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: Background: Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype–phenotype and phenotype–disease studies, and the observed odds ratio from a meta-analysis of genotype–disease association studies. Methods: We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test. Findings: 111 studies met the selection criteria. Among 15 635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1·93 μmol/L (95% CI 1·38 to 2·47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1·20 (1·10 to 1·31). In our genetic meta-analysis (n=13 928) the odds ratio for stroke was 1·26 (1·14 to 1·40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0·29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location. Interpretation: The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.The Lancet 01/2005; · 39.06 Impact Factor
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ABSTRACT: Elevated plasma homocysteine concentration has been suggested as a risk factor for schizophrenia, but the results of epidemiological studies have been inconsistent. The most extensively studied genetic variant in the homocysteine metabolism is the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, resulting in reduced enzyme activity and, subsequently, in elevated homocysteine. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) was carried out to examine the association between homocysteine and schizophrenia. In addition, a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C>T polymorphism was carried out to assess if this association is causal. A 5 micromol/l higher homocysteine level was associated with a 70% (95% confidence interval, CI: 27-129) higher risk of schizophrenia. The TT genotype was associated with a 36% (95% CI: 7-72) higher risk of schizophrenia compared to the CC genotype. The performed meta-analyses showed no evidence of publication bias or excessive influence attributable to any given study. In conclusion, our study provides evidence for an association of homocysteine with schizophrenia. The elevated risk of schizophrenia associated with the homozygous genotype of the MTHFR 677C>T polymorphism provides support for causality between a disturbed homocysteine metabolism and risk of schizophrenia.Molecular Psychiatry 02/2006; 11(2):143-9. · 14.90 Impact Factor
- Pharmacological Reviews 01/2000; 51(4):593-628. · 22.35 Impact Factor