Low folate levels may protect against colorectal cancer

Bethany Van Guelpen ^1*, Johan Hultdin ¹, Ingegerd Johansson ¹, Göran Hallmans ¹, Roger Stenling ¹, Elio Riboli ², Anna Winkvist ³ and Richard Palmqvist ¹

¹ Umeå University, Sweden
² International Agency for Research on Cancer, France
³ The Sahlgrenska Academy, Sweden

^* To whom correspondence should be addressed. E-mail: bethany.van.guelpen{at}medbio.umu.se.

Accepted 1 March 2006

Abstract

Background and aims: Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC.

Subjects: Subjects were 226 cases and 437 matched referents from the population-based Northern Sweden Health and Disease Cohort.

Results: We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% CI 1.13-3.56). In subjects with follow-up times greater than the median of 4.2 years, however, plasma folate concentrations were strongly, positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52-9.87, P-trend=0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19-0.85, P- trend=0.062) and, for 1298 CC versus AA, 1.62 (95% CI 0.94-2.81, P-trend=0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT-homozygotes was independent of plasma folate status.

Conclusions: Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.

Keywords: colorectal neoplasm, folate, homocysteine, methylenetetrahydrofolate reductase (MTHFR), risk factors

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Folate: a magic bullet or a double edged sword for colorectal cancer prevention?

