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Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case–control studies

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Abstract

Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three large prospective studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Physicians’ Health Study. A total of 602 incident cases were identified and individually matched to controls who provided blood specimens. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI) and then pooled the estimates using a random effects model. We found a lower risk of colorectal cancer among participants with low plasma folate levels: compared with the lowest quartile, RRs (95% CIs) for each successively higher quartile of plasma folate levels were 1.55 (1.14–2.11), 1.37 (1.00–1.88), and 1.47 (1.07–2.01; P for trend = 0.10). For the MTHFR polymorphisms, RRs (95% CIs) were 0.62 (0.44–0.90) for 677TT versus CC/CT and 0.68 (0.31–1.51) for 1298CC versus AC/AA, and these lower-risk genotypes were associated with lower circulating plasma folate levels. When we partitioned the variation in plasma folate levels, variation due to folate intake was not positively associated with colorectal cancer risk. We found that low plasma folate levels were associated with lower risk of colorectal cancer. The reasons underlying a lower risk of colorectal cancer with low plasma folate levels require elucidation because plasma folate levels can reflect dietary intake, genetic influences, and other factors.

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Acknowledgments

Our study is supported by National Cancer Institute CA87969, CA55075, CA42182, CA34944, CA40360, and CA97193, National Heart, Lung, and Blood Institute HL26490 and HL34595, and Prevent Cancer Foundation. The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

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Authors and Affiliations

  1. Department of Food and Nutrition, Sookmyung Women’s University, Seoul, Korea

    Jung Eun Lee

  2. California Pacific Medical Center Research Institute, San Francisco, CA, USA

    Esther K. Wei

  3. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA

    Esther K. Wei, Charles S. Fuchs, David J. Hunter, Meir J. Stampfer, Walter C. Willett, Jing Ma & Edward Giovannucci

  4. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    I-Min Lee

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Charles S. Fuchs

  6. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    David J. Hunter, I-Min Lee, Meir J. Stampfer, Walter C. Willett & Edward Giovannucci

  7. Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

    Jacob Selhub

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  1. Jung Eun Lee
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  2. Esther K. Wei
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  3. Charles S. Fuchs
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  10. Edward Giovannucci
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Correspondence to Edward Giovannucci.

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Jung Eun Lee and Esther K. Wei share the first authorship.

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Lee, J.E., Wei, E.K., Fuchs, C.S. et al. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case–control studies. Cancer Causes Control 23, 537–545 (2012). https://doi.org/10.1007/s10552-012-9911-3

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  • DOI: https://doi.org/10.1007/s10552-012-9911-3

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