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,4
* Epidemiology Group, Department of Medicine & Therapeutics, University of Aberdeen, UK, Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30341, and ** Rowett Research Institute, Aberdeen, UK
4 To whom correspondence should be addressed. E-mail: j.little{at}abdn.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • colorectal neoplasia • folate • methylenetetrahydrofolate reductase • epidemiology prevention • treatment
With the completion of the Human Genome Project (1), great opportunities exist to investigate the effects of genetic variation of the host on the use and metabolism of nutrients and other food components. The ultimate goals of this investigation are to enable more precise public health advice to be given about dietary intake, use of supplements, and genetic testing. These goals are important for several reasons. First, evidence about the relation between diet and disease may change as different types of evidence accrue, for example, before and after data from large-scale cohort studies of diet and cancer became available (2,3). Investigation of the association between specific diseases and variants of genes coding for enzymes known to be involved in their metabolism is an approach to identifying the effect of specific nutrients or food components and therefore may corroborate data on the relations between nutrients or food components and disease. For example, the gene coding for the 5,10-methelenetetrahydrofolate reductase (MTHFR)5 C677T variant affects the metabolism of folate and, in turn, causes elevated homocysteine levels. The relation between this MTHFR polymorphism and coronary heart disease has been investigated in a number of studies, and in a recent meta-analysis, individuals who were homozygous for the C677T variant were found to have a 16% higher risk of coronary heart disease compared with individuals homozygous for the common variant (4). This finding corroborates evidence suggesting a relation between higher homocysteine levels and ischemic heart disease (5). Second, the extent of change in diet that has been achieved by population-based interventions has in general not been substantial. A better understanding of the effects of variants of genes modulating the effect of nutrients and other food components and gene-nutrient interaction in disease processes may enable the development of interventions, such as more precise dietary recommendations and chemopreventive agents to be applied to the general population, as well as be relevant to possible tailoring of primary prevention (6–8). This work would aid in identifying nutrients or other dietary components to be tested in randomized controlled trials and in determining whether strategies of mass prevention, selective intervention, or a combination would be optimal in terms of public health impact. Third, companies are offering tests for genotypic or phenotypic markers of gene variants influencing nutrient metabolism to consumers either directly or through physicians, nutritionists, and pharmacists (9,10). It is important to enhance the development of the evidence base to be ready to evaluate genetic tests for variation in metabolism of nutrients and other food components that are being developed. Fourth, behavioral interventions may be inadequate to produce preventive effects in groups at high risk of disease. Genetic variation in the metabolism of nutrients (or therapeutic or pharmacologic agents) may, at least in part, account for variation in the toxicity and efficacy of chemotherapy in disease management. Again, improved understanding of gene variants in nutrient metabolism would be relevant to possible tailoring of prevention or therapy. The relation between colon cancer and genetic variation in folate metabolism is an exemplar of these issues.
Colorectal neoplasia and folate
Although the evidence on the possible protective effects of vegetables against colon cancer was considered to be convincing just over 5 y ago (2), the results of recent cohort studies suggest that the relation is complex (11–15). In the recent evaluation by the International Agency for Research on Cancer (3), it was concluded that a higher intake of vegetables probably lowers the risk of cancers of the colon and rectum. Thus, the evidence is considered to be less strong than was previously the case.
Vegetables, particularly green leafy vegetables, are a major source of folate. Most prospective and case-control studies of serum folate, red cell folate, or reported dietary or total folate intake are compatible with inverse associations with colon cancer and adenoma (16). No consistent association exists between rectal cancer and folate intake. Many studies are compatible with a positive association between alcohol intake, which adversely affects folate metabolism (17), and colorectal neoplasia (18).
The evidence about the relation between folate and colon cancer is insufficient to lead to specific public health interventions. One concern about the epidemiologic evidence on folate and colon cancer is the effect of misclassification of intake of folate and folic acid and of confounders. When confounders are measured inaccurately, it follows that the analysis will not properly control for confounding. If both the primary exposure of interest and the confounder are measured inaccurately, it is possible that both sets of errors may be interrelated, so the apparent relationship between exposure and confounder may be quite different from that between the underlying variables (19). In addition, it is difficult to disentangle effects of nutrients whose intakes are highly intercorrelated; people eat foods that are the source of several nutrients, and when they consume supplements, these tend to comprise several vitamins and minerals rather than one specific nutrient.
