Clinical Chemistry Link to Randox Laboratories Web Site
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 49: 1292-1296, 2003; 10.1373/49.8.1292
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (67)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Castro, R.
Right arrow Articles by Tavares de Almeida, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Castro, R.
Right arrow Articles by Tavares de Almeida, I.
Related Collections
Right arrow Molecular Diagnostics and Genetics
Right arrow Heart Health and the Clinical Laboratory
Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
Right arrow Endocrinology and Metabolism
(Clinical Chemistry. 2003;49:1292-1296.)
© 2003 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Increased Homocysteine and S-Adenosylhomocysteine Concentrations and DNA Hypomethylation in Vascular Disease

Rita Castro1, Isabel Rivera1, Eduard A. Struys3, Erwin E.W. Jansen3, Paula Ravasco2, Maria Ermelinda Camilo2, Henk J. Blom4, Cornelis Jakobs3 and Isabel Tavares de Almeida1,a

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.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DNA methylation is an important epigenetic feature of DNA that plays a critical role in gene regulation (1) and has recently been implicated in chronic disease states, including atherosclerosis (2)(3). DNA methylation patterns are maintained by DNA methyltransferases (4)(5)(6)(7), which use S-adenosylmethione (AdoMet)1 as the methyl group donor. AdoMet is also the methyl donor in other cellular methyltransferase reactions, including in RNA and protein methylation, synthesis, and detoxification processes. As a result of the transfer of the methyl group, AdoMet is converted to S-adenosylhomocysteine (AdoHcy) and a decrease in the AdoMet/AdoHcy ratio is often taken as an indicator of reduced cellular methylation capacity (8)(9)(10). Under physiologic conditions, AdoHcy is hydrolyzed to Hcy and adenosine. This reaction is reversible, with a dynamic equilibrium that strongly favors AdoHcy synthesis rather than hydrolysis (8). For this reason, the removal of Hcy and adenosine is crucial, and disturbed metabolic pathways that lead to increased intracellular Hcy concentrations will also increase AdoHcy (10). AdoHcy binds to methyltransferases with higher affinity than does AdoMet, and as a potent inhibitor of most methylation reactions, including those of DNA methyltransferases, it potentially affects cell homeostasis (11).

Hyperhomocysteinemia is a well-established risk factor for vascular disease, but the underlying pathogenic mechanism remains poorly understood, although thoroughly studied. Most studies have been focused on the direct effect of Hcy, but it was recently suggested that a chronic increase in AdoHcy (as a result of the Hcy-mediated reversal of the AdoHcy hydrolase reaction) might have significant pathologic consequences (12). Furthermore, the role of epigenetic alterations has emerged as a crucial mechanism for regulating genes responsible for cell proliferation in atherosclerosis (3). The present study was undertaken to assess the possible association between increased Hcy and epigenetic alterations in vascular disease. Plasma total homocysteine (tHcy), AdoMet, and AdoHcy concentrations, as well as leukocyte DNA methylation status, were evaluated in vascular disease and control groups. The results support the hypothesis that the pathogenic role of hyperhomocysteinemia in vascular disease might be mediated by AdoHcy accumulation and DNA hypomethylation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
participants and sample collection
We studied 17 male atherosclerotic vascular patients [mean (SD) age, 54 (5.8) years] and 15 healthy male controls [mean (SD) age, 53 (6.9) years]. Cases were recruited among patients who had been admitted to hospital with a diagnosis of stroke (n = 8) or angiographically confirmed myocardial infarction (n = 9); samples were collected at least 3 months after the occurrence. Controls were selected among hospital employees whose lifestyle details (i.e., smoking, alcohol consumption, medication, physical exercise, and personal and family histories) and baseline laboratory measurements were established by use of standardized questionnaires and protocols. The criteria for inclusion in the control group were: normal hematology and liver/renal function tests and no history of vascular pathology. Exclusion criteria for both groups were metabolic, hepatic, or renal pathology; cancer; alcohol or drug abuse; and use of vitamin B6, vitamin B12, or folic acid supplements within the 2 previous months. Written informed consent was obtained from all participants, and the Local Ethical Committee approved the study.

