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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Pharmacology and Center
for Pharmacogenetics, University of Pennsylvania School of Medicine,
Philadelphia, PA; the Cardiovascular Research Centre, Queen's
University Belfast, Belfast, Northern Ireland; the Northern Ireland
Centre for Diet and Health, University of Ulster, Coleraine, Northern
Ireland; and the Department of Clinical Medicine, Trinity College,
Dublin, Ireland.
A modestly elevated total plasma homocysteine
concentration (tHcy) is generally accepted as an independent and graded
risk factor for various pathologies, including vascular diseases,
neural tube defects, Alzheimer disease, and pregnancy complications. We
analyzed 5 common functional polymorphisms in enzymes involved in
homocysteine metabolism (ie,
methylenetetrahydrofolate reductase [MTHFR] 677C>T and
1298A>C, methionine synthase [MTR] 2756A>G, cystathionine
Homocysteine, a branch-point intermediate in the
metabolism of the essential amino acid methionine, is a product of
important transmethylation reactions that utilize S-adenosylmethionine
(AdoMet) as a methyl donor (Figure 1).
Once formed, homocysteine can be used to regenerate AdoMet, or can be
catabolized to form the amino acid cysteine.
McCully postulated, 3 decades ago, that the clinical
manifestation of vascular disease in 2 patients with different inborn errors of methionine metabolism was attributable to the effects of very
high levels of total plasma homocysteine (tHcy), as severe hyperhomocysteinemia was the most prominent shared feature of the
clinical phenotype.1 In recent years, many, though not all, prospective and retrospective studies have supported the association of mild hyperhomocysteinemia with an increased risk of
cardiovascular diseases (CVDs).2 Meta-analysis of the
available studies suggests that the risk is graded and independent of
established CVD risk factors.3 Hyperhomocysteinemia has
also been linked to an increased risk of neural tube
defects,4 Alzheimer disease,5 pregnancy
complications,6 and inflammatory bowel
disease.7
The etiology of hyperhomocysteinemia is considered to be
multifactorial, and includes genetic, nutritional, and lifestyle factors,2 and there is an ongoing debate regarding the
relative contribution of each. The cDNAs of cystathionine Most studies to date have assessed the effects of only a single
polymorphism on tHcy levels, and have focused mainly on middle-aged or
elderly individuals (ie, those who are old enough for diseases of aging
to manifest). However, genetic effects are often more prominent in the
young, as cumulative environmental factors have not had the time to
substantially modify phenotype. We therefore undertook the current
population-based study of young subjects aged 20 to 25 years, to
investigate the genetic contribution to hyperhomocysteinemia in a
relatively naive population. We analyzed the independent and
interactive effects of various functional polymorphisms on tHcy levels
and assessed potential interactions with the most relevant nutritional
variables, serum and red cell folate (RCF), and vitamin B12 status.
Study subjects
There were 250 males (49.7% of the male members of the
cohort) and 239 females (46.7% of the original female members) who participated in YH3. As an indicator of socioeconomic position of the
subjects, information about the occupation of the main breadwinner in the family was collected, and categorized using the
Standard Occupational Classification of the Office of Population Consensus and Surveys Statistics (OPCS). The 6 categories
(professional occupations; managerial and technical occupations;
skilled nonmanual occupations; skilled manual occupations; partly
skilled occupations; and unskilled occupations) were dichotomized into
a nonmanual (upper 3 classes) and manual (lower 3 classes) social
class.23 Response rates were higher in nonmanual social
classes compared with manual social classes: of the subjects who
attended YH3, 52.7% (n = 228) were from nonmanual social class
defined at YH1, and 47.3% (n = 205) were from manual social classes
( Biochemical parameters
DNA extraction and genetic analyses Genomic DNA was isolated from peripheral blood leukocytes using an established method.26 All polymorphic variants, except for the 844ins68 variant in the CBS gene, were analyzed using heteroduplex generator (HG) techniques. Briefly, this technology is an adaptation of single-stranded conformation polymorphism analysis, in which each DNA segment that contains the polymorphic nucleotide being tested is coamplified with a synthetic constructed HG. An HG is identical to the genomic DNA segment except for a microdeletion close to the polymorphic site. Denaturation of the DNA strands and subsequent reannealing lead to the formation of homoduplexes of both genomic and HG origin and heteroduplexes comprising mixed hybrids of genomic and HG DNA. The presence or absence of the polymorphic variant leads to the formation of heteroduplexes with distinct protruding loops that mandate different migration properties in polyacrylamide gel electrophoresis. We have developed a multiplex genotyping system, that allows simultaneous genotyping of the MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, and CBS 844ins68 variants in a single tube.27 In addition, a similar HG assay was developed for analysis of the MTRR 66A>G transition.19,20 The duplexes were separated in 12% polyacrylamide/5% glycerol gels at 150 V for 12 to 16 hours, and visualized by ethidium bromide staining and ultraviolet (UV) illumination.Statistical analyses The distributions of tHcy, vitamin B12, RCF, and serum folate concentrations were all skewed; therefore, data were logarithmically transformed prior to all statistical analyses. Differences in the above biochemical and nutritional variables among different genotype subgroups were assessed by one-way analysis of variance (ANOVA) followed by pair-wise t tests, corrected for multiple comparisons (Bonferroni). Differences in genotype frequencies among different tHcy strata, and deviations from Hardy-Weinberg equilibrium were assessed by 2 analysis.
