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.
"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). "
"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. "
"The interactive effect of these two gene polymorphisms on susceptibility for disease reached an OR of 3.02 for NTDs and 3.39 for anencephaly. A previous study showed that increased COMT (Val/Val) enzyme activity is linked to elevated plasma Hcy levels, especially in the presence of the MTHFR TT genotype (Tunbridge et al. 2008). In the present study, we did not observe any effects of a COMT rs4680 × MTHFR rs1801133 interaction on risk of NTDs or of any subtype of NTD. "
[Show abstract][Hide abstract] ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) C677T and catechol-O-Methyltransferase (COMT) G158A are associated with a risk of neural tube defects (NTDs) in offspring. This study examined the effect of a MTHFR × COMT interaction on the risk of NTDs in a Chinese population with a high prevalence of NTDs. A total of 576 fetuses or newborns with NTDs and 594 controls were genotyped for MTHFRrs1801133, MTHFRrs1801131, and COMTrs4680 and COMTrs737865. Information on maternal sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Possible interactions between genetic variants of MTHFR and COMT were examined. MTHFR C677T homozygous TT was associated with an elevated risk of total NTDs (odds ratio [OR] = 1.37, 95 % confidence interval [CI] = 0.93-2.03) and of anencephaly (OR = 1.67, 95 % CI = 0.98-2.84) compared with the CC genotype. There was a COMT rs737865 CC × MTHFR rs1801133 TT interaction for total NTDs (OR = 3.02, 95 % CI = 1.00-9.14) and for anencephaly (OR = 3.39, 95 % CI = 0.94-12.18). No interaction was found between COMT rs4680 AA/AG and MTHFR CT/TT genotypes for total NTDs or any subtype of NTD. The interaction of COMT rs737865 and MTHFR C677T was associated with an increased risk of NTDs, especially anencephaly, in a Chinese population with a high prevalence of NTDs.
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