In theory, the ideal method of identifying the effects of specific nutrients or other food components would be to undertake randomized controlled trials. Clearly, these could only be done for nutrients or food components for which a protective effect was postulated (e.g., folic acid). For chronic diseases such as colon cancer, there are issues about the feasibility of trials for endpoints with a long latent period. As a possible solution to this problem, trials of the effects of interventions on intermediate endpoints such as colorectal adenomas have been proposed. One small trial of the effect of folic acid supplementation on adenoma recurrence has been reported (20); four moderately sized trials of folic acid and adenoma recurrence are ongoing (16). In addition, exposure to a nutritional intervention is likely to be different from exposure to the nutrient in the general population. It is likely that it would be unfeasibly costly as well as time inefficient to conduct randomized controlled trials of all nutrients and food components in relation to a wide range of chronic disease endpoints.
Corroboration of evidence of association between folate and colorectal neoplasia
The investigation of gene-disease associations potentially could offer a level of evidence that approaches that of randomized controlled trials. Because of Mendelian randomization (21,22), an association between a disease and a genotype is unlikely to be due to confounding if the study is designed according to principles of population-based studies (23). In a population-based study of a genotype-disease association, the random assortment of alleles at the time of gamete formation (Mendel's second law) results in a random association between loci in a population and is independent of environmental factors (22). In theory, this random assortment brings about a similar distribution of variants at unlinked genetic loci between individuals with and without disease. This situation is analogous to a randomized controlled trial (provided the trial is of adequate size) in which the random assignment to the intervention or placebo results in similar distributions of confounders (both measured and unmeasured) between the trial arms. For genes known to modulate the effects of environmental exposure, genetic variants with known functional effects can be considered as markers of altered exposure to an environmental factor of putative causal importance, such as intake of a specific nutrient. Therefore, the investigation of associations between genes affecting the metabolism of nutrients and other food components potentially enables the effect of the nutrients and food components themselves to be determined, excluding confounding as an explanation for the association. In addition, the investigation of gene-disease associations differs from the investigation of nutrient-disease associations in that the assessment of genotypes by DNA assays (polymerase chain reaction methods) is more accurate than is generally the case for assessment of diet and depends less heavily on study design. Although this is a promising approach to determining the effects of specific nutrients, at least five issues need to be considered: knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction.
Gene function. We now consider the application of this strategy to colon cancer and folate. First, what genes may influence folate metabolism, and what is known about the effects of variants of these genes on the metabolism of folate and related nutrients? At least 30 genetic loci have been identified as related to folate metabolism, contributing to folate mediated 1-carbon transfer reactions or the binding, transport, and metabolism of folate (24). In addition, folate metabolism is closely interlinked with that of cobalamin, with 15 genetic loci identified as cobalamin related, and pyridoxine, with a further eight loci involved in pyridoxine metabolism (24). Of the five polymorphic genes investigated in relation to colon cancer—MTHFR, and the genes coding for thymidylate synthase (TS), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS) (16)—MTHFR is the most studied. Even for a well-studied gene such as MTHFR, information on the functional effects of the variants on enzyme activity is relatively limited. For the most common variants, C677T and A1298C, the few papers on enzyme activity in vitro have reported decreased activity (25–27). Nondiseased persons homozygous for the C677T variant have lower red cell folate, plasma folate, and vitamin B-12 and higher homocysteine levels than do persons with other genotypes (28–30). The relationship between homozygosity for the A1298C variant and plasma folate and homocysteine levels is inconsistent (27,31–34). Because the C677T variant is associated with a reduced enzyme activity in vitro and low red cell and plasma folate, and because various measures of high folate status are associated with reduced risk for colorectal neoplasia, it might have been expected that the variant would be associated with an increased risk for colorectal cancer. However, several studies found a reduced risk of colorectal cancer in subjects homozygous for the C677T variant compared with those homozygous for the common variant (Fig. 1).
