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Methylenetetrahydrofolate Reductase Polymorphisms: Pharmacogenetic Effects

and .

The MTHFR enzyme is not a primary target of drug therapy. However, the investigation of possible pharmacogenetic effects of MTHFR polymorphisms is an emerging field that is being explored for an increasing number of pharmaceutical compounds and dietary supplements. This chapter reviews the current literature on the pharmacogenetic effects of the MTHFR 677C→T polymorphism in response to various nutrients in homocysteine metabolism and in response to such medications as antifolates, anticonvulsants and some neuropsychotropic drugs.

Unequivocal pharmacogenetic effects of the MTHFR 677 TT genotype have been demonstrated for the response of plasma homocysteine to folate supplementation in humans. However, other effects might be too weak to be reliably detected, particularly in the absence of large-scale studies. This situation is well reflected in the available data that often present conflicting results and that, in many cases, must be regarded as preliminary until additional studies with larger sample sizes are performed. Nonetheless, this effort is warranted, particularly for therapies with such common medications as the antifolates and the neuropsychotropic drugs.

Introduction

The human phenotype is determined by the genome of the individual, but is heavily influenced by nongenetic interacting factors such as nutrition, behaviour, exposure to microorganisms, and physicochemical environmental conditions. Phenotypic variability in the pathogenesis of disease or in the response to exogenous chemical compounds results, in part, from interindividual variation in gene structure or gene expression. Treating patients of similar disease phenotype with a chemically defined substance often reveals wide interindividual variability in efficacy and toxicity, i.e., in the pharmacokinetics of a compound and in the pharmacodynamic response of the individual to medication. Drug concentrations and kinetics in various body compartments are influenced by genetic variation in the gene products involved in drug transport and metabolism. Furthermore, drug action may be altered by polymorphisms that affect drug targets, either directly (e.g., by variant structure of a drug receptor) or indirectly (e.g., by changing the biochemical conditions required for certain drug effects).

Though it is somewhat arbitrary to distinguish between pharmacogenetics and pharmacogenomics, we follow a recent definition1 that uses the term pharmacogenetics to describe “the differential effects of a drug in vivo in different patients, depending on the presence of inherited gene variants”, whereas pharmacogenomics applies to “differential effects of a number of compounds in vivo or in vitro on gene expression, among the entirety of expressed genes”.1 Pharmacogenetics hence focuses on patient variability and pharmacogenomics on compound variability.

The MTHFR enzyme is not a primary target of drug therapy. However, the exploration of possible pharmacogenetic effects of MTHFR polymorphisms is a new field that is challenging many investigators. MTHFR activity controls the distribution of one-carbon units between nucleotide synthesis and the labile methyl pool. Polymorphisms in the MTHFR gene that lead to altered MTHFR activity will change the individual metabolome and could therefore exert a pharmacogenetic effect whenever supplements or drugs (e.g., folic acid, folinic acid, methyltetrahydrofolate, or antimetabolites such as methotrexate or fluoropyrimidines) directly interact with compounds in one-carbon metabolism. Indirect effects of MTHFR polymorphisms may be expected for other drugs whose metabolism is methylation-dependent, e.g., niacin, mercaptopurine or arsenic trioxide. One can imagine an even more indirect effect of MTHFR polymorphisms, through alteration of gene-specific or general DNA methylation, leading to differential gene expression and thereby to a different transcriptome and proteome, which can influence drug response.

A number of drugs known to influence plasma homocysteine concentrations have also been evaluated for a possible pharmacogenetic effect of MTHFR polymorphisms, although there are no clear mechanistic hypotheses as to how they interact with one-carbon metabolism.

The functional consequences of the two main MTHFR genetic variants on the human enzyme have been examined in a recent paper2 and the evidence for clinical and epidemiological consequences is the subject of other chapters in this book. Two recent reviews have specifically addressed the pharmacogenetic aspects.3,4

This chapter reviews the increasing number of reports of pharmacogenetic effects of the MTHFR 677C→T polymorphism and the few available reports on the functionally less significant MTHFR 1298A→C polymorphism.

