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.
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ABSTRACT: Increasing evidence suggests that the catechol-O-methyltransferase (COMT) gene might be associated with cognition in patients with mental disorders and healthy people. The metabolic pathways of COMT and methylenetetrahydrofolate reductase (MTHFR) are closely interconnected. In this study, we aimed to examine whether the COMT-MTHFR genotype interacted with cognitive function in late-onset depression (LOD) patients and COMT Val/Val homozygous individuals who also carried the MTHFR T allele and had poor neuropsychological test performance. Ninety-seven unrelated LOD patients who met DSM-IV criteria for major depressive disorder were recruited for the study and 103 normal controls were recruited from the local community. All of these patients and 44 normal controls completed a series of neuropsychological tests. Patients and normal controls were genotyped for COMT (rs4680) and MTHFR (rs1801133) variants using polymerase chain reaction-restriction fragment length polymorphism. There were no significant differences in the frequencies of the single alleles and genotypes of two polymorphisms between LOD patients and normal controls. No main effects of COMT or MTHFR genotype on any neuropsychological test performance were observed. There was a significant interactive effect of COMT Val158Met and MTHFR C677T polymorphisms on the Symbol Digit Modalities Test independent of diagnosis (P < 0.05). After controlling for covariates, the subjects with COMT Met/ Met and MTHFR C/C genotype had better Symbol Digit Modalities Test performance. The results suggest no major effect of COMT or MTHFR on cognitive function alone. However, an interaction of COMT Val158Met and MTHFR C677T polymorphisms may be associated with cognitive function. Further studies in a large sample are needed to replicate the genetic role in the LOD patients.Psychiatry and Clinical Neurosciences 12/2013; · 2.04 Impact Factor
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ABSTRACT: Maternal tea consumption was reported to increase the risk of fetal neural tube defects (NTDs). Catechol-O-methyltransferase (COMT) may be involved in the metabolism of polyphenolic methylation of tea, thus influence the risk of fetal NTDs. A total of 576 fetuses or newborns with NTDs and 594 healthy newborns were included in the case-control study. Information on maternal tea consumption, sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Maternal blood samples were collected to examine polymorphisms in COMT, and the possible interaction of COMT and tea consumption was analyzed. After controlling for potential confounders, homozygotes of rs737865 showed an elevated risk for total NTDs (odds ratio [OR] = 2.04, 95% confidence interval [CI], 1.24-3.35) and for the anencephaly subtype (OR = 1.99, 95% CI, 1.17-3.39). The CC genotype of rs4633 was positively associated with the overall risk of NTDs (OR = 3.66, 95% CI, 1.05-12.83). Heterozygotes for rs4680 were associated with a decreased risk of spina bifida (OR = 0.71, 95% CI, 0.51-0.98). The COMT rs4680 A allele was negatively related with the risk of spina bifida, with adjusted OR = 0.64 (95% CI, 0.45-0.89). An interaction between tea consumption (1 to 2 cups/day) and the rs4680AA/AG genotype was found in the spina bifida subtype (Pinteraction = .08). Several COMT variants were associated with elevated risk of NTDs in a Chinese population. Maternal tea consumption may be associated with an increased risk for fetal NTDs in genetically susceptible subgroups. Birth Defects Research (Part A), 2013. © 2013 Wiley Periodicals, Inc.Birth Defects Research Part A Clinical and Molecular Teratology 12/2013; · 2.27 Impact Factor
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ABSTRACT: The catechol-O-methyltransferase (COMT) enzyme has been widely studied due to its multiple roles in neurological functioning, estrogen biology, and methylation metabolic pathways. Numerous studies have investigated variation in the large COMT gene, with the majority focusing on single nucleotide polymorphisms (SNPs). This body of work has linked COMT genetic variation with a vast array of conditions, including several neurobehavioral disorders, pain sensitivity, and multiple human cancers. Based on COMT's numerous biological roles and recent studies suggesting that methylation of the COMT gene impacts COMT gene expression, we comprehensively interrogated methylation in over 200 CpG dinucleotide sequences spanning the length of the COMT gene. Using saliva-derived DNA from a non-clinical sample of human subjects, we tested for associations between COMT CpG methylation and factors reported to interact with COMT genetic effects, including demographic factors and alcohol use. Finally, we tested associations between COMT CpG methylation state and COMT gene expression in breast cancer cell lines. We interrogated >200 CpGs in 13 amplicons spanning the 5' UTR to the last exon of the CpG dinucleotide-rich COMT gene in n = 48 subjects, n = 11 cell lines and 1 endogenous 18S rRNA control. With the exception of the CpG island in the 5'UTR and 1st exon, all other CpG islands were strongly methylated with typical dynamic ranges between 50-90%. In the saliva samples, methylation of multiple COMT loci was associated with socioeconomic status or ethnicity. We found associations between methylation at numerous loci and genotype at the functional Val158Met SNP (rs4680), and most of the correlations between methylation and demographic and alcohol use factors were Val158Met allele-specific. Methylation at several of these loci also associated with COMT gene expression in breast cancer cell lines. We report the first comprehensive interrogation of COMT methylation. We corroborate previous findings of variation in COMT methylation with gene expression and the Val158Met genotype, and also report novel associations with socioeconomic status (SES) and ethnicity at several methylated loci. These results point to novel mechanisms for COMT regulation, which may have broad therapeutic implications.BMC Medical Genomics 01/2014; 7(1):5. · 3.47 Impact Factor