Genome-wide DNA hypomethylation is believed to be one of the early molecular abnormalities in carcinogenesis and there is great interest in identifying traits and exposures that contribute to genomic DNA hypomethylation. One-carbon metabolism has been extensively studied in relation to cancer because its key metabolite, S-adenosylmethionine (SAM), is a methyl donor for DNA methylation reactions which are catalyzed by DNA methyltransferases (DNMTs). Here we have tested the hypothesis that plasma SAM levels alone or in combination with DNMT1 and DNMT3A genetic variation are associated with DNA methylation levels at long interspersed nucleotide element-1 (LINE-1), a surrogate marker for genome-wide DNA methylation. A total of 440 healthy Singapore Chinese adults (192 men and 248 women, 46-77 y) were selected from participants of the Singapore Chinese Health Study, who donated biospecimens during 1994-1998. Plasma SAM levels and LINE-1 DNA methylation were measured using stored blood samples. We chose tagging SNPs of the DNMT1 and DNMT3A genes for the Han Chinese population based on the HapMap database and literature search. LINE-1 methylation was compared among quartiles of plasma SAM levels and DNMT genotypes using multivariate linear regression methods in men and women separately. We also evaluated the effect modification of DNMT genotypes on the association between plasma SAM levels and LINE-1 methylation. Age-adjusted LINE-1 methylation was significantly higher in men (mean=78.1%, 95%CI=77.7-78.4%) than in women (mean=77.4%, 95%CI=77.1-77.7%, p=0.002). Higher LINE-1 methylation was associated with older age in men (ptrend=0.004) but not in women. LINE-1 methylation was significantly lower among those with the lowest quartile of plasma SAM compared with those with higher plasma SAM in both men and women. LINE-1 methylation increased with increasing plasma SAM levels, with a plateau at 55 nmol/L SAM in men and 50 nmol/L in women. Compared with men carrying wildtype genotype, men carrying at least one copy of the variant DNMT1 rs2114724 allele had higher LINE-1 methylation (ptrend=0.007), while men carrying at least one copy of the variant DNMT3A rs7581217 allele had lower LINE-1 methylation (ptrend=0.004). No similar associations were observed in women. When stratified by DNMT1 rs2114724 genotype, a positive association between plasma SAM levels and LINE-1 methylation was present among men with low LINE1 methylation and wildtype genotype, but not with variant genotypes of DNMT1. DNMT1 and DNMT3A haplotypes were not associated with LINE-1 methylation in either men or women. Our findings support a role of SAM on genome-wide DNA methylation. Further, DNMT1 genetic polymorphisms may exert modifying effect on the SAM-DNA methylation association. The study was supported by grant R01 CA144034.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1038. doi:1538-7445.AM2012-1038