Journal Article

Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review

Linda Sharp and Julian Little

in American Journal of Epidemiology

Published on behalf of Johns Hopkins Bloomberg School of Public Health

Volume 159, issue 5, pages 423-443
Published in print March 2004 | ISSN: 0002-9262
Published online March 2004 | e-ISSN: 1476-6256 | DOI:
Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia:  A HuGE Review

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Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism—methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine β-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3′ untranslated region)—have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a “high-methyl diet”) had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested.

Keywords: CBS; colorectal neoplasms; epidemiology; folic acid; MTHFR; MTR; MTRR; TS; Abbreviations: CBS, cystathionine β-synthase; CI, confidence interval; MSI, microsatellite instability; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MTRR, methionine synthase reductase; OR, odds ratio; rpt, repeat; TS, thymidylate synthase.

Journal Article.  14284 words.  Illustrated.

Subjects: Public Health and Epidemiology

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