xun Jiang
- Department of Gastroenterology, The Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of China
| | - Lie-sheng Lu
- Department of Gastroenterology, The Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of China
- * E-mail: (WXD); (LSL)
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Teng Z, Wang L, Cai S, Yu P, Wang J, Gong J, Liu Y. The 677C>T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. PLoS One 2013; 8:e55332. [PMID: 23437053 PMCID: PMC3577825 DOI: 10.1371/journal.pone.0055332] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 12/20/2012] [Indexed: 12/31/2022] Open
Abstract
Background The 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene is considered to have a significant effect on colorectal cancer susceptibility, but the results are inconsistent. In order to investigate the association between the MTHFR 677C>T polymorphism and the risk of colorectal cancer, a meta-analysis was held based on 71 published studies. Methods Eligible studies were identified through searching the MEDLINE, EMBASE, PubMed, Web of Science, Chinese Biomedical Literature database (CBM) and CNKI database. Odds ratios (OR) and 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with x2-based Q-test. Begg's and Egger's test were also carried out to evaluate publication bias. Sensitive and subgroup analysis were also held in this meta-analysis. Results Overall, 71 publications including 31,572 cases and 44,066 controls were identified. The MTHFR 677 C>T variant genotypes are significantly associated with increased risk of colorectal cancer. In the stratified analysis by ethnicity, significantly increased risks were also found among Caucasians for CC vs TT (OR = 1.076; 95%CI = 1.008–1.150; I2 = 52.3%), CT vs TT (OR = 1.102; 95%CI = 1.032–1.177; I2 = 51.4%) and dominant model (OR = 1.086; 95%CI = 1.021–1.156; I2 = 53.6%). Asians for CC vs TT (OR = 1.226; 95%CI = 1.116–1.346; I2 = 55.3%), CT vs TT (OR = 1.180; 95%CI = 1.079–1.291; I2 = 36.2%), recessive (OR = 1.069; 95%CI = 1.003-1.140; I2 = 30.9%) and dominant model (OR = 1.198; 95%CI = 1.101-1.303; I2 = 52.4%), and Mixed populations for CT vs TT (OR = 1.142; 95%CI = 1.005-1.296; I2 = 0.0%). However, no associations were found in Africans for all genetic models. Conclusion This meta-analysis suggests that the MTHFR 677C>T polymorphism increases the risk for developing colorectal cancer, while there is no association among Africans found in subgroup analysis by ethnicity.
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Affiliation(s)
- Zan Teng
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Lei Wang
- Department of Geriatrics, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Shuang Cai
- Department of Pharmacy, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Ping Yu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Jin Wang
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Jing Gong
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Yunpeng Liu
- Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
- * E-mail:
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Kjeldby IK, Fosnes GS, Ligaarden SC, Farup PG. Vitamin B6 deficiency and diseases in elderly people--a study in nursing homes. BMC Geriatr 2013; 13:13. [PMID: 23394203 PMCID: PMC3579689 DOI: 10.1186/1471-2318-13-13] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Accepted: 02/04/2013] [Indexed: 12/14/2022] Open
Abstract
Background Vitamin deficiency is a cause of health related problems in elderly people. The aims were to study associations between vitamin B6 (B6) and diseases (primarily functional gastrointestinal disorders) in elderly people in nursing homes, the prevalence of B6 deficiency and factors associated with B6 deficiency. Methods This cross-sectional study included residents in nursing homes. Demographics, nutritional status (Mini Nutritional Assessment, MNA® ), physical activity, activity of daily living (Katz Index), dietary habits, use of drugs, and psychiatric and somatic diseases were recorded. A blood sample was collected for haematological and biochemical screening, including B6 (p-PLP); p-PLP values < 20 nmol/l indicates B6 deficiency. The results are given as mean (SD). Results Sixty-one residents (men/women: 22/39) with an age of 85.3 (6.8) years and BMI 25.7 (4.5) kg/m2 were included. Malnutrition and risk of malnutrition were present in 11.5% and 61% respectively. Dietary intake of B6 (mg/day) in men and women were 1.60 (0.30) and 1.18 (0.31) (recommended 1.6 and 1.2 respectively), and 14 (23%) used B6 supplements. Median p-PLP was 20.7 (range <4.0-175.8), 30 subjects (49%) had B6 deficiency. B6 deficiency was associated with old age, low s-alanine aminotransferase and s-albumin, elevated s-homocysteine and inactivity (p-values 0.01-0.03). There were no clinically significant associations between B6 deficiency and somatic or psychiatric disorders, and B6 deficiency was not observed in subjects given B6 supplements. Conclusions Half of the residents had vitamin B6 deficiency. Vitamin supplement was effective prophylaxis for deficiency and should be recommended to all elderly people in nursing homes.