Odds ratios (OR) and 95% confidence intervals (95% CIs) were
calculated using logistic regression analysis. Bivariate correlations
were estimated using the Pearson correlation test. Gene-gene, and
gene-environment interactions were assessed using 2-way ANOVA, which
allowed the assessment of any interaction effect over and above the
main effects of the independent factors in the model. The relative
contribution of the factors to the variability in tHcy levels was
calculated from the adjusted R2 estimate in the
model being tested. All statistical analyses were performed using SPSS
for Windows version 9.0 (Statistical Product and Service Solutions,
Chicago, IL), and statistical significance was accepted for a 2-tailed
P < .05.
Characteristics of the study group The study group consists of 250 (51.1%) males and 239 (48.9%) females. The median (range) tHcy, serum folate, RCF, and vitamin B12 concentrations in males and females are presented in Table 1. Despite statistically significantly poorer RCF and vitamin B12 status (P < .001 for each variable), females had tHcy levels similar to those of males. Serum folate levels were also similar in both sexes. Geometric mean tHcy levels were similar in women who used hormonal contraception (ie, pill, minipill, and contraceptive injections) versus those who used other measures or no contraception (tHcy, 9.4 µM vs 8.8 µM; P = .23). Alcohol intake had no significant effect on tHcy levels (geometric mean, 9.5 µM in users vs 8.8 µM in nonusers; P = .11), nor on folate levels (geometric mean, 13.6 nM in both groups; P = .96).
Plasma creatinine levels were only weakly, but positively, associated with tHcy levels (r = 0.134, P < .01) in the overall study group, an association that was sex dependent (in females, r = 0.155, P = .04; in males, r = 0.084, P = .21). Genotyping Genotypes were obtained from 452 study subjects. The frequencies of the MTHFR 677TT, MTHFR 1298CC, MTR 2756GG, CBS 844ins68 WI, and MTRR 66GG genotypes were, respectively, 13.5%, 10.6%, 2.0%, 17.7%, and 29.6%, comparable with those reported in the literature for each of these genotypes in white populations, including the Northern Ireland population.9,18-20 All genotype distributions were similar in males and females, and were in accordance with Hardy-Weinberg predictions (data not shown).We combined the MTHFR 677C>T and 1298A>C genotypes to
generate composite MTHFR genotypes, which established that
1298C rarely occurs in cis with 677T. In our study group of 452 individuals, only 3 (0.7%) recombinant genotypes were observed: 2 individuals had the 677TT/1298AC genotype, and one had the 677CT/1298CC
genotype. Assuming that there are no double recombinants among those
with the 677CT/1298AC genotypes, the frequencies for the 677C/1298C, 677C/1298A, 677T/1298A, and recombinant 677T/1298C alleles were 31.2%,
33.2%, 35.3% and 0.3%, respectively; these allele frequencies mandate expected composite genotype frequencies that are similar to
those observed ( Associations between genotypes and biochemical variables We assessed the associations between the MTHFR, MTR, MTRR, and CBS genotypes and tHcy, RCF, serum folate, and vitamin B12 (Table 2). These associations were similar in males and females, and both groups were therefore combined. The MTHFR 677C>T genotypes significantly influence tHcy (P < .0005, ANOVA); pair-wise Bonferroni t tests showed that individuals with the MTHFR 677TT genotype have significantly higher tHcy than those with the 677CT and 677CC genotypes (P < .0005 for either comparison). Serum folate levels were also significantly associated with the MTHFR 677C>T genotypes (P = .010, ANOVA); 677TT homozygotes had significantly lower serum folate levels compared with 677CC homozygotes (P < .02), with the levels in 677CT heterozygotes being intermediate. A similar association between MTHFR 677C>T genotypes and RCF was observed: RCF levels were lowest in 677TT homozygotes, highest in 677CC homozygotes, and intermediate in 677CT heterozygotes (P < .03 for all intergenotype comparisons). Furthermore, vitamin B12 levels were significantly lower in those with the MTHFR 677TT genotype than in those with the MTHFR 677CT genotype (P = .02).