Blood samples were collected from all participants after overnight fasting by venipuncture into EDTA-containing tubes. One tube was immediately placed on ice and centrifuged at 4000g for 10 min at 4 °C. One plasma aliquot was stored at -20 °C until tHcy quantification, whereas 1000 µL was immediately deproteinized by adding 624 µL of 100 g/L perchloric acid and then stored at -20 °C until AdoMet and AdoHcy determinations. Hematologic analysis revealed no significant differences in the mononuclear vs polymorphonuclear cells ratios between the individuals of both groups. Genomic DNA was extracted from white blood cells according to standard phenol–chloroform procedures (13)(14) and then stored at 4 °C until quantification of global DNA methylation.

tHcy, AdoMet, AND AdoHcy MEASUREMENTS
Plasma tHcy was quantified in the thawed aliquots by a specific immunoassay (IMx; Abbott Laboratories).

For plasma AdoMet and AdoHcy quantification, the deproteinized samples were thawed and centrifuged, and the obtained supernatant was analyzed by stable-isotope-dilution tandem mass spectrometry, as described previously in detail (15).

global dna methylation status
The global DNA methylation status was assessed by use of the cytosine extension assay (16). Briefly, 1 µg of genomic DNA was digested overnight with a methylation-sensitive endonuclease (HpaII), which left a single guanine overhang at unmethylated CpG sites. A second DNA aliquot was incubated without HpaII and served as background control. A single nucleotide extension with [3H]dCTP (Amersham Biosciences) was then performed. Duplicate 10-µL aliquots from each reaction were applied on Whatman DE-81 ion-exchange filters, dried, and washed three times with sodium phosphate buffer (pH 7.0) at room temperature. Filters were dried and processed for scintillation counting. Background radiolabel incorporation was subtracted from enzyme-treated samples, and the results were expressed as relative [3H]dCTP incorporation/µg of DNA. Incorporation of the radiolabel was considered proportional to the number of unmethylated (cleaved) sites in DNA. All samples were analyzed at the same time to minimize variation. The within-assay imprecision of the cytosine extension assay was <6%.

statistical analysis
Data are presented as medians and interquartile ranges. The distributions of plasma tHcy, AdoMet, and AdoHcy and the relative [3H]dCTP incorporation/µg of DNA were positively skewed and logarithmically transformed before further statistical analysis. Differences between patient and control groups were evaluated with the independent-samples Student t-test. Correlations were determined with the Spearman method; P values were two-tailed. Statistical significance was set at P <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The median plasma tHcy, AdoMet, and AdoHcy concentrations, the AdoMet/AdoHcy ratios, and the global DNA methylation status in the studied population are presented in Table 1 . Compared with controls, patients had significantly higher (P <0.01) plasma tHcy and AdoHcy concentrations, decreased (P <0.01) plasma AdoMet/AdoHcy ratios, and lower (P <0.05) global DNA methylation status. We observed no significant differences in plasma AdoMet concentrations between the two groups. The variables displaying statistical difference were subdivided into quartiles, and the patients and controls were distributed accordingly, as shown in Fig. 1 . More than 50% of the patients fell into the highest quartiles of plasma tHcy and AdoHcy concentrations and [3H]dCTP incorporation/µg of DNA (i.e., the lowest quartile of DNA methylation status) and into the lowest quartile of plasma AdoMet/AdoHcy ratios for the controls. When we considered the patients and controls together, we observed that the increase in plasma tHcy was significantly correlated with a parallel increase in plasma AdoHcy (r = 0.81; P <0.0001) and with a decrease in plasma AdoMet/AdoHcy ratios (r = -0.68; P <0.0001; Fig. 2 ).


