Negative ResultsGenetic variation in homocysteine metabolism, cognition, and 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).
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