Abstract
Individuals with Down syndrome (DS) present decreased homocysteine (Hcy) concentration, reflecting a functional folate deficiency secondary to overexpression of the cystathionine ss-synthase gene. Since plasma Hcy may be influenced by genetic polymorphisms, we evaluated the influence of C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR), of A2756G polymorphism in the methionine synthase gene (MTR), and of A80G polymorphism in the reduced folate carrier 1 gene on Hcy concentrations in Brazilian DS patients. Fifty-six individuals with free trisomy 21 were included in the study. Plasma Hcy concentrations were measured by liquid chromatography_tandem mass spectrometry with linear regression coefficient r(2) = 0.9996, average recovery between 92.3 to 108.3% and quantification limits of 1.0 micromol/L. Hcy concentrations >15 micromol/L were considered to characterize hyperhomocystinemia. Genotyping for the polymorphisms was carried out by polymerase chain reaction followed by enzyme digestion and allele-specific polymerase chain reaction. The mean Hcy concentration was 5.2 +/- 3.3 micromol/L. There was no correlation between Hcy concentrations and age, gender or MTHFR C677T, A1298C and reduced folate carrier 1 A80G genotype. However, Hcy concentrations were significantly increased in the MTR 2756AG heterozygous genotype compared to the MTR 2756AA wild-type genotype. The present results suggest that the heterozygous genotype MTR 2756AG is associated with the increase in plasma Hcy concentrations in this group of Brazilian patients with DS.
Highlights
Down syndrome (DS), or trisomy 21, results from the gene expression of an extra chromosome 21, which occurs in most cases due to the failure of normal chromosomal segregation during maternal meiosis [1]
The allele distribution of the polymorphisms was in Hardy-Weinberg equilibrium (χ2 = 0.41; d.f. = 1; P = 0.521 for methylenetetrahydrofolate reductase (MTHFR) C677T; χ2 = 3.71; d.f. = 1; P = 0.054 for MTHFR A1298C; χ2 = 1.22; d.f. = 1; P = 0.269 for MTR A2756G)
The MTHFR C677T and A1298C haplotype frequencies inferred by the Phase program were 0.4116 for C-A, 0.2134 for C-C, 0.3742 for T-A, and 0.0008 for T-C
Summary
Down syndrome (DS), or trisomy 21, results from the gene expression of an extra chromosome 21, which occurs in most cases due to the failure of normal chromosomal segregation during maternal meiosis [1]. Individuals with DS present decreased homocysteine (Hcy) concentrations [2]. Hcy is an amino acid formed during folate metabolism. Braz J Med Biol Res 41(1) 2008 www.bjournal.com.br centration observed in individuals with DS is consistent with the location of the CßS gene on chromosome 21 and its overexpression [2] (Figure 1) [4]. Plasma Hcy is influenced by modifiable and non-modifiable factors, such as gender, vitamin status and genetic factors [5,6]. The C677T and A1298C polymorphisms of the MTHFR gene are important genetic determinants of Hcy concentrations. The polymorphic alleles result in an enzyme with reduced specific activity [7,8], leading to increased Hcy concentrations [9,10]
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