Circulating folate levels and colorectal adenoma: a case-control study and a meta-analysis

  • Park, Yeong Mi (Department of Food and Nutrition, Sookmyung Women's University) ;
  • Youn, Jiyoung (Department of Food and Nutrition, Seoul National University) ;
  • Cho, Chang Ho (Department of Pathology, Daegu Catholic University Medical Center) ;
  • Kim, Sung Hi (Department of Family Medicine, Daegu Catholic University Medical Center) ;
  • Lee, Jung Eun (Department of Food and Nutrition, Seoul National University)
  • Received : 2017.03.27
  • Accepted : 2017.06.15
  • Published : 2017.10.02


BACKGROUND/OBJECTIVES: The relationship between folate and colorectal neoplasia remains controversial. We examined the association between serum folate concentrations and colorectal adenomas in a case-control study of Korean adults and conducted a meta-analysis. SUBJECTS/METHODS: Our case-control study included 113 pairs of case and control who underwent colonoscopy and provided blood samples. We used multivariable conditional logistic regression models to obtain the odds ratios and 95% confidence interval (CIs). For meta-analysis, we identified the relevant studies by searching the PubMed database up to February 2017, included our case-control study and combined the study-specific relative risks (RRs) using a random-effects model. RESULTS: In this case-control study, we included 58 men and 55 women with colorectal adenomas and sex and fasting status matched the controls. We did not find any significant association between the serum folate levels and colorectal adenomas in either men or women. For meta-analysis, a total of eleven studies were included in our analysis and classified into two groups; polyp clearance group (PC) for the studies that included participants who underwent endoscopies and had their polyps removed at baseline; and no polyp clearance group (NPC) for the studies that included participants whose histories of endoscopies were unknown or who underwent their first endoscopies. Four PC (1,311 cases and 1,672 non-cases) and eight NPC studies (3,501 cases and 11,347 non-cases) were included. The combined RRs (95% CIs) comparing the bottom with the top categories of circulating folate levels were 1.07 (0.97-1.18) for the NPC group but 1.45 (1.16-1.74) for the PC group. CONCLUSIONS: Low circulating folate levels were associated with new adenoma formation.