The relative risk of being in the top 5%, 10%, 20%, and 50% of the
tHcy distribution for individuals with the MTHFR 677TT genotype versus those with the MTHFR 677CC genotype was
calculated separately for males and females (Table
3). The MTHFR 677TT genotype confers a much higher risk of hyperhomocysteinemia in males than in
females at each of the different, sex-specific tHcy rank cutoff values.
For males, there is a highly significant 4.2-fold risk of being in the
top 50% of the tHcy distribution (ie, tHcy > 9.2 µM) for 677TT
homozygotes relative to 677CC homozygotes (P < .005), a
risk that increases to more than 40-fold for being in the top 5% of
the distribution (ie, tHcy > 20.8 µM). In females, the
corresponding risk estimates increase from 2.4 (top 50%; tHcy > 8.6
µM) to 7.1 (top 5%; tHcy > 17.9 µM). The risk that the
MTHFR 677TT genotype will lead to a potentially pathogenic
Hcy phenotype is therefore much more extreme in males than in females.
We also assessed the effect of the composite MTHFR genotypes
on tHcy; individuals with the 677TT/1298AA genotype have the highest
tHcy concentrations, significantly higher than those of all others with
nonrecombinant genotypes. In contrast to an earlier report,28 tHcy levels in MTHFR 677CT/1298AC
compound heterozygotes (median [range], 8.7 µM [4.4 Interaction analysis Serum folate and vitamin B12 concentrations were both inversely related to tHcy in this study population (r = 0.481 and r = 0.369, respectively;
P < .01 for both correlations); in addition, their levels
were dependent on MTHFR 677C>T genotypes. We therefore assessed the potential interaction between serum folate and vitamin B12 status and the MTHFR genotypes. In each
quartile of the folate distribution, we plotted the mean tHcy
concentration per MTHFR 677C>T genotype. Figure
2A shows that the influence of the
MTHFR 677TT genotype on tHcy levels is confined to the
lowest folate quartile; in contrast to the top 3 quartiles of the
folate distribution, MTHFR 677TT homozygotes in the lowest
quartile (n = 17) have significantly higher tHcy (median, 17.3 µM)
than their 677CT (n = 42) and 677CC (n = 30) peers (median tHcy,
10.7 and 10.9 µM, respectively; P < .01). Subdivision
by sex of the 17 MTHFR 677TT individuals in the lowest
folate quartile confirmed a divergent impact of this genotype on tHcy
concentration in males and females; that is, 6 of 7 MTHFR
677TT males, but only 2 of 10 MTHFR 677TT females (both
using hormonal contraception) in the lowest folate quartile have a tHcy
of 18.7 µM or higher (95th percentile of entire study group;
2 = 7.1, df = 1, P < .01). Creatinine
levels were within the normal range in these males and females. An
analysis of variance with MTHFR 677TT, folate, sex, and a
sex-MTHFR 677TT interaction term showed a significant
contribution of the sex-genotype interaction (P < .02) on
tHcy variance. Figure 2B shows the association between the composite
MTHFR genotypes and tHcy in each of the folate quartiles. The potentiation of a high tHcy phenotype is restricted to those with
the 677TT/1298AA composite genotype (n = 15; median tHcy, 19.1 µM)
who are in the lowest folate quartile. Interaction analyses between
vitamin B12 and the MTR 2756A>G and
MTRR 66A>G genotypes showed that none of the MTR
or MTRR genotypes modify tHcy levels in a vitamin
B12-dependent manner (data not shown).
The effects of the single genotypes and genotype combinations on the variation in plasma tHcy levels were assessed using 2-way ANOVA, in which the interactive effects can be estimated, over and above the main effects in the model being tested. The overall variance in tHcy levels explained by the genetic factors under consideration was 9%. After inclusion of folate and vitamin B12 concentrations in the model, almost 42% of the variation in tHcy levels could be explained. The latter estimate changed to 45% after inclusion of creatinine in the model.