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Linkage disequilibrium
The concept of Mendelian randomization is predicated on a lack of effect of linkage disequilibrium (alleles at nearby loci preferentially associated with the alleles of interest). Empirical studies in humans suggest that variation in linkage disequilibrium at all distances is great and is not predictable from one region of the genome to another (41). Studies of microsatellite polymorphisms have shown linkage disequilibrium between a few loci that are separated by many megabases (
1 cM) (42). In addition, uncertainty exists about whether patterns are similar between populations. For example, for the MTHFR C677T and A1298C variants, individuals with more than two variant alleles have not been observed in most series, but there may be an increased frequency of MTHFR alleles with both variants in some parts of Canada and the United Kingdom (43). Differences in patterns of linkage disequilibrium between populations may in part account for the variable study results of gene-disease associations (44). In five of the six studies of the MTHFR A1298C polymorphism and colorectal cancer, the risk was modestly reduced in those homozygous for the A1298C variant compared with those homozygous for the common variant (Fig. 2). Because this is similar to the pattern observed for C677T, it raises the possibility that the relation between A1298C and colorectal cancer is actually due to C677T. However, this does not appear to be the case in any of the studies in which there was an inverse association with homozygosity for the A1298C variant (34,45–48) or in the study in which there was a suggestion of a positive association (49). Nevertheless, in general, care is needed when making inferences in view of the current lack of knowledge about linkage disequilibrium patterns.
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Concern has been raised about the possible effects of population stratification on the results of population-based case-control studies (50–52). Population stratification includes differences between groups in ethnic origin; it can also arise because of differences between groups of similar ethnic origin but between which there has been limited admixture, such as in isolated populations. On the basis of work on the non-Hispanic white population of the United States and in Europe, this bias does not appear to be substantial when epidemiologic principles of study design, conduct, and analysis are rigorously applied (53,54). However, this finding may not apply to all genes and all populations (54).
Study size and quality
In contrast to the theoretical promise of Mendelian randomization, many recent commentaries have highlighted the nonreplication of association study results (44,55–57). Davey Smith and Ebrahim (22) noted that the major factor accounting for nonreplication of study results is likely to be inadequate statistical power coupled with publication bias. In relation to homozygosity for the MTHFR C677T variant and colorectal cancer, it is noteworthy that an inverse association was less likely to be found when the study was small (Fig. 1). The issue of lack of statistical power is analogous to the experience with randomized controlled trials, where evidence from small-scale trials has not been confirmed in subsequent larger trials (58). Publication bias is one explanation for this phenomenon, but the distribution of confounders also may have differed between trial arms in smaller trials. Another important issue is adherence to principles of population-based studies in study design. Differences in the extent to which these principles are followed may contribute to inconsistencies in study results. In some of the studies of the MTHFR polymorphisms and colorectal neoplasia, it is not clear whether the controls came from the population that gave rise to the cases, thus bias is possible (59). Few reports provided information on participation rates, making it difficult to assess potential biases and external generalizability of the results (16). In the nonprospective studies, the case series were limited to those who were still alive to provide a DNA sample. If any of the polymorphisms were associated with survival, this may have biased the results. In addition, differences in genotyping accuracy may contribute to nonreplication of study results (60). In two of the studies, the types of samples from which DNA was extracted differed between cases and controls (61,62); this may have introduced a systematic difference in genotyping quality. As has been the case with trials, more consistent associations will be likely to be observed as the investigation of gene-disease associations matures (i.e., moves from small innovative studies to large well-designed studies in which potential biases are minimized). It is of key importance to make the scientific record as complete as possible (63), and this will be facilitated by initiatives such as the Human Genome Epidemiology Network (64).
Gene-environment interaction
The absence of a gene-disease association in an epidemiologic study may not exclude the possibility of different effects of genotype (or the nutrient) in subgroups (i.e., gene-environment interaction) (65,66). For example, the evidence overall suggests no association between homozygosity for the C677T variant and colorectal adenoma (Fig. 3). However, in the only two studies to investigate gene-diet interactions and adenomas, the stratum of highest risk comprised TT individuals who had the lowest red cell or plasma folate levels (67) or lowest intakes of folate, methionine, vitamin B-6, or vitamin B-12 (68), although the gene-nutrient interactions were not statistically significant. More generally, the effect of a gene variant is expected to depend on the context of both environmental factors and other genes. Some inconsistency between the results of gene-disease association studies may be secondary to variation among studies in the prevalence of interacting environmental factors that have not been assessed.
