Dataset Information

Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore.

ABSTRACT: 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.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.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.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.

SUBMITTER: Inoue-Choi M

PROVIDER: S-EPMC3765398 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore.

Inoue-Choi Maki M Nelson Heather H HH Robien Kim K Arning Erland E Bottiglieri Teodoro T Koh Woon-Puay WP Yuan Jian-Min JM

BMC cancer 20130817

<h4>Background</h4>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 ...[more]

PMID: 23957506

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Project description:BackgroundThe aim of the study was to examine the relations of individual lifestyle factors and its composite score with healthy ageing among Chinese adults.MethodWe included 14 159 participants aged 45-74 years at baseline from the Singapore Chinese Health Study, a population-based prospective cohort. A protective lifestyle score (0-5 scale) was calculated at baseline (1993-1998) and updated at the second follow-up visit (2006-2010) on the basis of optimal body mass index (18.5-22.9 kg/m2), healthy diet (upper 40% of the Alternative Healthy Eating Index score), being physically active (≥2 h/wk of moderate activity or ≥0.5 h/wk of strenuous activity), nonsmoking (never smoking), and low-to-moderate alcohol drinking (>0 to ≤14 drinks/wk for men and >0 to ≤7 drinks/wk for women). Healthy ageing was assessed at the third follow-up visit (2014-2016) and was defined as absence of specific chronic diseases, absence of cognitive impairment and limitations in instrumental activities of daily living, good mental and overall self-perceived health, good physical functioning, and no function-limiting pain.ResultsAbout 20.0% (2834) of the participants met the criteria of healthy ageing after a median follow-up of 20 years. Each 1-point increase in the protective lifestyle score computed at baseline and second follow-up visits was associated with higher likelihood of healthy ageing by 25% (95% CI: 20%-30%) and 24% (18%-29%), respectively. The population-attributable risk percent of adherence to 4-5 protective lifestyle factors was 34.3% (95% CI: 25.3%-42.3%) at baseline and 31.3% (23.0%-38.7%) at second follow-up visits for healthy ageing. In addition, positive increase in lifestyle scores from baseline to second follow-up visits was also significantly associated with a higher likelihood of healthy ageing with an odds ratio of 1.18 (95% CI: 1.12%-1.24%) for each increment in protective lifestyle score.ConclusionsOur findings confirmed that adopting healthy lifestyle factors, even after midlife, was associated with healthy ageing at old age.

Project description:DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (|r|≥ 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.

Dataset Information

Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore.

Publications

Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore.

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