Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population

University of Oxford, Oxford, England, United Kingdom
American Journal of Clinical Nutrition (Impact Factor: 6.77). 03/2006; 83(3):708-13.
Source: PubMed


Homocysteine concentrations are influenced by vitamin status and genetics, especially several polymorphisms in folate-metabolizing genes.
We examined the interactions and associations with serum total homocysteine (tHcy) and folate concentrations of polymorphisms in the following folate-metabolizing genes: methylenetetrahydrofolate reductase (MTHFR), reduced folate carrier 1 (RFC1), and glutamate carboxypeptidase II (GCPII).
Healthy volunteers (436 men and 606 women; mean age: 77.9 y) were randomly selected from among residents of Oxford, United Kingdom. We determined the individual effects and interactions of the MTHFR 677C-->T, MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms on serum tHcy and folate concentrations.
Subjects with the MTHFR 677TT genotype had higher serum tHcy concentrations than did those with the MTHFR 677CC genotype (P < 0.001), and this effect was greater in subjects with low serum folate status (P for interaction = 0.026). The MTHFR 1298A-->C, RFC1 80G-->A, and GCPII 1561C-->T polymorphisms had no individual effects on serum tHcy or folate concentrations. There was no interactive effect of the MTHFR 677C-->T and MTHFR 1298A-->C polymorphisms on tHcy concentrations. An interaction (P = 0.05) was observed between the MTHFR 677TT and RFC1 80GG genotypes, whereby persons with this genotype combination had a mean (+/-SEM) serum tHcy concentration (18.5 +/- 1.2 micromol/L) that was 5.1 micromol/L greater than the mean value of 13.4 +/- 0.2 micromol/L for the whole population.
Folate and tHcy concentrations were not affected individually by the MTHFR 1298A-->C, RFC1 80G-->A, or GCPII 1561C-->T polymorphisms or by combinations of the MTHFR 677C-->T and MTHFR 1298A-->C genotypes. An interaction between the MTHFR 677TT and RFC1 80GG genotypes was observed whereby persons with this combination had higher serum tHcy.

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Available from: Jacqueline Birks, Feb 06, 2015
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    • "As a consequence, data shown in Table 3 should be taken with caution, and replication in a larger cohort of Italian elderly subjects is warranted prior to exclude a role for the studied polymorphism on circulating folate, hcy, and vitamin B12 levels. In this regard, a large similar study, performed in over 1.000 elderly English subjects (mean age 77.9 years), revealed no association of the RFC-1 80G>A polymorphism with circulating folate or hcy levels [36], supporting present and previous observations in patients with neurodegenerative diseases and their matched controls [15, 21, 22, 27]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. Polymorphisms of genes involved in folate metabolism have been frequently suggested as risk factors for sporadic AD. A common c.80G>A polymorphism (rs1051266) in the gene coding for the reduced folate carrier (SLC19A1 gene, commonly known as RFC-1 gene) was investigated as AD risk factor in Asian populations, yielding conflicting results. We screened a Caucasian population of Italian origin composed of 192 sporadic AD patients and 186 healthy matched controls, for the presence of the RFC-1 c.80G>A polymorphism, and searched for correlation with circulating levels of folate, homocysteine, and vitamin B12. No difference in the distribution of allele and genotype frequencies was observed between AD patients and controls. No correlation was observed among the genotypes generated by the RFC-1 c.80G>A polymorphism and circulating levels of folate, homocysteine, and vitamin B12 either in the whole cohort of subjects or after stratification into clinical subtypes. Present results do not support a role for the RFC-1 c.80G>A polymorphism as independent risk factor for sporadic AD in Italian Caucasians.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "Variations in genes that play key roles in the folic acid cycle have been widely investigated, where single nucleotide polymorphisms (SNPs) have been found to be associated with folic acid and Hcy metabolism. The variants of MTHFR and RFC1 were found to interact with Hcy levels [11] [12], "
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    ABSTRACT: Objective: To investigate the joint effects of the single nucleotide polymorphisms (SNPs) of genes in the folic acid pathway on homocysteine (Hcy) metabolism. Methods: Four hundred women with normal pregnancies were enrolled in this study. SNPs were identified by MassARRAY. Serum folic acid and Hcy concentration were measured. Analysis of variance (ANOVA) and support vector machine (SVM) regressions were used to analyze the joint effects of SNPs on the Hcy level. Results: SNPs of MTHFR (rs1801133 and rs3733965) were significantly associated with maternal serum Hcy level. In the different genotypes of MTHFR (rs1801133), SNPs of RFC1 (rs1051266), TCN2 (rs9606756), BHMT (rs3733890), and CBS (rs234713 and rs2851391) were linked with the Hcy level adjusted for folic acid concentration. The integrated SNPs scores were significantly associated with the residual Hcy concentration (RHC) (r = 0.247). The Hcy level was significantly higher in the group with high SNP scores than that in other groups with SNP scores of less than 0.2 (P = 0.000). Moreover, this difference was even more significant in moderate and high levels of folic acid. Conclusion: SNPs of genes in the folic acid pathway possibly affect the Hcy metabolism in the presence of moderate and high levels of folic acid.
    Full-text · Article · Jan 2014
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    • "Hyperhomocysteinemia and low blood levels of folate have been reported in AD (Anello et al., 2004). Some studies showed that the TT genotype (or the T allele) increases homocysteine levels (particular in folate deficiency state) (Devlin et al., 2006; Martinez et al., 2006). Genotyping of this polymorphism could ensure more accurate diagnosis and help medical practitioners in improving the treatment. "

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