Pharmacogenetic Effects of MTHFR Variants

The pharmacogenetic effects of the 677C→T polymorphism in the MTHFR gene have been investigated for direct effects on the response of plasma homocysteine levels to supplementation with folate, cobalamin, riboflavin, and betaine. Other direct effects have been evaluated for therapy with methotrexate, either low-dose for rheumatic disease or high-dose for leukemia, for treatment of solid cancers with fluoropyrimidines and for the therapeutic use of anticonvulsants in epileptic patients. Indirect effects have been investigated for anti-Parkinsonian drugs, neuroleptic drugs, hormone replacement therapy, and lipid-lowering drugs. Table 1 provides an overview of compounds that have been explored for possible pharmacogenetic effects of MTHFR polymorphisms. All the data except for those on folate supplementation must still be regarded as preliminary since the number of studies for each agent is limited.

Table 1. Overview of compounds that have been explored for possible pharmacogenetic effects of MTHFR polymorphisms.

Table 1

Overview of compounds that have been explored for possible pharmacogenetic effects of MTHFR polymorphisms.

Direct Effects

MTHFR Polymorphism and Response to Folate Supplementation

The lower circulating total folate concentration in blood of homozygotes for the MTHFR 677T allele, due to decreased methyltetrahydrofolate synthesis, provides a rationale for the evaluation of a pharmacogenetic effect of the MTHFR 677 variant on supplementation with folate. Plasma total homocysteine (tHcy) and folate concentrations serve as endpoints.

Several studies have investigated the responsiveness of tHcy to high intake of dietary folate or to supplementation with folic acid. Some recent studies elegantly summarize and extend the findings of earlier investigators.

A recent cross-sectional population-based study of 2051 Dutch5 found significantly lower serum folate associated with the 677CT and 677TT genotypes among individuals with self-reported low folate intake. The 677TT genotype even conferred lower serum folate on individuals with high folate intake compared to other genotype groups. As expected, individuals with the 677TT genotype had elevated tHcy only when folate status was low.

Three dietary intervention studies with randomized controlled design studied the influence of the MTHFR polymorphism on folate effects measured as changes in tHcy.6-8 More than 40 healthy individuals of each genotype completed 3 dietary interventions, each of 4 months duration, with a low-folate diet, a folate-rich diet, and a low-folate diet supplemented with 0.4mg folic acid. Individuals with the 677TT genotype had consistently higher tHcy and lower folate than those with the 677CC genotype throughout the study.6 Women carrying the 677TT genotype had a more pronounced drop in tHcy and a bigger increase in serum folate concentrations than those with the 677CC or 677CT genotype after switching from a low-folate to a high-folate diet8 or after supplementation with either folic acid or methyltetrahydrofolate.7 Both latter studies showed a higher requirement for folate in subjects with the 677TT genotype, presumably due to decreased formation of methyltetrahydrofolate, and provided a clear pharmacogenetic effect of the MTHFR 677 polymorphism on the response to folate supplementation.

MTHFR Polymorphism and Response to Cobalamin Supplementation

Folate and cobalamin metabolism are linked through the vitamin B12-dependent remethylation of homocysteine to methionine by methionine synthase; 5-methyltetrahydrofolate, generated by MTHFR, is the methyl donor for this reaction.