Folate;colorectal adenoma;meta-analysis


Supported by : National Research Foundation of Korea


  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.
  2. Oh C-M, Won Y-J, Jung K-W, Kong H-J, Cho H, Lee J-K, Lee DH, Lee KH. Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2013. Cancer Res Treat 2016;48:436-50.
  3. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 2003;3:601-14.
  4. Park LK, Friso S, Choi SW. Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 2012;71:75-83.
  5. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525-32.
  6. Boyapati SM, Bostick RM, McGlynn KA, Fina MF, Roufail WM, Geisinger KR, Hebert JR, Coker A, Wargovich M. Folate intake, MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colorectal adenoma (United States). Cancer Causes Control 2004;15:493-501.
  7. Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ, Logan RF, Baron JA. Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials. Int J Cancer 2011;129:192-203.
  8. Lee JE, Willett WC, Fuchs CS, Smith-Warner SA, Wu K, Ma J, Giovannucci E. Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr 2011;93:817-25.
  9. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005;113:825-8.
  10. Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Harnack L, Jacobs EJ, Leitzmann M, Mannisto S, Miller AB, Potter JD, Rohan TE, Schatzkin A, Speizer FE, Stevens VL, Stolzenberg-Solomon R, Terry P, Toniolo P, Weijenberg MP, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control 2010;21:1919-30.
  11. Chuang SC, Rota M, Gunter MJ, Zeleniuch-Jacquotte A, Eussen SJ, Vollset SE, Ueland PM, Norat T, Ziegler RG, Vineis P. Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model. Am J Epidemiol 2013;178:1028-37.
  12. Martinez ME, Giovannucci E, Jiang R, Henning SM, Jacobs ET, Thompson P, Smith-Warner SA, Alberts DS. Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 2006;119:1440-6.
  13. Ibrahim EM, Zekri JM. Folic acid supplementation for the prevention of recurrence of colorectal adenomas: metaanalysis of interventional trials. Med Oncol 2010;27:915-8.
  14. Ulrich CM, Potter JD. Folate and cancer--timing is everything. JAMA 2007;297:2408-9.
  15. Peipins LA, Sandler RS. Epidemiology of colorectal adenomas. Epidemiol Rev 1994;16:273-97.
  16. Neugut AI, Jacobson JS, De Vivo I. Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 1993;2:159-76.
  17. Ahn Y, Kwon E, Shim JE, Park MK, Joo Y, Kimm K, Park C, Kim DH. Validation and reproducibility of food frequency questionnaire for Korean genome epidemiologic study. Eur J Clin Nutr 2007;61:1435-41.
  18. Figueiredo JC, Levine AJ, Grau MV, Barry EL, Ueland PM, Ahnen DJ, Byers T, Bresalier RS, Summers RW, Bond J, McKeown-Eyssen GE, Sandler RS, Haile RW, Baron JA. Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels. Cancer Epidemiol Biomarkers Prev 2008;17:2625-31.
  19. Song Y, Manson JE, Lee IM, Cook NR, Paul L, Selhub J, Giovannucci E, Zhang SM. Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma. J Natl Cancer Inst 2012;104:1562-75.
  20. Wu K, Platz EA, Willett WC, Fuchs CS, Selhub J, Rosner BA, Hunter DJ, Giovannucci E. A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. Am J Clin Nutr 2009;90:1623-31.
  21. Gao QY, Chen HM, Chen YX, Wang YC, Wang ZH, Tang JT, Ge ZZ, Chen XY, Sheng JQ, Fang DC, Yu CG, Zheng P, Fang JY. Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial. Cancer Prev Res 2013;6:744-52.
  22. Bird CL, Swendseid ME, Witte JS, Shikany JM, Hunt IF, Frankl HD, Lee ER, Longnecker MP, Haile RW. Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 1995;4:709-14.
  23. Levine AJ, Siegmund KD, Ervin CM, Diep A, Lee ER, Frankl HD, Haile RW. The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2000;9:657-63.
  24. Martinez ME, Henning SM, Alberts DS. Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence. Am J Clin Nutr 2004;79:691-7.
  25. Marugame T, Tsuji E, Kiyohara C, Eguchi H, Oda T, Shinchi K, Kono S. Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas. Int J Epidemiol 2003;32:64-6.
  26. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-12.
  27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
  28. Higgins J, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539-58.
  29. Orsini N, Bellocco R, Greenland S. Generalized least squares for trend estimation of summarized dose-response data. Stata J 2006;6:40.
  30. Grizzle JE, Starmer CF, Koch GG. Analysis of categorical data by linear models. Biometrics 1969;25:489-504.
  31. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
  32. de Vogel S, Schneede J, Ueland PM, Vollset SE, Meyer K, Fredriksen A, Midttun O, Bjorge T, Kampman E, Bretthauer M, Hoff G. Biomarkers related to one-carbon metabolism as potential risk factors for distal colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2011;20:1726-35.
  33. Fujimori S, Gudis K, Takahashi Y, Kotoyori M, Tatsuguchi A, Ohaki Y, Sakamoto C. Determination of the minimal essential serum folate concentration for reduced risk of colorectal adenoma. Clin Nutr 2011;30:653-8.
  34. Ding H, Gao QY, Chen HM, Fang JY. People with low serum folate levels have higher risk of colorectal adenoma/advanced colorectal adenoma occurrence and recurrence in China. J Int Med Res 2016;44:767-78.
  35. 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.
  36. Kim J, Cho YA, Kim DH, Lee BH, Hwang DY, Jeong J, Lee HJ, Matsuo K, Tajima K, Ahn YO. Dietary intake of folate and alcohol, MTHFR C677T polymorphism, and colorectal cancer risk in Korea. Am J Clin Nutr 2012;95:405-12.
  37. Park JY, Vollset SE, Melse-Boonstra A, Chajes V, Ueland PM, Slimani N. Dietary intake and biological measurement of folate: a qualitative review of validation studies. Mol Nutr Food Res 2013;57:562-81.
  38. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:3290-5.
  39. Duthie SJ, Narayanan S, Blum S, Pirie L, Brand GM. Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells. Nutr Cancer 2000;37:245-51.
  40. Choi SW, Kim YI, Weitzel JN, Mason JB. Folate depletion impairs DNA excision repair in the colon of the rat. Gut 1998;43:93-9.
  41. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER, Polyp Prevention Study G. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351-9.
  42. Eussen SJ, Vollset SE, Igland J, Meyer K, Fredriksen A, Ueland PM, Jenab M, Slimani N, Boffetta P, Overvad K, Tjonneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Weikert C, Pischon T, Linseisen J, Kaaks R, Trichopoulou A, Zilis D, Katsoulis M, Palli D, Berrino F, Vineis P, Tumino R, Panico S, Peeters PH, Bueno-de-Mesquita HB, van Duijnhoven FJ, Gram IT, Skeie G, Lund E, Gonzalez CA, Martinez C, Dorronsoro M, Ardanaz E, Navarro C, Rodriguez L, Van Guelpen B, Palmqvist R, Manjer J, Ericson U, Bingham S, Khaw KT, Norat T, Riboli E. Plasma folate, related genetic variants, and colorectal cancer risk in EPIC. Cancer Epidemiol Biomarkers Prev 2010;19:1328-40.
  43. Le Marchand L, White KK, Nomura AM, Wilkens LR, Selhub JS, Tiirikainen M, Goodman MT, Murphy SP, Henderson BE, Kolonel LN. Plasma levels of B vitamins and colorectal cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 2009;18:2195-201.
  44. Lee JE, Wei EK, Fuchs CS, Hunter DJ, Lee IM, Selhub J, Stampfer MJ, Willett WC, Ma J, Giovannucci E. Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies. Cancer Causes Control 2012;23:537-45.
  45. Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S, Japan Public Health Center-based Prospective Study G. Plasma folate and risk of colorectal cancer in a nested case-control study: the Japan Public Health Center-based prospective study. Cancer Causes Control 2008;19:67-74.
  46. Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A, Palmqvist R. Low folate levels may protect against colorectal cancer. Gut 2006;55:1461-6.
  47. Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE, Akhmedkhanov A, Zeleniuch-Jacquotte A, Riboli E. Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer 1999;79:1917-22.
  48. Weinstein SJ, Albanes D, Selhub J, Graubard B, Lim U, Taylor PR, Virtamo J, Stolzenberg-Solomon R. One-carbon metabolism biomarkers and risk of colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 2008;17:3233-40.
  49. Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008;134:29-38.