Abstract
Background: Global 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.Methods: Plasma 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.Results: LINE-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.Conclusions: Circulating 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.
| Original language | English (US) |
|---|---|
| Article number | 389 |
| Journal | BMC Cancer |
| Volume | 13 |
| DOIs | |
| State | Published - Aug 17 2013 |
Bibliographical note
Funding Information:We thank Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study, Kazuko Arakawa and Renwei Wang for the development and maintenance of the cohort study database, and Kenneth Beckman and Dinesha Walek at the University of Minnesota BMGC for performing DNA extraction and genotyping. Finally, we acknowledge the founding, long-standing Principal Investigator of the Singapore Chinese Health Study – Mimi C. Yu. This study was funded by the National Institutes of Health (grant numbers R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA144034), the University of Minnesota, Division of Epidemiology and Community Health, J. B. Hawley Student Research Awards, and the University of Minnesota Graduate School Doctoral Dissertation Fellowship.
