Homocysteine and DNA methylation: A review of animal and human literature

• Hyperhomocysteinemia in animals is associated with high SAH and low SAM/SAH ratio, but changes in SAM were not consistent.
• SAM:SAH ratio is not a good proxy for DNA methylation levels in hyperhomocysteinemic animal models.
• Both diet- and genetically induced hyperhomocysteinemic animal models have altered methylation indicating homocysteine as a keyplayer.
• Global DNA methylation was not consistently altered in humans with hyperhomocysteinemia.
• Homocysteine-lowering trials did not result in a clear improvement of DNA methylation patterns in most studies.

Homocysteine (Hcy) is a sulfur-containing non-protein forming amino acid, which is synthesized from methionine as an important intermediate in the one-carbon pathway. High concentrations of Hcy in a condition called hyperhomocysteinemia (HHcy) are an independent risk factor for several disorders including cardiovascular diseases and osteoporotic fractures. Since Hcy is produced as a byproduct of the methyltransferase reaction, alteration in DNA methylation is studied as one of the underlying mechanisms of HHcy-associated disorders. In animal models, elevated Hcy concentrations are induced either by diet (high methionine, low B-vitamins, or both), gene knockouts (Mthfr, Cbs, Mtrr or Mtr) or combination of both to investigate their effects on DNA methylation or its markers. In humans, most of the literature involves case–control studies concerning patients. The focus of this review is to study existing literature on HHcy and its role in relation to DNA methylation. Apart from this, a few studies investigated the effect of Hcy-lowering trials on restoring DNA methylation patterns, by giving a folic acid or B-vitamin supplemented diet. These studies which were conducted in animal models as well as humans were included in this review.