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Affiliation(s)
- Ida K Kjeldby
- Department of Research, Innlandet Hospital Trust, Brumunddal, Norway
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Figueiredo JC, Levine AJ, Crott JW, Baurley J, Haile RW. Folate-genetics and colorectal neoplasia: what we know and need to know next. Mol Nutr Food Res 2013; 57:607-27. [PMID: 23401104 DOI: 10.1002/mnfr.201200278] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 10/11/2012] [Accepted: 11/07/2012] [Indexed: 12/18/2022]
Abstract
SCOPE The metabolism of folate involves a complex network of polymorphic enzymes that may explain a proportion of the risk associated with colorectal neoplasia. Over 60 observational studies primarily in non-Hispanic White populations have been conducted on selected genetic variants in specific genes, MTHFR, MTR, MTRR, CBS, TCNII, RFC, GCPII, SHMT, TYMS, and MTHFD1, including five meta-analyses on MTHFR 677C>T (rs1801133) and MTHFR 1298C>T (rs1801131); two meta-analyses on MTR-2756A>C (rs1805087); and one for MTRR 66A>G (rs1801394). METHODS AND RESULTS This systematic review synthesizes these data, highlighting the consistent inverse association between MTHFR 677TT genotype and risk of colorectal cancer (CRC) and its null association with adenoma risk. Results for other variants varied across individual studies; in our meta-analyses we observed some evidence for SHMT 1420C>T (rs1979277) ((odds ratio) OR = 0.85; 95% confidence interval (CI) = 0.73-1.00 for TT v. CC) and TYMS 5' 28 bp repeat (rs34743033) and CRC risk (OR = 0.84; 95% CI = 0.75-0.94 for 2R/3R v. 3R/3R and OR = 0.82; 95% CI = 0.69-0.98 for 2R/2R v. 3R/3R). CONCLUSION To gain further insight into the role of folate variants in colorectal neoplasia will require incorporating measures of the metabolites, including B-vitamin cofactors, homocysteine and S-adenosylmethionine, and innovative statistical methods to better approximate the folate one-carbon metabolism pathway.
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Affiliation(s)
- Jane C Figueiredo
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Galluzzi L, Vacchelli E, Michels J, Garcia P, Kepp O, Senovilla L, Vitale I, Kroemer G. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene 2013; 32:4995-5004. [PMID: 23334322 DOI: 10.1038/onc.2012.623] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 11/21/2012] [Accepted: 11/26/2012] [Indexed: 12/17/2022]
Abstract
Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.
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Affiliation(s)
- L Galluzzi
- 1] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [2] Institut Gustave Roussy, Villejuif, France
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Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis. J Cancer Epidemiol 2012; 2012:952508. [PMID: 23125859 PMCID: PMC3483802 DOI: 10.1155/2012/952508] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 05/26/2012] [Accepted: 05/26/2012] [Indexed: 12/31/2022] Open
Abstract
Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms "folic acid," "folate," "colorectal cancer," "methylenetetrahydrofolate reductase," "MTHFR." Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95-1.10) and for 677TT versus CC was 0.88 (95% CI 0.80-0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56-0.89) and the 677TT genotype 0.63 (95% CI 0.41-0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes.
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Zhang X, Lee JE, Ma J, Je Y, Wu K, Willett WC, Fuchs CS, Giovannucci EL. Prospective cohort studies of vitamin B-6 intake and colorectal cancer incidence: modification by time? Am J Clin Nutr 2012; 96:874-81. [PMID: 22875713 PMCID: PMC3441113 DOI: 10.3945/ajcn.112.037267] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The relation between vitamin B-6 intake and colorectal cancer risk remains uncertain. OBJECTIVE We prospectively evaluated whether a higher vitamin B-6 intake in the remote past is more strongly associated with a lower risk of colorectal cancer than is an intake in the recent past in the Nurses' Health Study and the Health Professionals Follow-Up Study. DESIGN We assessed vitamin B-6 intake every 4 y by using validated food-frequency questionnaires and followed 86,440 women and 44,410 men for ≤28 y. Cox proportional hazards regression was used to estimate multivariable RRs and 95% CIs. RESULTS The total vitamin B-6 intake was significantly associated with an ∼20-30% lower risk of colorectal cancer in age-adjusted results, but this association became attenuated and nonsignificant after additional adjustment for nondietary and dietary factors. When the highest to lowest quintiles of cumulative total vitamin B-6 intake were compared, RRs (95% CIs) for colorectal cancer were 0.99 (0.80, 1.24; P-trend = 0.55) for women and 0.95 (0.73, 1.23; P-trend = 0.75) for men. For the same comparison, RRs were 0.92 (0.73, 1.16) for total vitamin B-6 intake 0-4 y before diagnosis, 0.99 (0.78, 1.26) for intake 4-8 y before diagnosis, 0.92 (0.71, 1.21) for intake 8-12 y before diagnosis, and 0.93 (0.69, 1.26) for intake 12-16 y before diagnosis in women. Corresponding RRs for men were 0.86 (0.63, 1.17), 0.96 (0.70, 1.32), 0.90 (0.63, 1.29), and 1.16 (0.75, 1.79). Results did not differ by cancer subsite, source of vitamin B-6 (food or supplement), alcohol consumption, or folate intake. CONCLUSION Our data do not support a strong role of adulthood vitamin B-6 intake in colorectal carcinogenesis in these US health professionals.
