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

Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 09/2008; 147B(6):996-9. DOI: 10.1002/ajmg.b.30700
Source: PubMed


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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    • "The criteria used for endothelial dysfunction was an RH-PAT value of b1.67 as previously discussed. Both the MTHFR and COMT variants have shown a relationship between CVD risk and/or hyperhomocysteinemia with presence of the MTHFR 677 T allele in subjects with the COMT 158 Val allele (Tunbridge et al., 2008; Klerk et al., 2002; Lewis et al., 2005). Therefore, for the MTHFR genotype subjects were grouped based on those carrying at least one variant allele (677CT or CC and 1298 AC or CC) and those who were homozygous dominant (677TT or 1298CC). "

    Full-text · Article · Nov 2015
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    • "Our results in larger groups confirmed the role of the CC genotype of A1298C polymorphism , although only in women. It is also important to consider the correlation between MTHFR and other genes as COMT (Htun et al., 2014), due also the demonstrate correlation between COMT gene and homocysteine plasma levels (Tunbridge et al., 2008). One study has reported in the Chinese Han population a significant increased risk of MDD due to COMT Val158Met and MTHFR C677T polymorphism interactions but without influence on treatment response (Shen et al., 2014). "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. We did not measure folate and homocisteine levels. This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · May 2015 · Journal of Affective Disorders
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    • "In addition to MTHFR, the COMT variant (158Val/Met) is another crucial component within the AldoMet cycle, as the COMT Val/Val genotype exhibits 30–50% greater activity than the Met/Met genotype (Chen et al., 2004), which may also lead to hyperhomocysteinemia. Moreover, the effects of the COMT 158 variant may be exaggerated in individuals who also have an MTHFR T allele (Tunbridge et al., 2008). While both COMT and MTHFR genotypes have been individually and additively associated with neurocognitive deficits in schizophrenia (Roffman et al., 2008b, 2011b; Ceaser et al., 2013; Kontis et al., 2013), the relationship between folate metabolism, neurocognition, and CVD in schizophrenia has not been examined. "
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    ABSTRACT: Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · Schizophrenia Research
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