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Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas.

Abstract

An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status.

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  • Authors+Show Affiliations

    ,

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston Massachusetts 02115, USA. edward.giovannucci@channing.harvard.edu

    , , , , , ,

    Source

    MeSH

    Adenoma
    Adult
    Aged
    Alcohol Dehydrogenase
    Alcohol Drinking
    Case-Control Studies
    Colorectal Neoplasms
    Diet
    Female
    Folic Acid Deficiency
    Genotype
    Humans
    Male
    Methylenetetrahydrofolate Reductase (NADPH2)
    Middle Aged
    Odds Ratio
    Polymorphism, Genetic
    Risk Factors

    Pub Type(s)

    Journal Article
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    14578131

    Citation

    Giovannucci, Edward, et al. "Methylenetetrahydrofolate Reductase, Alcohol Dehydrogenase, Diet, and Risk of Colorectal Adenomas." Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, vol. 12, no. 10, 2003, pp. 970-9.
    Giovannucci E, Chen J, Smith-Warner SA, et al. Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev. 2003;12(10):970-9.
    Giovannucci, E., Chen, J., Smith-Warner, S. A., Rimm, E. B., Fuchs, C. S., Palomeque, C., ... Hunter, D. J. (2003). Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored By the American Society of Preventive Oncology, 12(10), pp. 970-9.
    Giovannucci E, et al. Methylenetetrahydrofolate Reductase, Alcohol Dehydrogenase, Diet, and Risk of Colorectal Adenomas. Cancer Epidemiol Biomarkers Prev. 2003;12(10):970-9. PubMed PMID: 14578131.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. AU - Giovannucci,Edward, AU - Chen,Jia, AU - Smith-Warner,Stephanie A, AU - Rimm,Eric B, AU - Fuchs,Charles S, AU - Palomeque,Caroline, AU - Willett,Walter C, AU - Hunter,David J, PY - 2003/10/28/pubmed PY - 2004/3/23/medline PY - 2003/10/28/entrez SP - 970 EP - 9 JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology JO - Cancer Epidemiol. Biomarkers Prev. VL - 12 IS - 10 N2 - An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status. SN - 1055-9965 UR - https://www.unboundmedicine.com/medline/citation/14578131/Methylenetetrahydrofolate_reductase_alcohol_dehydrogenase_diet_and_risk_of_colorectal_adenomas_ L2 - http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=14578131 DB - PRIME DP - Unbound Medicine ER -