Folate, polymorphisms in folate-metabolising genes, and colorectal adenomas: results from a population-based case-only study


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Linda Sharp1, Julian Little2, Amanda Cardy3, Anne-Elie Carsin1, Susan Duthie4, Anne Molloy5, Nadine Holloway3, Ashley Mowat6, Bob Steele7, Roland Wolf8, John Wilson9, Neva Haites3

1National Cancer Registry, Cork, Ireland, 2University of Ottawa, Ottawa, Canada, 3University of Aberdeen, Aberdeen, UK, 4Rowett Research Institute, Aberdeen, UK, 5Trinity College, Dublin, Ireland, 6Aberdeen Royal Infirmary NHS Trust, Aberdeen, UK, 7Tayside University Hospitals, Dundee, UK, 8University of Dundee, Dundee, UK, 9Victoria Hospital, Kirkcaldy, UK

Abstract

Background

Folate is key in one-carbon metabolism, disruption of which interferes with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires optimal activity of multiple enzymes. Most colorectal cancers arise from adenomas. Although folate appears related to colorectal cancer risk, its role in adenomas is uncertain. We investigated interactions between folate and polymorphisms in folate-metabolising genes, in relation to adenoma risk.

Method

A case-only study was nested within the Scottish colorectal screening programme. Subjects with histologically confirmed adenoma(s) completed a food frequency questionnaire (for folate, vitamin B6, vitamin B12, riboflavin, protein and alcohol intakes) and provided blood samples. These were analysed for plasma folate, homocysteine, vitamin B12, and red cell folate and polymorphisms in MTHFR (C677T, A1298C), MTR (A2756G), MTRR (A66G), CBS (68bp insertion) and TS (28bp tandem repeat). Adjusted case-only odds ratios (ORca) for departure from multiplicative effects were calculated by logistic regression.

Results

468 subjects participated (response rate=68%). Plasma and red cell folate - but not dietary folate - interacted significantly with MTHFR C677T (p<0.01). MTHFR A1298C did not interact with blood or dietary folate, but did interact with dietary riboflavin (ORca=1.50, 95% CI 1.00-2.26). MTRR interacted with vitamin B12 intake (ORca=1.55, 95% CI 0.99-2.42). There were interactions between CBS and MTHFR C677T (ORca=0.63, 95% CI 0.39-1.01) and CBS and MTRR (ORca=0.57, 95% CI 0.34-0.97).

Conclusion

We observed several gene-environment and gene-gene interactions, but these were not entirely consistent with colorectal cancer findings. This is further evidence to suggest the role of folate in colorectal neoplasia is complex.

Background

Folate is key in one-carbon metabolism, disruption of which interferes with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires optimal activity of multiple enzymes. Most colorectal cancers arise from adenomas. Although folate appears related to colorectal cancer risk, its role in adenomas is uncertain. We investigated interactions between folate and polymorphisms in folate-metabolising genes, in relation to adenoma risk.

Method

A case-only study was nested within the Scottish colorectal screening programme. Subjects with histologically confirmed adenoma(s) completed a food frequency questionnaire (for folate, vitamin B6, vitamin B12, riboflavin, protein and alcohol intakes) and provided blood samples. These were analysed for plasma folate, homocysteine, vitamin B12, and red cell folate and polymorphisms in MTHFR (C677T, A1298C), MTR (A2756G), MTRR (A66G), CBS (68bp insertion) and TS (28bp tandem repeat). Adjusted case-only odds ratios (ORca) for departure from multiplicative effects were calculated by logistic regression.

Results

468 subjects participated (response rate=68%). Plasma and red cell folate - but not dietary folate - interacted significantly with MTHFR C677T (p<0.01). MTHFR A1298C did not interact with blood or dietary folate, but did interact with dietary riboflavin (ORca=1.50, 95% CI 1.00-2.26). MTRR interacted with vitamin B12 intake (ORca=1.55, 95% CI 0.99-2.42). There were interactions between CBS and MTHFR C677T (ORca=0.63, 95% CI 0.39-1.01) and CBS and MTRR (ORca=0.57, 95% CI 0.34-0.97).

Conclusion

We observed several gene-environment and gene-gene interactions, but these were not entirely consistent with colorectal cancer findings. This is further evidence to suggest the role of folate in colorectal neoplasia is complex.