View this table:
[in this window]
[in a new window]
  		Table 1. Plasma tHcy, AdoMet, and AdoHcy concentrations and global DNA methylation status in the studied population.1



View larger version (35K):
[in this window]
[in a new window]
  		Figure 1. Plasma tHcy (A) and AdoHcy (B) concentrations, AdoMet/AdoHcy ratios (C), and DNA methylation status (D) divided into quartiles and presented as percentages of the total number of studied controls () and patients with vascular disease ({blacksquare}) included in each group.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 2. Plots of individual values for plasma tHcy vs AdoHcy (r = 0.81; P <0.0001; A) and for plasma tHcy vs AdoMet/AdoHcy ratio (r = -0.68; P <0.0001; B) for each participant.

We found no apparent association between plasma tHcy and AdoMet concentrations (data not shown). In addition, there was a significant correlation between DNA methylation status and plasma tHcy (r = 0.47, P <0.01) and plasma AdoHcy concentrations (r = 0.54; P <0.01; Fig. 3 ), but no correlation with plasma AdoMet/AdoHcy ratios (data not shown).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. Plots of individual values for plasma tHcy vs global DNA methylation status (r = 0.47; P <0.01; A) and for plasma AdoHcy vs global DNA methylation status (r = 0.54; P <0.01; B) for each participant.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A growing body of evidence has documented the role of hyperhomocysteinemia as an independent vascular risk factor. However, the mechanisms through which increased plasma Hcy concentrations cause endothelial dysfunction and atherosclerosis remain elusive. At present, atherogenesis is believed to involve mainly gene function, such as epigenetic changes leading to alterations in gene expression and genomic integrity (2). Methylation is an important epigenetic feature of DNA, which is catalyzed by DNA methyltransferases with AdoMet as a methyl donor. Recently, it has been suggested that the pivotal biomarker of the association between hyperhomocysteinemia and vascular disease would not be Hcy itself, but increases in AdoHcy, secondary to the Hcy-mediated reversal of the AdoHcy hydrolase reaction. An increase in AdoHcy causes feedback inhibition of AdoMet-dependent methyltransferases, including the DNA methyltransferases (12)(17). The tissue-specific metabolic pathways are crucial in determining the relative sensitivity to alterations in AdoHcy concentrations (18). The demonstrated lack of cystathionine ß-synthase (19) and betaine-homocysteine methyltransferase (17) activity in endothelial cells may enhance their sensitivity to AdoHcy accumulation and, consequently, to DNA hypomethylation. Our findings are in line with the hypothesis that the pathogenic role of hyperhomocysteinemia in vascular disease might be caused by AdoHcy accumulation and DNA hypomethylation. However, because of the small size of the study sample, further larger studies are needed to confirm these findings.

In the present report, patients with vascular disease had significantly higher plasma tHcy and AdoHcy concentrations, decreased plasma AdoMet/AdoHcy ratios, and lower global DNA methylation status compared with controls. Significantly, >50% of the patients fell into the highest quartiles for plasma tHcy and AdoHcy concentrations and into the lowest quartiles for plasma AdoMet/AdoHcy ratios and DNA methylation status for the controls (Fig. 1Up ). In addition, when patients and controls were considered together, the increase in plasma tHcy was highly correlated with a parallel increase in plasma AdoHcy (Fig. 2AUp ) and with a decrease in plasma AdoMet/AdoHcy ratios (Fig. 2BUp ), but not with plasma AdoMet. Moreover, plasma tHcy and AdoHcy were significantly correlated with the global DNA methylation status (Fig. 3Up ). However, we observed no correlation between plasma AdoMet concentrations or AdoMet/AdoHcy ratios and the global DNA methylation status. Similar observations have also been reported by Yi et al. (20).

The intracellular AdoMet/AdoHcy ratio has been used as a predictor of cellular methylation capacity. A significant correlation between plasma and lymphocyte AdoMet/AdoHcy ratios has been reported (12). This observation suggests that the plasma AdoMet/AdoHcy ratio may be used as a reasonable predictor of the cellular methylation status. In the present study, the lack of correlation between the plasma AdoMet/AdoHcy ratio and DNA methylation status could seem unexpected. However, the authors of two recent studies in humans (20) and animals (18) claimed that intracellular AdoHcy is a more reliable biomarker for cellular methylation status. Our findings are in accordance with this observation.