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A further issue is how the environmental factor is classified. For example, in the analyses of the interaction between alcohol and MTHFR genotype, alcohol exposure was classified as ever versus never (46) whereas the other studies considered the amount of alcohol consumed (28, 71). In addition, different methods have been used to assess the statistical significance of gene-environment interactions (69, 72). These differences will contribute to inconsistencies between studies. In view of these challenges, it is perhaps not surprising that possible interaction between MTHFR genotype and folate intake has been investigated in only six of the 14 studies of the C677T variant (28,45–48,71,73), and four of the six studies of the A1298C variant (34,45,46,48). In four studies the inverse association with homozygosity for the C677T variant was not observed (or was weakest) in persons with a low intake of folate (28,45,71,73), but this pattern was not observed in two other studies (46,48). One study of A1298C variant and folate and related nutrients showed a statistically significant interaction whereby those homozygous for the variant allele who had a low folate intake were at reduced risk (46). This was not observed in the other three studies. In regard to possible interaction between MTHFR genotype and alcohol, in two studies in the United States, subjects consuming the largest amounts of alcohol who were homozygous for the C677T variant were at highest cancer risk (28,71) and there was a suggestion of an interaction between amount of alcohol consumed and carriage of this variant in a small study from Japan (47). However, no interaction with alcohol was observed by Keku et al. (46).
Thus, although the challenges of testing hypotheses about interaction are recognized, abandoning attempts to investigate the joint effects of exposure and genotype would be inappropriate. Because of the implications of gene-environment interaction, a high risk intervention approach may have a greater public health effect than a mass prevention strategy. For example, a screen-and-treat strategy was shown to be more cost-effective than universal supplementation in lowering homocysteine by folic acid and vitamin B-12 supplementation (74).
In regard to the context dependence of gene-disease associations, the metabolism of any exposure will likely depend on the balance between the relative activities of all the enzymes active within the metabolic pathway (75). This has not been investigated for the folate pathway. So far, the joint effects of some (but not all) genes influencing folate metabolism have been considered only in two studies of colorectal neoplasia, one of cancer (45) and the other of adenomas (68).
More generally, in the etiology of common chronic diseases, it seems likely that complex pathways in which multiple genes and multiple exposures interact will be involved rather than interaction between a single gene and a single dietary factor (76). The relation between folate and colon cancer is a good example, with the potential involvement of multiple genes influencing the metabolism of folate and related nutrients (including vitamin B-12, vitamin B-6, methionine, and alcohol).
Information on genetic variation in folate metabolism and primary prevention
One possible strategy to prevent colorectal cancer would be to increase folate levels, either by a whole-population approach (as in the United States and Canada) or by targeting persons at higher risk, such as those from whom an adenoma has been removed, those with inflammatory bowel disease, or those with a family history of colorectal neoplasia. Information on genetic variants influencing folate metabolism may be relevant in determining whether a folate intervention should be aimed at everyone in any of the above groups or whether it would be targeted at or tailored to those with particular genotypes. For example, patients who have had an adenoma removed might have their MTHFR genotype determined and then either the folate intervention would be offered only to those with a particular genotype or different levels of folate intake or folic acid supplementation would be suggested according to genotype.
The results of the studies of MTHFR, particularly the inverse association with homozygosity for the C677T variant, have suggested the possibility that folic acid in itself may not be the optimal agent for the chemoprevention of colorectal cancer. Other forms of folate may be more effective (77); preliminary findings in cell lines imply that different coenzymatic forms of folate might affect cellular proliferation in different ways (78). Because this area is at an early stage of development, the reminder of this discussion will relate to a prevention strategy based on folic acid. However, the general issues are relevant to supplementation or fortification with other forms of folate.
Would the effects of raising levels of folate intake in the population (regardless of how this is done) vary by genotypes influencing folate metabolism? Increasing intakes of folate or folic acid increases systemic blood folate concentrations, with natural folates having a smaller effect on serum folate than folic acid (79–81). Folate depletion in the colorectal mucosa may predispose the mucosa to malignant transformation in humans (82). A small study suggests that supplemental folic acid intake can increase colonic mucosal concentration (83).
