Linkage disequilibrium of the common mutations 677C &gt; T and 1298A &gt; C of the human methylenetetrahydrofolate reductase gene as proven by the novel polymorphisms 129C &gt; T, 1068C &gt; T

Linnebank, Michael; Homberger, Anja; Nowak‐Göttl, Ulrike; Marquardt, Thorsten; Harms, Erik; Koch, Hans Georg

doi:10.1007/s004310051311

Cited by 20 publications

(22 citation statements)

References 4 publications

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“…Five subjects were homozygous for both MTHFR polymorphisms—an insufficient number to detect an elevation in homocysteine compared with those with the wild-type or heterozygous for both genes ( P > 0.05). Unlike most populations studied previously (38, 39), the MTHFR 677C>T and 1298A>C SNPs did not appear to be in linkage disequilibrium in this population (linkage disequilibrium correlation R = 0.002; HelixTree v6.2.1, Bozeman, MT).…”

Section: Resultscontrasting

confidence: 85%

Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations

DeVos

Chanson

Liu

et al. 2008

The American Journal of Clinical Nutrition

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Background:Folate is an essential nutrient that supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases, including colorectal cancer. Folate status is also inversely related to plasma homocysteine concentrations-a risk factor for cardiovascular disease. Objective: We sought to gain further understanding of the genetic determinants of plasma folate and homocysteine concentrations. Because folate is required for the synthesis of thymidine from uracil, the latter accumulating and being misincorporated into DNA during folate depletion, the DNA uracil content was also measured. Design: Thirteen single nucleotide polymorphisms (SNPs) in genes involved in folate uptake and metabolism, including folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), ␥-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1), were studied in a cohort of 991 individuals. Results: The MTHFR 677TT genotype was associated with increased plasma homocysteine and decreased plasma folate. MTHFR 1298AC and RFC1 intron 5AG polymorphisms were associated with significantly altered plasma homocysteine concentrations. The FOLH1 1561CT SNP was associated with altered plasma folate concentrations. The MTHFR 677TT genotype was associated with a Ȃ34% lower DNA uracil content (P ҃ 0.045), whereas the G allele of the GGH Ҁ124TG SNP was associated with a stepwise increase in DNA uracil content (P ҃ 0.022). Conclusion: Because the accumulation of uracil in DNA induces chromosome breaks, mutagenic lesions, we suggest that, as for MTHFR C677T, the GGH Ҁ124 TG SNP may modulate the risk of carcinogenesis and therefore warrants further attention.

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Section: Resultscontrasting

confidence: 85%

Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations

DeVos

Chanson

Liu

et al. 2008

The American Journal of Clinical Nutrition

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“…Allele frequencies of the control group did not significantly differ from those reported in the literature (Harmon et al, 1999;Linnebank et al, 2000Linnebank et al, , 2001; Table 1). The MS c.2756A4G polymorphism (G-allele) was significantly less frequent in patients than in controls.…”

Section: Resultsmentioning

confidence: 51%

“…Five functional polymorphisms were analysed as previously described: Cystathionin beta-synthase (CBS) c.833T4C (I278 T) and 844ins68 (splice variant), methionine synthase (MS) c.2756A4G (D919G), and methylenetetrahydrofolate reductase (MTHFR) c.677C4T (A222 V) and c.1298A4C (E429A). With the exception of CBS I278 T, these polymorphisms have a high prevalence within the healthy German population with allele frequencies ranging between 0.08 and 0.34 (Harmon et al, 1999;Linnebank et al, 2000Linnebank et al, , 2001.…”

Section: Methodsmentioning

confidence: 99%

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma

et al. 2004

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Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A4G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI 95% : 0.09 -0.74; P ¼ 0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.

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“…Some preliminary investigation of the two SNPs in MTFHR suggests that possession of both polymorphisms confers risk greater than that of either polymorphism alone (Botto and Yang, 2000;Richter et al, 2001;Relton et al, 2004a). More recently, it has been determined that these two SNPs are almost in complete linkage disequilibrium (Stegmann et al, 1999;Linnebank et al, 2000;Chen et al, 2002); homozygosity for both SNPs is undetected at the same loci. Thus, conclusions regarding the effect of the MTHFR A1298C transition on NTD risk are limited.…”

Section: Genes Within the Methionine/homocysteine Metabolic Cyclementioning

confidence: 95%

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Beaudin

Stover

2007

Birth Defects Research Pt C

128

119

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Neural tube defects (NTDs) refer to a cluster of neurodevelopmental conditions associated with failure of neural tube closure during embryonic development. Worldwide prevalence of NTDs ranges from approximately 0.5 to 60 per 10,000 births, with regional and population-specific variation in prevalence. Numerous environmental and genetic influences contribute to NTD etiology; accumulating evidence from population-based studies has demonstrated that folate status is a significant determinant of NTD risk. Folate-mediated one-carbon metabolism (OCM) is essential for de novo nucleotide biosynthesis, methionine biosynthesis, and cellular methylation reactions. Periconceptional maternal supplementation with folic acid can prevent occurrence of NTDs in the general population by up to 70%; currently several countries fortify their food supply with folic acid for the prevention of NTDs. Despite the unambiguous impact of folate status on NTD risk, the mechanism by which folic acid protects against NTDs remains unknown. Identification of the mechanism by which folate status affects neural tube closure will assist in developing more efficacious and better targeted preventative measures. In this review, we summarize current research on the relationship between folate status and NTDs, with an emphasis on linking genetic variation, folate nutriture, and specific metabolic and/or genomic pathways that intersect to determine NTD outcomes.

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Linkage disequilibrium of the common mutations 677C > T and 1298A > C of the human methylenetetrahydrofolate reductase gene as proven by the novel polymorphisms 129C > T, 1068C > T

Cited by 20 publications

References 4 publications

Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations

Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

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