In the current study, we have determined the genotypes for 5 common functional variants of enzymes involved in homocysteine metabolism (ie, MTHFR, MTR, MTRR, and CBS) and tHcy levels in subjects aged 20 to 25 years. The contribution of these genetic factors and important environmental factors (ie, folate, vitamin B12, and creatinine) to the variability in tHcy concentrations has been estimated. In this young adult population, the only genetic polymorphism that significantly influenced tHcy, serum folate, RCF, and vitamin B12 levels was MTHFR 677C>T. The MTHFR 677TT genotype strongly interacted with low folate levels to produce a high tHcy phenotype, an effect that was more pronounced in males than in females. In previous studies of a male population aged 30 to 49 years from the same geographical region, we found that MTR 2756AA and MTRR 66GG homozygotes had significantly elevated tHcy levels compared with their MTR 2756GG and MTRR 66AA peers, respectively.18-20 In the younger population studied here, however, tHcy concentrations did not differ according to MTRR genotype, and the difference in tHcy levels between the MTR 2756AA, MTR 2756AG, and MTR 2756GG genotypes did not reach statistical significance, although an apparent trend toward higher tHcy levels in MTR 2756AA homozygotes was observed. These results suggest that there may be additional environmental, nutritional, or genetic factors that act cumulatively to potentiate, via the tHcy-raising MTR and MTRR genotypes, a phenotypic effect that becomes more prominent (and significant) over time. There is precedent for such an environmental factor: in middle-aged Australian men, Wang et al demonstrated that smoking interacts with the MTR 2756GG genotype to increase the risk of coronary artery disease to a level greater than that observed in smokers with the other MTR genotypes29; however, as tHcy concentrations were not reported by these investigators, the precise nature of the interaction with respect to biochemical aspects of Hcy metabolism is not clear. In a recent study of subjects ranging in age from 21 to 82 years (mean age, 48.9 years) recruited from the upper midwestern region of the US, Tsai et al30 estimated that only 1.49% of the variability in fasting tHcy was attributable to genetic factors. This is much lower than the estimates that we have calculated for the Northern Ireland population; in men aged 30 to 49, we have calculated that genetic factors account for approximately 7% of the variability in tHcy,18,19 and in the younger population reported here it is somewhat higher at approximately 9%. Taken together, these data suggest that the genetic contribution to a high tHcy phenotype is generally more prominent in early life and that cumulative environmental factors may become more important in modifying phenotype as individuals reach middle age. The results shown in Table 3 also support a more pronounced genetic effect on tHcy levels in young subjects, especially males, as the risk estimates of having a tHcy in the top 5%, 10%, and 20%, conferred by the MTHFR 677TT genotype relative to the MTHFR 677CC genotype (ie, 40.8-, 11.4-, and 6.8-fold, respectively), are all much higher than those observed in the published study of 30 to 49 year old males (ie, 9.7-, 5.7-, and 2.6-fold, respectively).9 Furthermore, in the younger population, we observed interactive effects between the MTHFR 677TT genotype, the MTR 2756AA genotype, and the MTRR 66GG genotype that contribute significantly to the variance in tHcy. In contrast with an earlier observation,16 carriers of the CBS 844ins68 insertion variant had similar tHcy levels as noncarriers. Although the comparison was based on a limited number of individuals, we observed a striking difference in the risk of being hyperhomocysteinemic between MTHFR 677TT males and females. This difference was not dependent on kidney function and may be explained by sex-specific differential interactions between MTHFR 677C>T genotypes and folate. The primary phenotypic effect of being a MTHFR 677TT female is the reduced level of circulating 5-methylTHF, without accompanying strong effects on tHcy levels. In contrast, tHcy concentrations are strongly influenced by the MTHFR 677TT genotype in combination with low folate in males. A similar disparity between the sexes was recently reported in a French study,31 in which tHcy levels differed according to MTHFR 677C>T genotype in men, but not in women. This suggests that there may be fundamental differences in the interactions between nutritional and genetic variables in males and females with respect to elicited biochemical phenotype. In the present study, approximately 