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Affiliation(s)
- Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Yoo JY, Kim SY, Hwang JA, Hong SH, Shin A, Choi IJ, Lee YS. Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans. Genomics Inform 2012; 10:184-93. [PMID: 23166529 PMCID: PMC3492654 DOI: 10.5808/gi.2012.10.3.184] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 08/23/2012] [Accepted: 08/24/2012] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index ≥ 25 kg/m2), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated.
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Affiliation(s)
- Jae-Young Yoo
- Cancer Genomics Branch, National Cancer Center, Goyang 410-769, Korea
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Sheng X, Zhang Y, Zhao E, Lu S, Zheng X, Ge H, Lu W. MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case-control studies. Mol Biol Rep 2012; 39:9669-79. [PMID: 22729883 DOI: 10.1007/s11033-012-1832-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 06/10/2012] [Indexed: 02/08/2023]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case-control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR = 0.89, 95 % CI = 0.82-0.97; for TT vs. CT/CC: OR = 0.88, 95 % CI = 0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR = 0.82, 95 % CI = 0.69-0.97; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR = 0.82, 95 % CI = 0.71-0.93; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC.
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Affiliation(s)
- Xuewen Sheng
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
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Zhou D, Mei Q, Luo H, Tang B, Yu P. The polymorphisms in methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and the risk of colorectal cancer. Int J Biol Sci 2012; 8:819-30. [PMID: 22719222 PMCID: PMC3372886 DOI: 10.7150/ijbs.4462] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Accepted: 05/24/2012] [Indexed: 12/20/2022] Open
Abstract
Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.
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Affiliation(s)
- Daijun Zhou
- 4th team of Cadet Brigade, Third Military Medical University, Chongqing 400038, China
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Effect of butyrate on aromatase cytochrome P450 levels in HT29, DLD-1 and LoVo colon cancer cells. Biomed Pharmacother 2012; 66:77-82. [PMID: 22386365 DOI: 10.1016/j.biopha.2011.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 12/15/2011] [Indexed: 02/07/2023] Open
Abstract
Epidemiological studies suggest that colonic production of butyrate and estrogen may be involved in human susceptibility to colorectal cancer (CRC). Estrone (E1) can be produced by the aromatase pathway during the conversion of androstenedione (A) to E1. Therefore, we studied the effect of sodium butyrate (NaBu) on the CYP19A1 transcript and protein levels and on the conversion of A to E1 in HT29, DLD-1 and LoVo CRC cells. We found that NaBu significantly downregulated CYP19A1 transcript and protein levels, a phenomenon that was associated with reduced conversion of A to E1 in HT29, DLD-1 and LoVo cells. Our studies demonstrated that, although butyrate exhibited a protective role in CRC development, this compound may reduce aromatase activity and the production of E1 in colon cancer cells.
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Kayashima T, Tanaka K, Okazaki Y, Matsubara K, Yanaka N, Kato N. Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine. Oncol Lett 2011; 2:1243-1246. [PMID: 22848295 DOI: 10.3892/ol.2011.370] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 07/15/2011] [Indexed: 12/31/2022] Open
Abstract
Mounting evidence indicates that vitamin B6 is a protective factor for colon cancer. Elevations in colonic damage, cell proliferation and heat shock proteins (HSPs, molecular chaperones) have been suggested to be associated with colon carcinogenesis. This study was performed to examine the effect of dietary levels of vitamin B6 (1, 7 or 35 mg pyridoxine HCl/kg diet) for 22 weeks on colon damage, epithelial cell proliferation and expression of HSPs in rats exposed to 1,2-dimethylhydrazine (DMH). Supplemental vitamin B6 with a low vitamin B6 diet (1 mg pyridoxine HCl/kg diet) significantly reduced fecal activity of intestinal alkaline phosphatase (an index of intestinal damage) and the colonic epithelium PCNA labeling index (a marker of cell proliferation). Analysis using ELISA indicated that supplemental vitamin B6 significantly lowered protein levels of colonic HSP70 and heme oxygenase-1, HSP32 (HO-1). However, real-time RT-PCR analysis revealed that the mRNA levels of these HSPs were not decreased by supplemental vitamin B6, suggesting that the lowering effect of vitamin B6 on the colon protein expression of the HSPs is mediated by mechanisms not involving altered gene expression. This study provided evidence that dietary supplemental vitamin B6 suppresses colon damage, epithelial cell proliferation and protein expression of HSP70 and HO-1, the targets for anti-tumor agents, in rats exposed to DMH.