Two relatively small studies have reported the association of low cobalamin with hyperhomocysteinemia in homozygotes for the MTHFR 677T allele>9,10 and one study in homozygotes for the MTHFR 1298C allele,10 compared to the MTHFR wild type genotype. The pathophysiological basis of this interaction, however, is not clear. In a small cohort of hyperhomocysteinemic patients undergoing hemodialysis, no significant effect of cobalamin supplementation on tHcy was observed in any of the MTHFR 677 genotype groups.11 In contrast, in a similar study, patients responded to cobalamin supplementation and the decrease of tHcy was most pronounced in those with the MTHFR 677TT genotype.12

MTHFR Polymorphism and Response to Riboflavin Supplementation

Riboflavin is the precursor of flavin adenine dinucleotide (FAD), the cofactor of MTHFR which binds and stabilizes the enzyme. The enzyme product of the MTHFR 677T allele loses its FAD cofactor faster than the wild type enzyme,2 and FAD has been shown to stabilize both the wild type and mutant enzymes.13 Low cytosolic FAD may therefore contribute to the functional impairment of the thermolabile MTHFR 677T variant and increase the tHcy elevation, particularly in individuals with low-folate status. An effect of riboflavin supplementation would be expected in the latter group. Four studies have reported an association of low riboflavin status with elevated tHcy,14-17 and three of them have confirmed the interaction between the MTHFR 677TT genotype and riboflavin status.14-16 One recent preliminary report describes a statistically significant homocysteine-lowering effect of riboflavin supplementation in individuals with the MTHFR 677TT genotype,18 suggesting higher riboflavin requirements in this group.

MTHFR Polymorphism and Response to Betaine Supplementation

Folate-dependent remethylation of homocysteine to methionine is observed in all tissues but an alternate remethylation pathway in liver and kidney is carried out by betaine homocysteine methyltransferase (BHMT), which utilizes betaine as the methyl donor. When folate-dependent remethylation is disrupted, the alternate pathway may be particularly important. Large doses of oral betaine are the mainstay of therapy for patients with homocystinuria due to severely compromised MTHFR activity, although betaine can also lower homocysteine in healthy subjects.19 The betaine effect can be monitored by measurement of plasma homocysteine concentrations. Using serial measurements of plasma homocysteine, betaine, and dimethylglycine (the product of the BHMT reaction), it is possible to describe the pharmacokinetics of betaine20 and to model its pharmacodynamic effects.21,22

The elimination rate of betaine and the homocysteine-lowering effect are increased in patients with severe MTHFR deficiency,22 but there are no studies thus far on the impact of MTHFR polymorphisms on betaine administration. However, corresponding data have been generated in a mouse model for mild and severe MTHFR deficiency. The relative decrease of homocysteine (approximately 50%) with a betaine supplement was not influenced by MTHFR activity, but the absolute decrease in homocysteine was higher in mice with mild MTHFR deficiency than that in wild-type mice.23 Humans with the MTHFR 677TT genotype might therefore be expected to show a greater homocysteine-lowering response to betaine than those with the other MTHFR genotypes.

MTHFR Polymorphism and Antifolates

The antifolate drugs methotrexate (MTX), pernetrexed, edatrexate, and lometrexol are structural folate analogues that target different enzymes of the folate cycle and/or purine or pyrimidine synthesis. Pharmacogenetic effects of the MTHFR polymorphisms in antitumor therapy with these substances are of utmost importance, given their widespread use, efficacy and unexpected deleterious toxicity after standardized dosing. Altered antiproliferative efficacy and toxicity might be observed in those with the 677TT genotype due to a relative preponderance of oxidized folates that are available for nucleotide synthesis, while other toxic effects, such as neurotoxicity, could occur due to the hyperhomocysteinemia and disruption of transmethylation reactions. In contrast to the potential clinical significance of pharmacogenetic effects, only a few reports have been published thus far.

The first case report observed a high prevalence of the MTHFR 677TT genotype (5 out of 6) in patients who were treated for breast cancer with a combination of cyclophosphamide, methotrexate and 5-fluorouracil and who experienced major antiproliferative toxicity.24 One retrospective study addressed the pharmacogenetic effect of the MTHFR 677 polymorphism on acute MTX toxicity in 220 patients with chronic myeloid leukemia undergoing post bone marrow transplant methotrexate prophylaxis for graft-versus-host disease.25 A borderline significant higher degree of mucositis and a trend towards slower recovery from thrombocytopenia was found in those with the 677TT genotype. However, the MTHFR genotype of the bone marrow graft was not available.25 Two groups reported increased antiproliferative26,27 and hepatotoxic27 effects associated with the 677TT genotype in retrospective studies on 43 patients with ovarian cancer and 61 patients with acute leukemia undergoing low-dose maintenance therapy with MTX.26,27

