Elsevier

Neurobiology of Aging

Volume 31, Issue 11, November 2010, Pages 2020-2022
Neurobiology of Aging

Negative Results
Genetic variation in homocysteine metabolism, cognition, and white matter lesions

https://doi.org/10.1016/j.neurobiolaging.2008.10.004Get rights and content

Abstract

Several studies have shown an association between homocysteine concentration and cognitive performance or cerebral white matter lesions. However, variations in genes encoding for enzymes and other proteins that play a role in homocysteine metabolism have hardly been evaluated in relation to these outcome measures. In the population-based Rotterdam Scan Study, we examined the association of seven polymorphisms of genes involved in homocysteine metabolism (MTHFR 677C>T, MTHFR 1298A>C, RFC 80G>A, TC 776C > G, MTR 2756A > G, MTRR 66A > G, and CBS 844ins68) with plasma total homocysteine, cognitive performance, and cerebral white matter lesions among 1011 non-demented elderly participants. Of all the studied polymorphisms, only MTHFR 677C > T was associated with homocysteine concentration. No significant relationship was observed for any of the polymorphisms with cognitive performance or severity of cerebral white matter lesions.

Introduction

Elevated homocysteine concentrations have been associated with worse cognitive performance and greater severity of cerebral white matter lesions in several studies (Dufouil et al., 2003, Nurk et al., 2005; Prins et al., 2002; Seshadri et al., 2002, Vermeer et al., 2002). Many enzymes and other proteins play a role in the different pathways of homocysteine metabolism (see Supplementary Material). Except for the MTHFR 677C > T polymorphism, variations in genes encoding for these factors have hardly been explored in relation to cognition or structural brain changes, and results have been inconsistent. We evaluated the association of seven polymorphisms (methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C, which are in linkage disequilibrium (D’ 1.0 in HapMap CEU population [www.hapmap.org]), reduced folate carrier (RFC) 80G > A, transcobalamin (TC) 776C > G, methionine synthase (MTR) 2756A > G, methionine synthase reductase (MTRR) 66A > G, and cystathionine-ß-synthase (CBS) 844ins68) with plasma levels of homocysteine, cognitive function, and severity of cerebral white matter lesions in a large population-based study.

Section snippets

Subjects and methods

This study was conducted using cross-sectional data from 1011 non-demented participants aged 60–90 years of the population-based Rotterdam Scan Study (see Supplementary Material for extensive description of study population and methods). We compared plasma homocysteine, Z-scores for global cognitive function, psychomotor speed, and memory function, and severity of subcortical and periventricular white matter lesions on brain MRI across genotypes of the studied polymorphisms by analysis of

Results and discussion

Genotype distributions were in Hardy–Weinberg equilibrium (Table 1 [Tables in Supplementary Material]). Participants with the MTHFR 677TT genotype, in particular those with low folate status, had higher homocysteine concentrations than CC or CT subjects. Total homocysteine levels did not differ significantly between the genotypes of any of the other studied polymorphisms, neither overall nor in strata of high or low folate (Table 2). We did not observe any significant differences in Z-scores

Conflict of interest

None.

Acknowledgements

This study was supported by grants from the International Foundation for Alzheimer Research (ISAO) (grant number 4520) (MMBB) and the Alzheimer’s Research Trust (HR, ADS) and in part by an Advanced Research Programme grant from the Norwegian Research Council (NFR 117997/320 NORUT 2003) and The Throne Holst Foundation for Nutrition Research (HR).

References (7)

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