In conclusion, the present study shows that patients with vascular disease have disturbed global DNA methylation status associated with increased plasma tHcy and AdoHcy concentrations. Whether these observations contribute to the pathogenic role of hyperhomocysteinemia in vascular disease needs to be further ascertained.


   Acknowledgments
 
We gratefully acknowledge support from Dr. Adelaide Belo (Hospital Distrital de Beja). We also thank Fernanda Ramalho, Elisa Alves, and Amélia Pereira for expert sampling and routine biochemical determinations. This study was supported in part by a grant (Praxis XXI/BD/11383/97) from the F.C.T. (Fundação para a Ciência e Tecnologia) to Rita Azevedo e Castro. Henk Blom is supported by the Netherlands Heart Foundation (D97.021).


   Footnotes
 
1 Nonstandard abbreviations: AdoMet, S-adenosylmethionine; AdoHcy, S-adenosylhomocysteine; and tHcy, total homocysteine.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A 2002;99:5606-5611.[Abstract/Free Full Text]
  2. Domagala TB, Undas A, Libura M, Szczeklik A. Pathogenesis of vascular disease in hyperhomocysteinaemia [Review]. J Cardiovasc Risk 1998;5:239-247.[CrossRef][Medline] [Order article via Infotrieve]
  3. Dong C, Yoon W, Goldschmidt-Clermont PJ. DNA methylation and atherosclerosis [Review]. J Nutr 2002;132:2406S-2409S.[Abstract/Free Full Text]
  4. Bestor TH. The DNA methyltransferases of mammals [Review]. Hum Mol Genet 2000;9:2395-2402.[Abstract/Free Full Text]
  5. Vilkaitis G, Merkiene E, Serva S, Weinhold E, Klimasauskas S. The mechanism of DNA cytosine-5 methylation. Kinetic and mutational dissection of HhaI methyltransferase. J Biol Chem 2001;276:20924-20934.[Abstract/Free Full Text]
  6. Clark SJ, Harrison J, Frommer M. CpNpG methylation in mammalian cells. Nat Genet 1995;10:20-27.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  7. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-257.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  8. Cantoni GL. The role of S-adenosylhomocysteine in the biological utilization of S-adenosylmethionine. Prog Clin Biol Res 1985;198:47-65.[Medline] [Order article via Infotrieve]
  9. Chiang PK, Cantoni GL. Perturbation of biochemical transmethylations by 3-deazaadenosine in vivo. Biochem Pharmacol 1979;28:1897-1902.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  10. Hoffman DR, Marion DW, Cornatzer WE, Duerre JA. S-Adenosylmethionine and S-adenosylhomocystein metabolism in isolated rat liver. Effects of L-methionine, L-homocystein, and adenosine. J Biol Chem 1980;255:10822-10827.[Abstract/Free Full Text]
  11. Hoffman DR, Cornatzer WE, Duerre JA. Relationship between tissue levels of S-adenosylmethionine, S-adenylhomocysteine, and transmethylation reactions. Can J Biochem 1979;57:56-65.[ISI][Medline] [Order article via Infotrieve]
  12. Melnyk S, Pogribna M, Pogribny IP, Yi P, James SJ. Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: alterations with plasma homocysteine and pyridoxal 5'-phosphate concentrations. Clin Chem 2000;46:265-272.[Abstract/Free Full Text]
  13. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.[Free Full Text]
  14. Leadon SA, Cerutti PA. A rapid and mild procedure for the isolation of DNA from mammalian cells. Anal Biochem 1982;120:282-288.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  15. Struys EA, Jansen EE, de Meer K, Jakobs C. Determination of S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid by stable-isotope dilution tandem mass spectrometry. Clin Chem 2000;46:1650-1656.[Abstract/Free Full Text]
  16. Pogribny I, Yi P, James SJ. A sensitive new method for rapid detection of abnormal methylation patterns in global DNA and within CpG islands. Biochem Biophys Res Commun 1999;262:624-628.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  17. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr 2002;132:2361S-2366S.[Abstract/Free Full Text]
  18. Caudill MA, Wang JC, Melnyk S, Pogribny IP, Jernigan S, Collins MD, et al. Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine ß-synthase heterozygous mice. J Nutr 2001;131:2811-2818.[Abstract/Free Full Text]
  19. van der Molen EF, Hiipakka MJ, van Lith-Zanders H, Boers GH, van den Heuvel LP, Monnens LA, et al. Homocysteine metabolism in endothelial cells of a patient homozygous for cystathionine ß-synthase (CS) deficiency. Thromb Haemost 1997;78:827-833.[ISI][Medline] [Order article via Infotrieve]
  20. Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem 2000;275:29318-29323.[Abstract/Free Full Text]



