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      The Common Mutations C677T and A1298C in the Human Methylenetetrahydrofolate Reductase Gene Are Associated with Hyperhomocysteinemia and Cardiovascular Disease in Hemodialysis Patients

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          Background: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C have not been evaluated concurrently in patients on hemodialysis. Methods: A cross-sectional study was performed in 120 maintenance HD patients to determine the prevalence of MTHFR C677T and A1298C mutations and their relative association to hyperhomocysteinemia and CVD. Results: Both mutations, the C677T and the A1298C, were highly prevalent in HD patients with allele frequencies of 0.41 and 0.27, respectively. The prevalence of CVD in HD patients was 55% and its significant risk factors included, in descending order, hyperhomocysteinemia, MTHFR C677T mutation, low serum folate levels, diabetes mellitus, hypertension, and double heterozygote state for both MTHFR mutations (677CT/1298AC). MTHFR A1298C mutation alone and gender were not associated with either hyperhomocysteinemia or increased CVD risk, but the HD patients with homozygotes 1298CC and wild alleles 677CC (677CC/1298CC) have significant increase of tHcy (37.7 ± 12) and high prevalence of CVD. Conclusions: Hyperhomocysteinemia, serum folate levels and both C677T and A1298C MTHFR mutations are associated with CVD in HD patients.

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          A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

          Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

            Author and article information

            S. Karger AG
            September 2002
            14 August 2002
            : 92
            : 1
            : 120-126
            aGeriatric Unit and bDepartment of Nephrology and Hypertension, Hebrew University Hadassah Medical Center, Jerusalem, Israel; cDivision of Human Gene Therapy, University of Alabama at Birmingham, Ala., USA
            64485 Nephron 2002;92:120–126
            © 2002 S. Karger AG, Basel

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            Figures: 1, Tables: 3, References: 33, Pages: 7
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