Polymorphisms in the catechol‐O‐methyltransferase (COMT) gene influence plasma total homocysteine levels

AbstractElevated plasma total homocysteine (tHcy) is a risk factor for various disorders. We investigated whether functional polymorphisms in catechol‐O‐methyltransferase (COMT) influence tHcy, since COMT activity produces S‐adenosylhomocysteine (SAH), a homocysteine precursor. We hypothesized that high activity COMT variants would be associated with high tHcy, since they presumably result in increased formation of SAH. We genotyped 780 community‐dwelling elderly individuals for functional COMT (Val158Met and A−287G) and methylenetetrahydrofolate reductase (MTHFR; C677T) polymorphisms, and measured plasma tHcy. As predicted, COMT Val158 carriers had significantly higher tHcy than Met158 homozygotes. The effect was limited to individuals homozygous for the MTHFR T677 allele. In addition, individuals homozygous for the COMT G−287 allele tended to have lower tHcy levels. High activity variants of COMT interact with the low activity variant of MTHFR to increase tHcy levels. The effect on tHcy may contribute to the reported associations of COMT genotype with psychiatric and neurobiological phenotypes. The results also indicate that COMT activity may influence a broader range of biochemical pathways than hitherto appreciated. © 2008 Wiley‐Liss, Inc.