The following articles in journals at HighWire Press have cited this article:


Home page
 DiabetesHome page
N. Mzhavia, S. Yu, S. Ikeda, T. T. Chu, I. Goldberg, and H. M. Dansky
Neuronatin: A New Inflammation Gene Expressed on the Aortic Endothelium of Diabetic Mice
Diabetes, October 1, 2008; 57(10): 2774 - 2783.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Malanovic, I. Streith, H. Wolinski, G. Rechberger, S. D. Kohlwein, and O. Tehlivets
S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast: IMPLICATIONS FOR HOMOCYSTEINE AS A RISK FACTOR OF ATHEROSCLEROSIS
J. Biol. Chem., August 29, 2008; 283(35): 23989 - 23999.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
P. W. B. Nanayakkara, J. C. Kiefte-de Jong, C. D. A. Stehouwer, F. J. van Ittersum, M. R. Olthof, R. M. Kok, H. J. Blom, C. van Guldener, P. M. ter Wee, and Y. M. Smulders
Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2-4 chronic kidney disease
Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2586 - 2592.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
P. Stenvinkel and T. J. Ekstrom
Epigenetics--a helpful tool to better understand processes in clinical nephrology?
Nephrol. Dial. Transplant., May 1, 2008; 23(5): 1493 - 1496.
[Full Text] [PDF]