A few studies have reported on the effects of folic acid supplementation by the MTHFR C677T genotype (84–88). Some tentatively suggest that folate supplementation can result in a greater increase in plasma and possibly red cell folate concentrations in persons homozygous for the C677T variant than for those with other genotypes. These observations should be viewed with caution because the studies were small, had some methodological flaws, and were of limited generalizability. A1298C genotype combined C677T/A1298C genotype, baseline folate status, and use of multivitamins during the supplementation period also may be relevant.
Little direct evidence exists as to whether increasing folate intake through diet, fortification, or supplementation influences the rates of formation of adenomas or carcinomas in any population or subgroup. Whether incorporating MTHFR genotyping would improve efficacy, or effectiveness, of such interventions also is unclear. The data on interaction between folate intake and MTHFR variants suggest that the effect of a low folate diet overrides the effect of genotype, but this is based on a limited number of observational studies and is not entirely consistent. Moreover, two studies of adenomas suggested the opposite. A further concern is the cost-benefit ratio of genotyping in this context. Vineis et al. (89) noted that in screening for single low penetrance gene variants, the number needed to screen to prevent one case of cancer often will be large. This implies that few people screened will benefit, and a large number of screening results will be false-positive, which has consequences both for health services (in terms of costs and resources) and for persons (in terms of psychosocial impact, unnecessary treatment, and possibly costs). However, Yang et al. (90) showed that evaluating multiple genetic loci that are involved in disease etiology could increase the predictive value of genetic susceptibility to common disease, especially in the presence of relevant exposures.
Potential adverse effects of folic acid supplementation have been discussed. In people with vitamin B-12 deficiency, high levels of folate intake can reverse the anemia associated with the deficiency but may precipitate neurologic complications, but no data exist on how commonly this may occur in a supplemented population (91) and concern about this potential adverse effect may have been overstated (92). To prevent vitamin B-12 deficiencies a staple food could be fortified with high levels of B-12 (
1 mg/d) but the effects of this in combination with folic acid supplementation are not known (93). There has been concern that folic acid supplementation would interfere with zinc absorption (94) but supplementation now does not appear to affect zinc status in humans (95). Folic acid supplementation in patients with advanced malignancy is thought to increase malignant cell turnover but is not thought to affect the efficiency of antifolate chemotherapeutic agents (96). High levels of folate interfere with metabolism of antiepileptic drugs, and this clinical group would be of concern in any colorectal neoplasia prevention strategy. In general, the potential harms of vitamin supplementation have not been well quantified (97).
Large randomized controlled trials of folate supplementation for the prevention of colorectal neoplasia (and other outcomes), including stratification by genotypes influencing folate metabolism, would be a major contribution to the evidence base. Results are awaited from four moderately sized trials of folic acid supplements and adenoma recurrence, three in the United States and one in Europe (16). Other trials are necessary, particularly in populations with different gene frequencies and baseline levels of folate intake. Because current evidence does not indicate what level of folate supplementation may be required—and this may differ by population—a range of levels should be considered (in the polyp recurrence trials currently underway, supplemental doses of 0.5–5 mg/d are being investigated). The addition of vitamin B-12 and related nutrients also should be considered. It would be appropriate to consider forms of folate other than folic acid. In view of previous debate about the value of polyp recurrence as a model for the prevention of colorectal cancer, it would be useful to consider implementing trials in other high risk groups such as persons with inflammatory bowel disease or with family histories of colorectal neoplasia. Both effectiveness and cost-effectiveness would need to be assessed with a particular focus on the value of testing for polymorphisms influencing folate metabolism. Further considerations include the psychosocial impact and acceptability of genotyping in the populations studied and the relation of such a chemopreventive strategy to existing programs or services for early detection of colorectal lesions (16).
MTHFR, alcohol, and primary prevention
The limited epidemiologic data suggest that consumption of excess amounts of alcohol may be particularly inadvisable for persons homozygous for the C677T variant in terms of the risk of developing an adenoma or carcinoma. Therefore, in theory another public health approach might be to consider screening for genotype as part of a health promotion program aimed at restricting alcohol intake, such as those in place in the United Kingdom and the United States. However, because of the diverse health effects of alcohol consumption, a strategy based solely on the consideration of colorectal cancer prevention would not be of practical value.
