Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study

Ting Yuan David Cheng, Karen W. Makar, Marian L. Neuhouser, Joshua W. Miller, Xiaoling Song, Elissa C. Brown, Shirley A A Beresford, Yingye Zheng, Elizabeth M. Poole, Rachel L. Galbraith, David J. Duggan, Nina Habermann, Lynn B. Bailey, David R. Maneval, Marie A. Caudill, Adetunji T. Toriola, Ralph Green, Cornelia M. Ulrich

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Abstract

BACKGROUND Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. METHODS Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5′-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. RESULTS Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P <.05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P <.05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). CONCLUSIONS Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Original languageEnglish (US)
Pages (from-to)3684-3691
Number of pages8
JournalCancer
Volume121
Issue number20
DOIs
StatePublished - Oct 1 2015

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Keywords

  • biomarker
  • colorectal cancer
  • gene-nutrient interaction
  • one-carbon metabolism
  • postmenopausal women

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cheng, T. Y. D., Makar, K. W., Neuhouser, M. L., Miller, J. W., Song, X., Brown, E. C., Beresford, S. A. A., Zheng, Y., Poole, E. M., Galbraith, R. L., Duggan, D. J., Habermann, N., Bailey, L. B., Maneval, D. R., Caudill, M. A., Toriola, A. T., Green, R., & Ulrich, C. M. (2015). Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study. Cancer, 121(20), 3684-3691. https://doi.org/10.1002/cncr.29465