Low-dose MTX is effective in immunomodulation of rheumatic disease, probably through release of adenosine, in combination with other anti-inflammatory drugs such as sulfasalazine. Long-term MTX therapy in rheumatoid arthritis resulted in elevation of tHcy in 93 patients with the MTHFR 677CC and CT genotypes to a final level similar to that of 10 patients with the 677TT genotype, who remained at their elevated tHcy level throughout the study. No difference in plasma folate or toxicity was observed between genotype groups.28 Another study on 106 patients with rheumatoid arthritis and MTX therapy reported an association with slightly increased efficacy in patients with the 1298C allele and slightly higher toxicity in those with the 677T allele29 while a third similar study showed no pharmacogenetic association of the MTHFR genotype with MTX in 93 patients.30 The latter two studies, however, did not take into account the folate status of their study subjects.

The widely-used thymidylate synthase (TS) inhibitors such as 5-fluorouracil (FU), capecitabine, raltitrexed, nolatrexed, and tegafur interact with folate metabolism in so far as the substrate of MTHFR, 5,10-methylenetetrahydrofolate, is also a substrate for TS and binds together with dUMP, or with the competitive inhibitor 5-fluorouracil, to the enzyme.31 The MTHFR 677TT variant confers a higher availability of 5,10-methylenetetrahydrofolate32 and should therefore increase the efficacy of FU, similarly to the therapeutic coadministration of leucovorin.

The first study did not observe increased efficacy or toxicity in 4 patients with the MTHFR 677TT genotype among 47 patients with colon cancer treated with FU and leucovorin.33 A second study evaluated 43 patients with advanced colorectal cancer and different TS-inhibitor treatment regimens (38 with FU and leucovorin). The MTHFR 677T allele conferred a significantly higher response rate to therapy without evidence of higher antiproliferative or hepatic toxicity.34 One other study investigated the combined use of irinotecan, an inhibitor of topoisomerase 1, and raltitrexed in 39 patients with different solid cancers and found significantly reduced raltitrexed-associated toxicity in homozygotes for the MTHFR 677T allele.35 All three association studies were limited due to their small sample size and, although some results suggest a pharmacogenetic influence, additional data are required to interpret the effect of MTHFR polymorphisms on the response to TS inhibitors.

In summary, the data are inconclusive thus far and do not definitively answer the question as to whether patients with the MTHFR 677TT genotype have an altered response when exposed to antifolate therapy.

MTHFR Polymorphism and Anticonvulsant Drugs

A number of commonly used anticonvulsant drugs have been shown to interfere with folate metabolism, possibly due to some interaction with the MTHFR enzyme. For a review see ref. 3. In a study of 103 patients with epilepsy, only those who were homozygous for the MTHFR 677T allele and who were receiving phenytoin or carbamazepine, but not those receiving valproic acid, had significantly higher tHcy and lower plasma folate, compared with matched healthy individuals with the same genotype; the few patients with the homozygous 677TT genotype receiving concomitant folate supplements had normal plasma homocysteine.36 In another study of 136 patients with childhood epilepsy, the MTHFR genotype influenced plasma folate and tHcy in patients receiving carbamazepine, but not in those with valproic acid therapy.37 A third study in 81 epileptic patients showed that hyperhomocysteinemia and folate deficiency occurred more often in individuals with the 677TT genotype than in those with other genotypes, but this was only true in the subgroup receiving multidrug therapy and not in patients with monotherapy.38 These few studies hint to a possible pharmacogenetic effect of MTHFR in patients treated with carbamazepine and phenytoin.

