Abstract
BackgroundGlobal hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis. There is a great interest in identifying factors that contribute to global DNA hypomethylation and associated cancer risk. We tested the hypothesis that plasma S-adenosylmethionine (SAM) level alone or in combination with genetic variation in DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) was associated with global DNA methylation extent at long interspersed nucleotide element-1 (LINE-1) sequences.MethodsPlasma SAM level and LINE-1 DNA methylation index were measured using stored blood samples collected from 440 healthy Singaporean Chinese adults during 1994-1999. Genetic polymorphisms of 13 loci in DNMT1, DNMT3A and DNMT3B were determined.ResultsLINE-1 methylation index was significantly higher in men than in women (p = 0.001). LINE-1 methylation index was positively associated with plasma SAM levels (p ≤ 0.01), with a plateau at approximately 78% of LINE-1 methylation index (55 nmol/L plasma SAM) in men and 77% methylation index (50 nmol/L plasma SAM) in women. In men only, the T allele of DNMT1 rs21124724 was associated with a statistically significantly higher LINE-1 methylation index (ptrend = 0.001). The DNMT1 rs2114724 genotype modified the association between plasma SAM and LINE-1 methylation index at low levels of plasma SAM in men.ConclusionsCirculating SAM level was associated with LINE-1 methylation status among healthy Chinese adults. The DNMT1 genetic polymorphism may exert a modifying effect on the association between SAM and LINE-1 methylation status in men, especially when plasma SAM level is low. Our findings support a link between plasma SAM and global DNA methylation status at LINE-1 sequences.
Highlights
Global hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis
Inter-individual variation in DNA methylation extent has been associated with increased risk for many chronic diseases including cancer [1,2,3,4]
One hypothesis is that an altered balance in onecarbon metabolism (OCM) metabolites results in an insufficient supply of methyl moieties for DNA methyltransferase (DNMT)-catalyzed reactions, resulting in global hypomethylation at DNA sequences [18,19]
Summary
Global hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis. Global DNA hypomethylation, the genome-wide loss of methylcytosine, has been observed in malignant and benign tumors and normal tissues surrounding tumors, indicating that global DNA hypomethylation may be one of the early molecular events in carcinogenesis [5,6,7]. One hypothesis is that an altered balance in OCM metabolites results in an insufficient supply of methyl moieties for DNMT-catalyzed reactions, resulting in global hypomethylation at DNA sequences [18,19]
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