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Affiliation(s)
- Tomoko Kayashima
- Graduate School of Education, Hiroshima University, Higashi-Hiroshima 739-8524
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Rawłuszko AA, Krokowicz P, Jagodziński PP. Butyrate induces expression of 17β-hydroxysteroid dehydrogenase type 1 in HT29 and SW707 colorectal cancer cells. DNA Cell Biol 2011; 30:661-9. [PMID: 21563966 DOI: 10.1089/dna.2010.1192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Epidemiological studies have revealed that butyrate and 17β-estradiol (E2) may decrease the incidence of colorectal cancer (CRC). In peripheral tissue, E2 can be produced locally by 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) estrone (E1) reduction. Using quantitative real-time polymerase chain reaction and western blotting analysis, we found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in HT29 and SW707 CRC cells. Chromatin immunoprecipitation analysis showed that upregulation of these transcript levels correlated with an increase in binding of Polymerase II to proximal and distal promoters of HSD17B1. Moreover, we observed that upregulation of HSD17B1 protein levels was associated with increased conversion of E1 to E2 in HT29 and SW707 CRC cells. Since sodium butyrate increases the conversion of E1 to E2, our findings may support the validity of butyrate in the prophylaxis of CRC incidence.
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Affiliation(s)
- Agnieszka Anna Rawłuszko
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
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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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La Merrill M, Torres-Sánchez L, Ruiz-Ramos R, López-Carrillo L, Cebrián ME, Chen J. The association between first trimester micronutrient intake, MTHFR genotypes, and global DNA methylation in pregnant women. J Matern Fetal Neonatal Med 2011; 25:133-7. [PMID: 21443409 PMCID: PMC3279137 DOI: 10.3109/14767058.2011.564242] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Objective Our aim was to evaluate possible associations between consumption of micronutrients involved in one-carbon metabolism, MTHFR genotypes, and global DNA methylation in pregnant women. Methods A semi-quantitative dietary questionnaire was administered to 195 women during their first trimester in Morelos, Mexico. Two functional polymorphisms of the key folate-metabolizing gene, i.e. MTHFR 677 C>T and 1298 A>C, as well as global DNA methylation were assessed in peripheral blood drawn during the interview. Results Independent of maternal age and caloric intake, vitamin B6 deficiency was associated with 1.8 fold increased risk of hypomethylation in women carrying the MTHFR 677 T allele. Conclusions There exists a subpopulation that is more susceptible to B vitamin deficiencies.
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Affiliation(s)
- Michele La Merrill
- Department of Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Le Marchand L, Wang H, Selhub J, Vogt TM, Yokochi L, Decker R. Association of plasma vitamin B6 with risk of colorectal adenoma in a multiethnic case-control study. Cancer Causes Control 2011; 22:929-36. [PMID: 21437631 DOI: 10.1007/s10552-011-9759-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 03/12/2011] [Indexed: 12/21/2022]
Abstract
Circulating level of vitamin B6 has been inversely associated with colorectal cancer (CRC) risk but, unlike for folate, few studies have examined the relationship of vitamin B6 to colorectal adenoma, the precursor lesion to most CRCs. We measured plasma levels of folate, vitamin B6, and vitamin B12 in 241 patients with pathologically confirmed first occurrence of colorectal adenoma and 280 controls among Caucasians, Japanese Americans, and Native Hawaiians undergoing flexible sigmoidoscopy screening in Hawaii. High plasma level of vitamin B6 was independently inversely associated with risk of colorectal adenoma [multivariate odds ratios (95% confidence intervals): 1.0, 0.71 (0.45-1.13) and 0.44 (0.26-0.74) from the lowest to the highest tertile, respectively, p (trend) = 0.002]. Plasma folate was not associated with adenoma after adjustment for plasma vitamin B6 (p (trend) > 0.3). No association was observed with plasma vitamin B12. No significant interaction was detected between the three B vitamins and alcohol intake, multivitamin use or MTHFR C677T. The results provide evidence for an inverse association of plasma vitamin B6 levels with risk of colorectal adenoma. This study expands previous findings and suggests that vitamin B6 may be protective against the early stages of colorectal carcinogenesis.
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Affiliation(s)
- Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
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