Y-I Kim
Gut 2006 55: 1387-1389. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Taioli, E., Garza, M. A., Ahn, Y. O., Bishop, D. T., Bost, J., Budai, B., Chen, K., Gemignani, F., Keku, T., Lima, C. S. P., Le Marchand, L., Matsuo, K., Moreno, V., Plaschke, J., Pufulete, M., Thomas, S. B., Toffoli, G., Wolf, C. R., Moore, C. G., Little, J. (2009). Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review. Am J Epidemiol 170: 1207-1221 [Abstract] [Full Text]  
• Lindzon, G. M., Medline, A., Sohn, K.-J., Depeint, F., Croxford, R., Kim, Y.-I. (2009). Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci. Carcinogenesis 30: 1536-1543 [Abstract] [Full Text]  
• Thomasset, S., Berry, D. P., Cai, H., West, K., Marczylo, T. H., Marsden, D., Brown, K., Dennison, A., Garcea, G., Miller, A., Hemingway, D., Steward, W. P., Gescher, A. J. (2009). Pilot Study of Oral Anthocyanins for Colorectal Cancer Chemoprevention. Cancer Prevention Research 2: 625-633 [Abstract] [Full Text]  
• Keszei, A. P., Verhage, B. A.J., Heinen, M. M., Goldbohm, R. A., van den Brandt, P. A. (2009). Dietary Folate and Folate Vitamers and the Risk of Pancreatic Cancer in the Netherlands Cohort Study. Cancer Epidemiol. Biomarkers Prev. 18: 1785-1791 [Abstract] [Full Text]  
• Lawrance, A K, Deng, L, Rozen, R (2009). Methylenetetrahydrofolate reductase deficiency and low dietary folate reduce tumorigenesis in Apcmin/+ mice. Gut 58: 805-811 [Abstract] [Full Text]  
• Scott, E. N., Gescher, A. J., Steward, W. P., Brown, K. (2009). Development of Dietary Phytochemical Chemopreventive Agents: Biomarkers and Choice of Dose for Early Clinical Trials. Cancer Prevention Research 2: 525-530 [Abstract] [Full Text]  
• Yang, Q., Bostick, R. M., Friedman, J.M., Flanders, W. D. (2009). Serum Folate and Cancer Mortality Among U.S. Adults: Findings from the Third National Health and Nutritional Examination Survey Linked Mortality File. Cancer Epidemiol. Biomarkers Prev. 18: 1439-1447 [Abstract] [Full Text]  
• Shrubsole, M. J., Yang, G., Gao, Y.-T., Chow, W. H., Shu, X. O., Cai, Q., Rothman, N., Gao, J., Wagner, C., Zheng, W. (2009). Dietary B Vitamin and Methionine Intakes and Plasma Folate Are Not Associated with Colorectal Cancer Risk in Chinese Women. Cancer Epidemiol. Biomarkers Prev. 18: 1003-1006 [Full Text]  
• de Vogel, S., Dindore, V., van Engeland, M., Goldbohm, R. A., van den Brandt, P. A., Weijenberg, M. P. (2008). Dietary Folate, Methionine, Riboflavin, and Vitamin B-6 and Risk of Sporadic Colorectal Cancer. J. Nutr. 138: 2372-2378 [Abstract] [Full Text]  
• Weinstein, S. J., Albanes, D., Selhub, J., Graubard, B., Lim, U., Taylor, P. R., Virtamo, J., Stolzenberg-Solomon, R. (2008). One-Carbon Metabolism Biomarkers and Risk of Colon and Rectal Cancers. Cancer Epidemiol. Biomarkers Prev. 17: 3233-3240 [Abstract] [Full Text]  
• Michels, K. B (2008). The promise and challenges of population strategies of prevention. Int J Epidemiol 37: 914-916 [Full Text]  
• Wali, R. K., Kunte, D. P., Koetsier, J. L., Bissonnette, M., Roy, H. K. (2008). Polyethylene glycol-mediated colorectal cancer chemoprevention: roles of epidermal growth factor receptor and Snail. Molecular Cancer Therapeutics 7: 3103-3111 [Abstract] [Full Text]  
• Wolpin, B. M., Wei, E. K., Ng, K., Meyerhardt, J. A., Chan, J. A., Selhub, J., Giovannucci, E. L., Fuchs, C. S. (2008). Prediagnostic Plasma Folate and the Risk of Death in Patients With Colorectal Cancer. JCO 26: 3222-3228 [Abstract] [Full Text]  
• Smith, A D., Kim, Y.-I., Refsum, H. (2008). Is folic acid good for everyone?. Am. J. Clin. Nutr. 87: 517-533 [Abstract] [Full Text]  
• Marsillach, J., Ferre, N., Camps, J., Riu, F., Rull, A., Joven, J. (2008). Moderately High Folic Acid Supplementation Exacerbates Experimentally Induced Liver Fibrosis in Rats. Exp. Biol. Med. 233: 38-47 [Abstract] [Full Text]  
• Pfeiffer, C. M, Johnson, C. L, Jain, R. B, Yetley, E. A, Picciano, M. F., Rader, J. I, Fisher, K. D, Mulinare, J., Osterloh, J. D (2007). Trends in blood folate and vitamin B-12 concentrations in the United States, 1988 2004. Am. J. Clin. Nutr. 86: 718-727 [Abstract] [Full Text]  
• Wald, N. J, Oakley, G. P (2007). Should folic acid fortification be mandatory? Yes. BMJ 334: 1252-1252 [Full Text]  
• Hubner, R. A, Houlston, R. D, Muir, K. R (2007). Should folic acid fortification be mandatory? No. BMJ 334: 1253-1253 [Full Text]  
• Cole, B. F., Baron, J. A., Sandler, R. S., Haile, R. W., Ahnen, D. J., Bresalier, R. S., McKeown-Eyssen, G., Summers, R. W., Rothstein, R. I., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Robertson, D. J., Beck, G. J., Bond, J. H., Byers, T., Mandel, J. S., Mott, L. A., Pearson, L. H., Barry, E. L., Rees, J. R., Marcon, N., Saibil, F., Ueland, P. M., Greenberg, E. R., for the Polyp Prevention Study Group, (2007). Folic Acid for the Prevention of Colorectal Adenomas: A Randomized Clinical Trial. JAMA 297: 2351-2359 [Abstract] [Full Text]  
• Hubner, R. A., Lubbe, S., Chandler, I., Houlston, R. S. (2007). MTHFR C677T has differential influence on risk of MSI and MSS colorectal cancer. Hum Mol Genet 16: 1072-1077 [Abstract] [Full Text]  
• Wang, L., Ke, Q., Chen, W., Wang, J., Tan, Y., Zhou, Y., Hua, Z., Ding, W., Niu, J., Shen, J., Zhang, Z., Wang, X., Xu, Y., Shen, H. (2007). Polymorphisms of MTHFD, Plasma Homocysteine Levels, and Risk of Gastric Cancer in a High-Risk Chinese Population. Clin. Cancer Res. 13: 2526-2532 [Abstract] [Full Text]  
• (2007). Abstracts. Gut 56: a1-a145 [Full Text]  
• (2007). Poster Abstracts. J. Nutr. 137: 278S-295S [Full Text]  
• Kim, Y-I (2006). Folate: a magic bullet or a double edged sword for colorectal cancer prevention?. Gut 55: 1387-1389 [Full Text]