|Lee, Jung Eun -|
|Wei, Esther -|
|Fuchs, Charles -|
|Hunter, David -|
|Lee, I-Min -|
|Selhub, Jacob -|
|Stampfer, Meir -|
|Willett, Walter -|
|Ma, Jing -|
|Giovannucci, Edward -|
Submitted to: Cancer Causes and Control
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 30, 2012
Publication Date: April 23, 2012
Citation: Lee, J., Wei, E.K., Fuchs, C.S., Hunter, D.J., Lee, I., Selhub, J., Stampfer, M.J., Willett, W.C., Ma, J., Giovannucci, E. 2012. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies. Cancer Causes and Control. 23(4):537-545. Interpretive Summary: Folate is a key B vitamin that is critical for synthesis and repair of DNA and modifications to DNA by adding a chemical group (methylation). Deficiency of folate has been suggested to increase the risk of colorectal cancer through aberrations in DNA methylation and imbalance of DNA precursors. Although a diet low in folate has been associated with increased risk of colorectal cancer, the results from studies that examined the associations between folate concentration in blood and colorectal cancer were not consistent. The objective of this study was to determine if the concentration of folate in blood samples collected years before the individuals developed cancer was associated with the risk of developing colorectal cancer later. Two genetic variations in the gene for a folate metabolizing enzyme methylene tetrahydrofolate reductase (MTHFR) were also evaluated for their association with the risk of colorectal cancer. The results of this study show that higher concentration of folate in plasma is associated with increased risk for colorectal cancer. The genetic variations in MTHFR that are often associated with low concentration of folate in plasma were associated with reduced risk for colorectal cancer. Further studies are required to clarify how low plasma folate concentration can reduce cancer risk.
Technical 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.