Associations between S-adenosylmethionine, S-adenosylhomocysteine, and colorectal adenoma risk are modified by sex.

Methionine metabolism is an important component of one-carbon metabolism. S-adenosylmethionine (SAM), the methyl donor for nearly all methylation reactions, is irreversibly converted to S-adenosylhomocysteine (SAH), an inhibitor of methyltransferases, some of which are key enzymes for methylation. Changes in DNA methylation are common in colorectal cancers. We evaluated plasma SAM and SAH with colorectal adenoma risk in a matched case-control study conducted among individuals undergoing routine colonoscopy. 216 cases were individually matched to polyp-free controls in a 1:1 ratio on age (± 5 years), sex, race (white/non-white), study site (academic medical center/VA hospital) and date of sample collection (± 60 days). Sex-specific quantiles were evaluated based on the control distribution due to vastly different metabolite levels by sex. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Among males, both higher SAM (OR = 0.38, 95% CI: 0.18-0.77, p for trend = 0.007) and higher SAH (OR = 0.45, 95% CI: 0.22-0.91, p for trend = 0.02) were associated with statistically significantly decreased risks of colorectal adenoma in comparison to lowest plasma SAM or SAH tertile. Conversely, among females, both higher SAM and higher SAH were associated with increased risk of colorectal adenoma, which was statistically significant for SAH (OR = 5.18, 95% CI: 1.09-24.62, p for trend = 0.04). The difference in these associations between men and women was statistically significant (p < 0.05). The ratio of SAM/SAH was not associated with colorectal adenoma risk among males or females. These findings suggest SAM and SAH may be involved in the development of colorectal adenoma and the association may be modified by sex.