Indirect Effects

MTHFR Polymorphism and Neuropsychotropic Drugs

Levodopa, the most common drug in the treatment of Parkinson's disease, is a potent methyl acceptor and has been shown to be associated with depletion of labile methyl groups, a condition that might be aggravated in individuals with the MTHFR 677TT genotype. In a study of patients with Parkinson's disease receiving combined therapy with levodopa, carbidopa, and other anti-Parkinsonian drugs, all patients had elevated tHcy compared with healthy controls, but this elevation was only significant for those with the 677 TT genotype.39

Patients with severe MTHFR deficiency can show psychotic symptoms and the MTHFR 677TT genotype might be associated with risk for schizophrenia (for review see ref. 3). Based on these findings and on the observation of interindividual heterogeneity in the response of patients to neuroleptic treatment, Joober et al40 studied the association of the MTHFR polymorphism in patients stratified by treatment outcome with conventional neuroleptics. They identified a clear over-representation of the MTHFR 677T allele in patients with schizophrenia that responded to therapy with conventional neuroleptics compared to the frequency in controls. Nonresponders did not differ from controls in their allele frequencies. The authors suggested that the MTHFR 677TT genotype might confer a more rapid and sustained response to neuroleptics. However, these findings remain to be confirmed by other groups.

Gene expression studies of multiple genes including the MTHFR 677 locus did not reveal a significant effect of MTHFR on the response to treatment for Alzheimer's disease41 or dementia.42 Considering the importance of the folate cycle and methylation reactions for the metabolism of biogenic amines that function as neurotransmitters, for cell proliferation, for DNA methylation, and for phospholipid/membrane biosynthesis, it is likely that MTHFR variation may modulate the response to many other pharmaceutical compounds that affect brain function.

MTHFR Polymorphisms and Hormone Replacement Therapy

Premenopausal women generally have lower fasting tHcy than men. These values rise after menopause to the level of those of men of similar age, but can be reduced by estrogen replacement therapy.43 One report of 90 women with adequate folate status suggested that the homocysteine-lowering effect of hormone replacement therapy was less pronounced in women who were homozygous for the 677T allele.44 This result could not be reproduced in a similar study of 217 Japanese women, in whom the MTHFR 677 genotype did not impair the response of tHcy to hormone replacement therapy.45

MTHFR Polymorphisms and Lipid-Lowering Drugs

Two classes of lipid-lowering drugs have been shown to interfere with homocysteine metabolism by unknown mechanisms. In one study, children with hypercholesterolemia who were heterozygous or homozygous for the MTHFR 677T allele had an increase in plasma homocysteine levels upon treatment with cholestyramine.46 Treatment with fenofibrate or bezafibrate, drugs that lower triglyceride levels and increase HDL levels in certain dyslipidemias, may increase fasting and postprandial tHcy, but MTHFR genotypes did not modify the fenofibrate-induced homocysteine changes in one study of men with cardiovascular disease and hypertriglyceridemia.47 The sample size in that study, however, was quite small.

Conclusions

Given the complex interaction of any drug with many body systems and a presumed mean prevalence of more than five amino-acid-changing polymorphisms per coding sequence in the human genome, a pharmacogenetic effect of a single genetic polymorphism must either be very strong or the polymorphism must have a high prevalence to generate reproducible results in association studies (see review in ref. 48). The MTHFR 677C→T polymorphism appears to fulfill both criteria when applied to direct pharmacogenetic effects. However, indirect effects might be too weak to be reliably detected without large-scale studies.

Although the pharmacogenetic data on the MTHFR 677 variant are somewhat preliminary for many of the compounds examined thus far, additional efforts in this field are clearly warranted considering the widespread use of such common medications as antifolates and neuropsychiatric drugs. Furthermore, given the fact that folate-dependent one-carbon transfer reactions and many pharmaceutical reagents can influence such fundamental cellular processes as DNA replication, neurotransmitter function and membrane biology, it is likely that a moderate disruption in folate metabolism could influence response to a wide variety of medications.

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