35% of the variability in tHcy could be explained by both folate and vitamin B12, confirming our a priori expectations that, as in older subjects, dietary intake of these micronutrients by young adults is centrally important in the control of tHcy levels. According to the definition of hyperhomocysteinemia used in a recent European study32 (ie, a fasting tHcy concentration more than 12 µM), 16.1% (n = 68) of our 20- to 25-year-old subjects are hyperhomocysteinemic. This indicates that 1 in every 6 of those entering the third decade of life already has a tHcy concentration that, in subjects of more advanced age, is strongly associated with a range of pathologies, including CVD, inflammatory bowel disease, and Alzheimer disease.3,5,7 Although conclusive evidence supporting a clinically beneficial effect
of folic acid supplementation on CVD incidence is still lacking, recent
data from clinical trials on intermediate end points showed that
homocysteine-lowering intervention by improving folate and B vitamin
status led to a reduction in the frequency of abnormal exercise
electrocardiography tests33 and restenosis rate after
angioplasty.34 Our data may therefore have implications for governments worldwide that are currently considering new
legislation to introduce mandatory fortification of food with folic
acid, primarily aimed at the prevention of neural tube defects but
recognizing the potential benefits on the incidence of CVD via
homocysteine lowering. In the US such a fortification policy,
introduced in 1998, has proved to be highly effective in reducing the
prevalence of low folate status (< 3 ng/mL In conclusion, the data presented here are consistent with the genetic factors that influence tHcy levels being more prominent in young subjects than in those of more advanced age. Nevertheless, the proportion of the variance in tHcy levels that is attributable to genetic factors is relatively modest. As is the case in the older population, the genetic effect is considerably smaller than that attributable to dietary factors, including folate and vitamin B12. If the outcomes of ongoing intervention trials support a clinically beneficial effect of homocysteine-lowering regimens, our data would suggest that long-term disease prevention benefits may be gained by improving folate and vitamin B12 status in the young, regardless of genetic factors, via the implementation of government mandated food fortification programs.
Submitted August 2, 2001; accepted October 15, 2002.
Supported by National Institutes of Health (NIH) grant HD 39081; European Union Biomed Demonstration Project BMH 4983549, Abbott, Germany; and the British Heart Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alexander S. Whitehead, Department of Pharmacology, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084; e-mail: aswhitehead{at}pharm.med.upenn.edu.
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© 2003 by The American Society of Hematology.
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 T. Yamaji, M. Iwasaki, S. Sasazuki, H. Sakamoto, T. Yoshida, and S. Tsugane Methionine Synthase A2756G Polymorphism Interacts with Alcohol and Folate Intake to Influence the Risk of Colorectal Adenoma Cancer Epidemiol. Biomarkers Prev., January 1, 2009; 18(1): 267 - 274. [Abstract] [Full Text] [PDF]
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 Q.-H. Yang, L. D Botto, M. Gallagher, J. Friedman, C. L Sanders, D. Koontz, S. Nikolova, J D. Erickson, and K. Steinberg Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank Am. J. Clinical Nutrition, July 1, 2008; 88(1): 232 - 246. [Abstract] [Full Text] [PDF]
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C. M. Ulrich, M. Neuhouser, A. Y. Liu, A. Boynton, J. F. Gregory III, B. Shane, S. J. James, M. C. Reed, and H. F. Nijhout Mathematical Modeling of Folate Metabolism: Predicted Effects of Genetic Polymorphisms on Mechanisms and Biomarkers Relevant to Carcinogenesis Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1822 - 1831. [Abstract] [Full Text] [PDF]
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 I.M. van Beynum, M. den Heijer, H.J. Blom, and L. Kapusta The MTHFR 677C->T polymorphism and the risk of congenital heart defects: a literature review and meta-analysis QJM, December 1, 2007; 100(12): 743 - 753. [Abstract] [Full Text] [PDF]
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A. Siva, M. De Lange, D. Clayton, S. Monteith, T. Spector, and M.J. Brown The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway QJM, August 1, 2007; 100(8): 495 - 499. [Abstract] [Full Text] [PDF]