Home page
 CJASNHome page
P. Stenvinkel, J. J. Carrero, J. Axelsson, B. Lindholm, O. Heimburger, and Z. Massy
Emerging Biomarkers for Evaluating Cardiovascular Risk in the Chronic Kidney Disease Patient: How Do New Pieces Fit into the Uremic Puzzle?
Clin. J. Am. Soc. Nephrol., March 1, 2008; 3(2): 505 - 521.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
C. Liu, Q. Wang, H. Guo, M. Xia, Q. Yuan, Y. Hu, H. Zhu, M. Hou, J. Ma, Z. Tang, et al.
Plasma S-Adenosylhomocysteine Is a Better Biomarker of Atherosclerosis Than Homocysteine in Apolipoprotein E-Deficient Mice Fed High Dietary Methionine
J. Nutr., February 1, 2008; 138(2): 311 - 315.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. M. Devlin, R. Singh, R. E. Wade, S. M. Innis, T. Bottiglieri, and S. R. Lentz
Hypermethylation of Fads2 and Altered Hepatic Fatty Acid and Phospholipid Metabolism in Mice with Hyperhomocysteinemia
J. Biol. Chem., December 21, 2007; 282(51): 37082 - 37090.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
C. Wagner and M. J Koury
S-Adenosylhomocysteine a better indicator of vascular disease than homocysteine?
Am. J. Clinical Nutrition, December 1, 2007; 86(6): 1581 - 1585.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
S. P Stabler, R. H Allen, E. T Dolce, and M. A. Johnson
Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment
Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1422 - 1429.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
H. Gellekink, D. van Oppenraaij-Emmerzaal, A. van Rooij, E. A. Struys, M. den Heijer, and H. J. Blom
Stable-Isotope Dilution Liquid Chromatography-Electrospray Injection Tandem Mass Spectrometry Method for Fast, Selective Measurement of S-Adenosylmethionine and S-Adenosylhomocysteine in Plasma
Clin. Chem., August 1, 2005; 51(8): 1487 - 1492.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. M. Devlin, T. Bottiglieri, F. E. Domann, and S. R. Lentz
Tissue-specific Changes in H19 Methylation and Expression in Mice with Hyperhomocysteinemia
J. Biol. Chem., July 8, 2005; 280(27): 25506 - 25511.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
D. Li, L. Pickell, Y. Liu, Q. Wu, J. S Cohn, and R. Rozen
Maternal methylenetetrahydrofolate reductase deficiency and low dietary folate lead to adverse reproductive outcomes and congenital heart defects in mice
Am. J. Clinical Nutrition, July 1, 2005; 82(1): 188 - 195.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
J-L Gueant, G Anello, P Bosco, R-M Gueant-Rodriguez, A Romano, C Barone, P Gerard, and C Romano
Homocysteine and related genetic polymorphisms in Down's syndrome IQ
J. Neurol. Neurosurg. Psychiatry, May 1, 2005; 76(5): 706 - 709.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
C. L. Ulrey, L. Liu, L. G. Andrews, and T. O. Tollefsbol
The impact of metabolism on DNA methylation
Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R139 - R147.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
S. Zaina, M. W. Lindholm, and G. Lund
Nutrition and Aberrant DNA Methylation Patterns in Atherosclerosis: More than Just Hyperhomocysteinemia?
J. Nutr., January 1, 2005; 135(1): 5 - 8.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
E. M Guerra-Shinohara, O. E Morita, S. Peres, R. A Pagliusi, L. F Sampaio Neto, V. D'Almeida, S. P Irazusta, R. H Allen, and S. P Stabler
Low ratio of S-adenosylmethionine to S-adenosylhomocysteine is associated with vitamin deficiency in Brazilian pregnant women and newborns
Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1312 - 1321.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
B. N. Ames
Supplements and Tuning Up Metabolism
J. Nutr., November 1, 2004; 134(11): 3164S - 3168S.
[Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
S. Narayanan, J. McConnell, J. Little, L. Sharp, C. J. Piyathilake, H. Powers, G. Basten, and S. J. Duthie
Associations between Two Common Variants C677T and A1298C in the Methylenetetrahydrofolate Reductase Gene and Measures of Folate Metabolism and DNA Stability (Strand Breaks, Misincorporated Uracil, and DNA Methylation Status) in Human Lymphocytes In vivo
Cancer Epidemiol. Biomarkers Prev., September 1, 2004; 13(9): 1436 - 1443.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Lund, L. Andersson, M. Lauria, M. Lindholm, M. F. Fraga, A. Villar-Garea, E. Ballestar, M. Esteller, and S. Zaina
DNA Methylation Polymorphisms Precede Any Histological Sign of Atherosclerosis in Mice Lacking Apolipoprotein E
J. Biol. Chem., July 9, 2004; 279(28): 29147 - 29154.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
R Castro, I Rivera, P Ravasco, M E Camilo, C Jakobs, H J Blom, and I T de Almeida
5,10-methylenetetrahydrofolate reductase (MTHFR) 677C->T and 1298A->C mutations are associated with DNA hypomethylation
J. Med. Genet., June 1, 2004; 41(6): 454 - 458.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Mizunuma, K. Miyamura, D. Hirata, H. Yokoyama, and T. Miyakawa
Involvement of S-adenosylmethionine in G1 cell-cycle regulation in Saccharomyces cerevisiae
PNAS, April 20, 2004; 101(16): 6086 - 6091.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
S. P. Stabler and R. H. Allen
Quantification of Serum and Urinary S-Adenosylmethionine and S-Adenosylhomocysteine by Stable-Isotope-Dilution Liquid Chromatography-Mass Spectrometry
Clin. Chem., February 1, 2004; 50(2): 365 - 372.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (67)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Castro, R.
Right arrow Articles by Tavares de Almeida, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Castro, R.
Right arrow Articles by Tavares de Almeida, I.
Related Collections
Right arrow Molecular Diagnostics and Genetics
Right arrow Heart Health and the Clinical Laboratory
Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
Right arrow Endocrinology and Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS