Relation between Plasma Homocysteine Concentration, the 844ins68 Variant of the Cystathionine β-Synthase Gene, and Pyridoxal-5′-Phosphate Concentration

Tsai, Michael Y.; Yang, Feng; Bignell, Michelle; Aras, Ömer; Hanson, Naomi Q.

doi:10.1006/mgme.1999.2874

Cited by 49 publications

(31 citation statements)

References 19 publications

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“…The frequencies of the mutated alleles for MTHFR 677C-T and 1298A-C were 44 and 35%, respectively, which were similar to those reported in other Caucasian populations: 35% for MTHFR 677C-T (Frosst et al, 1995;Gudnason et al, 1998) and 30% for MTHFR 1298A-C (van der Put et al, 1998). Allele frequencies for MS 2756A-G and CBS 844ins68 were somewhat higher (40 and 25%, respectively) in the present study compared with 20% (Leclerc et al, 1996) and 8% (Tsai et al, 1999), respectively, reported in other Caucasian populations. Individuals carrying the G allele for the MS 2756A-G genotype had higher genomic DNA methylation status in colonic mucosa, although DNA methylation was slightly higher in heterozygotes (AG) than in those homozygous for the G allele (GG).…”

Section: Discussioncontrasting

confidence: 80%

Influence of folate status on genomic DNA methylation in colonic mucosa of subjects without colorectal adenoma or cancer

et al. 2005

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DNA hypomethylation may increase the risk of colorectal cancer. The main aim of this study was to assess the influence of folate status (serum and erythrocyte folate and plasma homocysteine concentrations) on DNA methylation. Methylenetetrahydrofolate reductase (MTHFR 677C-T and 1298A-C), methionine synthase (MS 2756A-G) and cystathionine synthase (CBS 844ins68) polymorphisms were measured to account for potential confounding effects on folate status and DNA methylation. A total of 68 subjects (33 men and 35 women, 36 -78 years) free from colorectal polyps or cancer were recruited in a cross-sectional study. Tissue biopsies were obtained at colonoscopy for the determination of DNA methylation in colonic mucosa using an in vitro radiolabelled methyl acceptance assay. Serum and erythrocyte folate were inversely correlated with plasma homocysteine (r ¼ À0.573, Po0.001 and r ¼ À0.307, P ¼ 0.01 respectively) and DNA hypomethylation in colonic mucosa (r ¼ À0.311, P ¼ 0.01 and r ¼ À0.356, P ¼ 0.03). After adjusting for gender, age, body mass index, smoking and genotype, there were weak negative associations between serum and erythrocyte folate and colonic DNA hypomethylation (P ¼ 0.07 and P ¼ 0.08, respectively).

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Section: Discussioncontrasting

confidence: 80%

Influence of folate status on genomic DNA methylation in colonic mucosa of subjects without colorectal adenoma or cancer

et al. 2005

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“…Of the controls, 16.6% (N ϭ 97) had two 677C-T alleles, 53.7% (N ϭ 313) had one 677C-T allele, and 29.7% (N ϭ 173) had none. The corresponding distribution among case-subjects was 25.6% (N ϭ 52), 43.8% (N ϭ 89), and 30.6% (N ϭ 62), respectively. These proportions were similar between subjects born in the North and in the South.…”

Section: Resultsmentioning

confidence: 93%

“…19 This allele, however, unlike the 677C-T allele, has been associated with lower, rather than higher, plasma homocysteine levels compared with the wild-type allele. 42,43 The metabolic and clinical effects of the joint genotype (677C-T homozygosity and 844ins68 heterozygosity) are also inconsistent across studies. For example, the joint genotype has been associated with increased plasma homocysteine levels in some studies, 44 whereas in others the 844ins68 allele has been reported to counter the homocysteine-raising effect of the 677C-T allele.…”