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L. Bathum, I. Petersen, L. Christiansen, A. Konieczna, T. I.A. Sorensen, and K. O. Kyvik Genetic and Environmental Influences on Plasma Homocysteine: Results from a Danish Twin Study Clin. Chem., May 1, 2007; 53(5): 971 - 979. [Abstract] [Full Text] [PDF]
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 M. A. Guzman, M. A. Navarro, R. Carnicer, A. J. Sarria, S. Acin, C. Arnal, P. Muniesa, J. C. Surra, J. M. Arbones-Mainar, N. Maeda, et al. Cystathionine {beta}-synthase is essential for female reproductive function Hum. Mol. Genet., November 1, 2006; 15(21): 3168 - 3176. [Abstract] [Full Text] [PDF]
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 M. C. Reed, H. F. Nijhout, M. L. Neuhouser, J. F. Gregory III, B. Shane, S. J. James, A. Boynton, and C. M. Ulrich A Mathematical Model Gives Insights into Nutritional and Genetic Aspects of Folate-Mediated One-Carbon Metabolism J. Nutr., October 1, 2006; 136(10): 2653 - 2661. [Abstract] [Full Text] [PDF]
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I. J. Kullo, K. Ding, E. Boerwinkle, S. T. Turner, T. H. Mosley Jr, S. L.R. Kardia, and M. de Andrade Novel Genomic Loci Influencing Plasma Homocysteine Levels Stroke, July 1, 2006; 37(7): 1703 - 1709. [Abstract] [Full Text] [PDF]
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P. L Lutsey, L. M Steffen, H. A Feldman, D. H Hoelscher, L. S Webber, R. V Luepker, L. A Lytle, M. Zive, and S. K Osganian Serum homocysteine is related to food intake in adolescents: the Child and Adolescent Trial for Cardiovascular Health Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1380 - 1386. [Abstract] [Full Text] [PDF]
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B. Beagle, T. L. Yang, J. Hung, E. A. Cogger, D. J. Moriarty, and M. A. Caudill The Glycine N-Methyltransferase (GNMT) 1289 C->T Variant Influences Plasma Total Homocysteine Concentrations in Young Women after Restricting Folate Intake J. Nutr., December 1, 2005; 135(12): 2780 - 2785. [Abstract] [Full Text] [PDF]
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C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]
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I. M van Beynum, M. den Heijer, C. M. Thomas, L. Afman, D. Oppenraay-van Emmerzaal, and H. J Blom Total homocysteine and its predictors in Dutch children Am. J. Clinical Nutrition, May 1, 2005; 81(5): 1110 - 1116. [Abstract] [Full Text] [PDF]
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J. D. Vaughn, L. B. Bailey, K. P. Shelnutt, K. M. v.-C. Dunwoody, D. R. Maneval, S. R. Davis, E. P. Quinlivan, J. F. Gregory III, D. W. Theriaque, and G. P. A. Kauwell Methionine Synthase Reductase 66A->G Polymorphism Is Associated with Increased Plasma Homocysteine Concentration When Combined with the Homozygous Methylenetetrahydrofolate Reductase 677C->T Variant J. Nutr., November 1, 2004; 134(11): 2985 - 2990. [Abstract] [Full Text] [PDF]
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M. Kimura, K. Umegaki, M. Higuchi, P. Thomas, and M. Fenech Methylenetetrahydrofolate Reductase C677T Polymorphism, Folic Acid and Riboflavin Are Important Determinants of Genome Stability in Cultured Human Lymphocytes J. Nutr., January 1, 2004; 134(1): 48 - 56. [Abstract] [Full Text] [PDF]
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 N. K. Kim, B. O. Choi, W. S. Jung, Y. J. Choi, and K. G. Choi Hyperhomocysteinemia as an independent risk factor for silent brain infarction Neurology, December 9, 2003; 61(11): 1595 - 1599. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-synthase [CBS] 844ins68, and methionine synthase reductase
[MTRR] 66A>G) in 452 young adults, and quantified their independent
and interactive effects on tHcy concentrations. Serum folate, red cell
folate, vitamin B12, and tHcy concentrations were
significantly influenced by MTHFR 677C>T genotypes. A
particularly strong interaction was observed between the
MTHFR 677TT genotype and serum folate, which led to a high
tHcy phenotype that was more pronounced in males. The genetic
contribution to the variance in tHcy was estimated to be
approximately 9%, compared with approximately 35% that could
be attributed to low folate and vitamin B12. Our study
indicates that dietary factors are centrally important in the control
of tHcy levels in young adults with additional, but somewhat weaker,
genetic effects. These data underscore the potential benefits that may
be gained by improving the dietary status of young adults, and provide
support for the implementation of folate/B-vitamin food fortification programs.
(Blood. 2003;101:2483-2488)
7 nM) from 22.0% to
1.7%, and of mild hyperhomocysteinemia (a fasting tHcy > 13 µM)
from 18.9% to 9.8%.