We found no evidence that homocysteine-lowering interventions, in the form of supplements of vitamins B6, B9 or B12 given alone or in combination, at any dosage compared with placebo or standard care, prevent myocardial infarction or stroke, or reduce total mortality in participants at risk of or with established cardiovascular disease. Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer).
The other example is the hypomethylation in CpG islands within the IL-6 promoter gene in monocytes. IL-6 is a pro-inflammatory cytokine that participates in B cell response. When this promoter is hypermethylated, there is an overexpression of IL-6 that will cause an overexpression of pro-inflammatory cytokines at the same time. This will be associated with a local hyperactive of the inflammation circuit. But there is evidence that we can also find a hypermethylation mechanism in monocytes such as in the case of the CpG islands with the promoter of death receptor 3 (DR-3). DR-3 is a protein that cause apoptosis and activation of transcription factor NF-kappa-M. However, when there is a downregulation of tis protein because of the hypermethylation of its promoter, the RA synovial cell will be resistant to apoptosis.
Glucose and insulin levels are determinants of methylation. They alter homocysteine metabolism by increasing cell homocysteine production through its inhibition of trans-sulfuration. When there is an increase in the levels of homocysteine, methionine in cells will be catalyzed by DMNTs in S-adenosylmethionine. This will enhance DNMT activity that will subsequently lead to increased global DNA methylation.
Our analyses of data from three cohorts of subjects in two independent studies show a strong association between increased homocysteine levels and the risk of osteoporotic fracture. The age- and sex-adjusted risk of fracture increased by 30 percent for each increase of 1 SD in the homocysteine level. A serum homocysteine level in the highest quartile doubled the risk of fracture. The magnitude of this effect is similar to that previously observed for the increase in the risk of cardiovascular disease and dementia according to homocysteine level.12-14,28
According to a long-standing hypothesis, the mechanism underlying the association between the homocysteine level and the risk of fracture may involve interference by homocysteine in collagen cross-linking.7
Serum vitamin D was a significant positive explanatory variable for HDLC (partial R (2) = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R (2) = 6.0-12.6%).
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