Information on genetic variation in folate metabolism and management of colorectal cancer
The final group in whom knowledge of genetic variation in folate metabolism could potentially be used to improve health outcomes is persons diagnosed with colorectal cancer. 5-Fluorouracil (5-FU), commonly used in colorectal cancer chemotherapy, is a thymidylate synthase inhibitor and can cause severe folate depletion. For that reason, patients undergoing chemotherapy may be given folic acid supplements. Toxic effects of treatment are common. Knowledge of patient genotype potentially could be used to tailor chemotherapy regimes to avoid folate depletion and minimize toxicity and side effects, thus improving quality of life, and to increase the effectiveness of treatment and ultimately lengthen survival. The available evidence in this area relates to the MTHFR C677T variant and the TS tandem repeat.
One study attempted to address whether the effectiveness of treatment with 5-FU and leucovorin (folinic acid) was lower in MTHFR C677T homozygotes than in patients with other genotypes (98). In 51 patients with stage III colon cancer, presence of the T allele appeared to have little effect on probability of death or length of survival in those who had died; the analysis was not, however, adjusted for other prognostic indicators. Shannon et al. (99) reported that homozygosity for the MTHFR C677T variant was associated with improved survival in 365 nonadjuvant treated patients (hazard ratio = 0.77, 95% CI 0.6–0.99), but this association did not persist after adjustment for stage. In a study of 43 patients with metastatic colorectal cancer, the presence of the MTHFR C677T allele was associated with a higher complete or partial response to 5-FU or other fluoropyrimidines (100). The MTHFR genotype modifies responses of bone marrow transplantation patients to methotrexate, another antifolate chemotherapy agent; persons homozygous for the MTHFR C677T variant appeared to be at higher risk for toxicity (101). In a small study of breast cancer patients being treated with a regimen of fluorouracil, methotrexate, and cyclophosphamide, five of six patients developing severe acute toxicity were homozygous for the MTHFR C677T variant (102).
With regard to TS, one study of genotype in colorectal cancer patients suggested that presence of the 3rpt allele may increase risk of death (103). Studies of the relation between TS genotype and response to 5-FU suggest that patients with the 2rpt/2rpt genotype may be more responsive to 5-FU therapy but subject to greater toxicity (104–107). Most of the studies were small, included selected patient groups, and made limited adjustment for potentially important factors.
The bottom line
The observed association of the MTHFR homozygous variant genotypes with reduced risk of carcinoma was the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and MTHFR in DNA synthesis. The lack of association between MTHFR and adenoma suggests that folate and related nutrients may be important after adenoma formation. The results of the studies of MTHFR and colorectal cancer suggest that folic acid per se may not be the best agent for prevention of colorectal cancer and that it is important to consider other outcomes relating to the status of folate and related nutrients. The evidence is compatible with interactions between MTHFR genotype and folate, alcohol, or related nutrients in relation to risk for colorectal neoplasia, although problems exist likely because of misclassification of folate intake, statistical power, analytic approaches, and lack of consideration of variants of other genes that influence folate metabolism. The evidence is not strong enough to advocate population testing for MTHFR variants or those of other polymorphic genes influencing folate metabolism investigated so far (MTR, MTRR, TS, and CBS). Investigation of the role of polymorphisms influencing folate metabolism in treatment appears to be a promising area for further research.
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FOOTNOTES |
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2 This work was supported in part by the National Hospitals Trust and the Boyd Orr Research Foundation.
3 Funded by the Scottish Executive Environment and Rural Affairs Department (SEERAD) and by the World Cancer Research Fund (WCRF).
5 Abbreviations used: 5-FU, 5-fluorouracil; A1298C, adenine-to-cytosine transition at position 1298; C677T, cytosine-to-thymidine transition at position 677; CBS, gene coding for cystathionine ß-synthase; MTHFR, gene coding for 5,10-methelenetetrahydrofolate reductase; MTR, gene coding for methionine synthase; MTRR, gene coding for methionine synthase reductase; TS, gene coding for thymidylate synthase.
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