Section: Discussionmentioning

confidence: 99%

Spina bifida and folate-related genes: A study of gene-gene interactions

Franchis¹,

Botto

Sebastio³

et al. 2002

Genetics in Medicine

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Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk.Methods: Case-control study, comparing 203 children with spina bifida to 583 controls. Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02-2.38). For the 844ins68 allele of cystathionine-␤-synthase alone, the odds ratio was 0.83 (95% CI, 0.39 -1.64). For the joint genotype, the odds ratio was 3.69 (95% Spina bifida is a common and severe congenital anomaly that yearly affects approximately 1 in 1,000 newborns in Italy 1 and 200,000 newborns or more worldwide. 2,3 Clinical and epidemiologic evidence, such as the variability of occurrence rates by geography, time, socioeconomic status, and ethnicity, and the relatively low recurrence risk within families, suggests that the etiology of spina bifida involves interactions between multiple genetic and environmental factors. 4,5 However, defining these factors and interactions has proven difficult. The protective effect of folic acid on the occurrence of spina bifida 6 -8 suggests that the study of folate metabolism might identify some of the genetic determinants of spina bifida. Several candidate genes have been studied, including 5,10-methylenetetrahydrofolate reductase (MTHFR), cystathionine-␤-synthase (CBS), methionine synthase, and methionine synthase reductase. A pooled analysis suggests that homozygosity for the 677C-T allele of MTHFR in infants is associated with approximately a 70% increased risk for spina bifida. 9 Common mutations of other genes, such as the 844ins68 allele of CBS, 10 have also been described, although their association with spina bifida is still unclear. Limited data are available on potential interactions among alleles of different folate-related genes. In 1997, Ramsbottom and associates 11 from Ireland reported data on the 677C-T allele of MTHFR and the 844ins68 allele of CBS and suggested that they indicated no interaction effects for spina bifida. We suggested that these data were consistent with the presence of interaction, 12 although the original authors thought otherwise. 13 Subsequent studies yielded discordant findings, with one study from Germany reporting no interaction effects 14 and another study from the United States reporting possible evidence for interaction. 15 In this report, which expands findings reported in abstract, 16 we assess the independent and joint effects of these two common alleles (677C-T and 844ins84) on the risk for spina bifida, using data from a large case-control study from Italy. MATERIALS AND METHODS Study populationThe study population comprised 203 children with open spina bifida without other unrelated major malformations (case-subjects) and 583 healthy young adults and newborns (control-subjects). The subjects with spina bifida had been included in another study of MTHFR allelic variants. 17 Of the 203 children with spina bifida, 173 (85%) had my...

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“…20 -22 Although the exact mechanism by which the 844ins68 allele affects CBS function is currently unknown, it may mandate an increase in CBS activity, possibly via up-regulation of the amount of CBS mRNA or though the action of another functional polymorphism with which it is in linkage disequilibrium. 20 Others have reported effects attributable to the 699C4T and 1080C4T polymorphisms; however, these are both silent changes that themselves are unlikely to have a direct effect indicating the possibility of linkage disequilibrium with as yet unknown transcriptional control elements. 15,23 Two reports, a European-wide study 9 and a subsequent study from the United Kingdom, 10 have suggested that the CBS 844ins68 allele may counterbalance the homocysteine-raising effect of the MTHFR 677TT genotype, although these findings were not replicated in a subsequent UK study.…”

Section: Discussionmentioning

confidence: 99%

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

et al. 2008

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A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine b-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C4T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 lmol/l, P ¼ 0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P ¼ 0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals.

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Relation between Plasma Homocysteine Concentration, the 844ins68 Variant of the Cystathionine β-Synthase Gene, and Pyridoxal-5′-Phosphate Concentration

Cited by 49 publications

References 19 publications

Influence of folate status on genomic DNA methylation in colonic mucosa of subjects without colorectal adenoma or cancer

Influence of folate status on genomic DNA methylation in colonic mucosa of subjects without colorectal adenoma or cancer

Spina bifida and folate-related genes: A study of gene-gene interactions

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

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