title: Unmetabolized Folic Acid in Prediagnostic Plasma and the Risk of Colorectal Cancer.
abstract: Higher folate has been associated with a reduced colorectal cancer (CRC) risk, but excessive folate may promote tumor progression. The role of unmetabolized folic acid (UFA) from high folic acid consumption in carcinogenesis is largely unexplored. We evaluated prediagnostic plasma levels of UFA in relation to CRC risk in nested case-control studies (618 CRC case patients and 1207 matched control) with blood samples collected prior to folic acid fortification. UFA was detected in 21.4% of control UFA levels were not associated with CRC risk. Compared with undetectable levels, the multivariable relative risks (RRs) of CRC were 1.03 (95% confidence interval [CI] = 0.73 to 1.46) for less than 0.5 nmol/L and 1.12 (95% CI = 0.81 to 1.55) for 0.5 nmol/L or more (Ptrend = .32). A positive association between UFA levels and CRC risk was observed among men (RR = 1.57, 95% CI = 0.99 to 2.49 for ≥0.5 nmol/L vs undetectable, Pinteraction = .04), and a positive association was also observed among those with the methylene-tetrahydrofolate reductase (MTHFR) CT/TT genotype (RR = 2.20, 95% CI = 1.22 to 3.94 for ≥0.5 nmol/L vs undetectable, Pinteraction=0.02). In conclusion, prediagnostic plasma levels of UFA from the prefortification period were not associated with risk of CRC.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF). eunyoung_cho@brown.edu.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Cho
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Mary K
authors.initials: MK
authors.lastname: Townsend
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Ligi
authors.initials: L
authors.lastname: Paul
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Bernard
authors.initials: B
authors.lastname: Rosner
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Walter C
authors.initials: WC
authors.lastname: Willett
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (EC, XZ, MKT, BR, WCW, ELG); Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI (EC); Department of Epidemiology, Brown University School of Public Health, Providence, RI (EC); Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA (JS, LP); Department of Biostatistics (BR), Department of Nutrition (WCW, ELG), and Department of Epidemiology (WCW, ELG), Harvard TH Chan School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (CSF).
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D003596:Cytosine; D019587:Dietary Supplements / Q000009:adverse effects; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D005527:Food, Fortified / Q000009:adverse effects; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013941:Thymine
chemical_list: D003596:Cytosine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013941:Thymine