5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites.

We evaluated polymorphisms in methylenetetrahydrofolate reductase (MTHFR), folate intake and alcohol consumption in relation to risk of colon cancer in a population-based case-control study in North Carolina. The study included 555 cases (244 African Americans and 311 whites) and 875 controls (331 African Americans and 544 whites). Total folate intake of <400 versus > or =400 microg/day showed a weak positive association with colon cancer among both African Americans [adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.0-2.0] and whites (OR = 1.6, 95% CI = 1.2-2.2). No association was observed with use of alcohol. Compared with wild-type genotypes, there was no association between the low activity MTHFR codon 677 TT genotype and colon cancer, but the low activity codon 1298 CC genotype was inversely associated with colon cancer in whites (OR = 0.5, 95% CI = 0.3-0.9). Unlike previous studies, we did not observe a strong protective effect of the codon 677 TT low-activity genotype when folate intake was high. Instead, we observed an increased risk of colon cancer when folate intake was low for participants with wild- type genotypes. Adjusted ORs for the combined effects of codon 677 CC and codon 1298 AA genotypes and folate intake <400 microg/day were 1.9 (95% CI = 1.1-3.4) in African Americans and 2.5 (95% CI = 1.2-5.2) in whites. Our results suggest that variation at MTHFR codon 1298 (within the COOH-terminal region) may be more important for colon cancer than variation at codon 677 (NH(2)-terminal region), and in populations where folate intake is low, wild-type MTHFR activity may increase risk for colon cancer.

[1]  D. Hunter,et al.  Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. , 2002, Pharmacogenetics.

[2]  Y. Ikeda,et al.  The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. , 2002, American journal of human genetics.

[3]  D. Midthune,et al.  Comparative validation of the Block, Willett, and National Cancer Institute food frequency questionnaires : the Eating at America's Table Study. , 2001, American journal of epidemiology.

[4]  R. Houlston,et al.  Polymorphisms and colorectal tumor risk. , 2001, Gastroenterology.

[5]  R. Sinha,et al.  Blood determinations of S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine: correlations with diet. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[6]  J. Mason,et al.  Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[7]  C. Ervin,et al.  The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[8]  S. Blum,et al.  Folate Deficiency In Vitro Induces Uracil Misincorporation and DNA Hypomethylation and Inhibits DNA Excision Repair in Immortalized Normal Human Colon Epithelial Cells , 2000, Nutrition and cancer.

[9]  J. Mason,et al.  Effects of dietary folate on DNA strand breaks within mutation-prone exons of the p53 gene in rat colon. , 2000, Gastroenterology.

[10]  Quanhe Yang,et al.  5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. , 2000, American journal of epidemiology.

[11]  A. Ziegler,et al.  Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD). , 1999, American journal of medical genetics.

[12]  P. Sham,et al.  Model-Free Analysis and Permutation Tests for Allelic Associations , 1999, Human Heredity.

[13]  D. B. Wilson,et al.  Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. , 1999, The American journal of clinical nutrition.

[14]  C. Ulrich,et al.  Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction? , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[15]  M. Leppert,et al.  Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[16]  P. Hartge.  Raising response rates: getting to yes. , 1999, Epidemiology.

[17]  B. Giusti,et al.  Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10-methylenetetrahydrofolate reductase. , 1998, American journal of human genetics.

[18]  F. Costa,et al.  Prevalence of the mutation C677 --> T in the methylene tetrahydrofolate reductase gene among distinct ethnic groups in Brazil. , 1998, American journal of medical genetics.

[19]  R. Rozen,et al.  A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. , 1998, Molecular genetics and metabolism.

[20]  J. Mason,et al.  Folate depletion impairs DNA excision repair in the colon of the rat , 1998, Gut.

[21]  R. Millikan,et al.  Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[22]  F. Gabreëls,et al.  A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? , 1998, American journal of human genetics.

[23]  W. Willett,et al.  Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. , 1997, Cancer research.

[24]  E. Rimm,et al.  A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. , 1996, Cancer research.

[25]  D. Pearl,et al.  The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans. , 1996, Thrombosis research.

[26]  C. L. Bird,et al.  Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. , 1995, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[27]  B. Ames,et al.  2 DNA damage in folate deficiency , 1995 .

[28]  E. Rimm,et al.  Alcohol, low-methionine--low-folate diets, and risk of colon cancer in men. , 1995, Journal of the National Cancer Institute.

[29]  B. Henderson,et al.  Alcohol and tobacco use: risk factors for colorectal adenoma and carcinoma? , 1995, Journal of the National Cancer Institute.

[30]  Jurg Ott,et al.  Handbook of Human Genetic Linkage , 1994 .

[31]  E. Rimm,et al.  Folate, methionine, and alcohol intake and risk of colorectal adenoma. , 1993, Journal of the National Cancer Institute.

[32]  C R Weinberg,et al.  Randomized recruitment in case-control studies. , 1991, American journal of epidemiology.

[33]  O. Skraastad.  [Dietary factors and risk of colon cancer]. , 1990, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[34]  G Block,et al.  Validation of a retrospective questionnaire assessing diet 10-15 years ago. , 1989, American journal of epidemiology.

[35]  G Block,et al.  Evaluation of two food frequency methods of measuring dietary calcium intake. , 1987, American journal of epidemiology.

[36]  G Block,et al.  A data-based approach to diet questionnaire design and testing. , 1986, American journal of epidemiology.

[37]  L. Cavalli-Sforza,et al.  The genetics of human populations. , 1972, Scientific American.

[38]  W. Willett,et al.  Diet and cancer: one view at the start of the millennium. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[39]  J. Mason,et al.  Folate and carcinogenesis: an integrated scheme. , 2000, The Journal of nutrition.

[40]  S. Duthie,et al.  Folic acid deficiency and cancer: mechanisms of DNA instability. , 1999, British medical bulletin.

[41]  J. Mok,et al.  The 677C > T mutation in 5,10-methylenetetrahydrofolate reductase and colorectal cancer risk. , 1999, Genetic testing.

[42]  N. Wenger,et al.  Relation of three genetic traits to venous thrombosis in an African-American population. , 1998, American journal of epidemiology.

[43]  M. Zago,et al.  Analysis of the 677 C→T Mutation of the Methylenetetrahydrofolate Reductase Gene in Different Ethnic Groups , 1998, Thrombosis and Haemostasis.

[44]  R. Stevenson,et al.  Differences in methylenetetrahydrofolate reductase genotype frequencies, between Whites and Blacks. , 1997, American journal of human genetics.

[45]  A. Motulsky.  Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. , 1996, American journal of human genetics.

[46]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.

[47]  B. Ames,et al.  DNA damage in folate deficiency. , 1995, Bailliere's clinical haematology.

[48]  R R Watson,et al.  Alcohol and cancer. , 1994, Alcohol and alcoholism (Oxford, Oxfordshire). Supplement.

[49]  J. Potter,et al.  Colon cancer: a review of the epidemiology. , 1993, Epidemiologic reviews.

[50]  G. Block.  Dietary guidelines and the results of food consumption surveys. , 1991, The American journal of clinical nutrition.

[51]  S. Baylin,et al.  Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression. , 1991, Cancer cells.

[52]  M. Singer,et al.  Nutritional Epidemiology , 2020, Definitions.

[53]  N. Breslow,et al.  The analysis of case-control studies , 1980 .

[54]  G. Dahlberg,et al.  Genetics of human populations. , 1948, Advances in genetics.