title: Polymorphisms in the catechol-O-methyltransferase (COMT) gene influence plasma total homocysteine levels.
abstract: Elevated 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 (Val(158)Met and A(-287)G) and methylenetetrahydrofolate reductase (MTHFR; C(677)T) polymorphisms, and measured plasma tHcy. As predicted, COMT Val(158) carriers had significantly higher tHcy than Met(158) homozygotes. The effect was limited to individuals homozygous for the MTHFR T(677) 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.
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom. elizabeth.tunbridge@psych.ox.ac.uk
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tunbridge
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: Donald R
authors.initials: DR
authors.lastname: Warden
authors.forename: Carole
authors.initials: C
authors.lastname: Johnston
authors.forename: Helga
authors.initials: H
authors.lastname: Refsum
authors.forename: A David
authors.initials: AD
authors.lastname: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide / Q000502:physiology
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase