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Molecular Diagnostics and Genetics |
1 Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, and
2 Centro de Nutrição e Metabolismo, Faculdade de Medicina da Universidade de Lisboa, 1649-039 Lisboa, Portugal.
3 Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.
4 Department of Paediatrics, University Medical Center St. Radboud, 6500 HB Nijmegen, The Netherlands.
aAddress correspondence to this author at: Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-039 Lisboa, Portugal. Fax 351-217946491; e-mail italmeida{at}ff.ul.pt.
Background: The pathogenic mechanism of homocysteine’s effect on cardiovascular risk is poorly understood. Recent studies show that DNA hypomethylation induced by increases in S-adenosylhomocysteine (AdoHcy), an intermediate of Hcy metabolism and a potent inhibitor of methyltransferases, may be involved in homocysteine-related pathology.
Methods: We measured fasting plasma total Hcy (tHcy), AdoHcy, and S-adenosylmethionine (AdoMet) and methylation in leukocytes in 17 patients with vascular disease and in 15 healthy, age- and sex-matched controls.
Results: Patient with vascular disease had significantly higher plasma tHcy and AdoHcy concentrations and significantly lower plasma AdoMet/AdoHcy ratios and genomic DNA methylation. AdoMet concentrations were not significantly different between the two groups. More than 50% of the patients fell into the highest quartiles of plasma tHcy, AdoHcy, and [3H]dCTP incorporation/µg of DNA (meaning the lowest quartile of DNA methylation status) and into the lowest quartile of the AdoMet/AdoHcy ratios of the control group. Plasma tHcy was significantly correlated with plasma AdoHcy and AdoMet/AdoHcy ratios (n = 32; P < 0.001). DNA methylation status was significantly correlated with plasma tHcy and AdoHcy (n = 32; P < 0.01) but not with plasma AdoMet/AdoHcy ratios.
Conclusion: Global DNA methylation may be altered in vascular disease, with a concomitant increase in plasma tHcy and AdoHcy.
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