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(Circulation. 1997;95:21-23.)
© 1997 American Heart Association, Inc.

Articles

Methylenetetrahydrofolate Reductase Gene and Coronary Artery Disease

Frank M. van Bockxmeer, PhD; Cyril D.S. Mamotte, BSc (Hons); Samuel D. Vasikaran, FRCPA; Roger R. Taylor, MB,BS

the Departments of Biochemistry (F.M. van B., C.D.S.M., S.D.V.), Cardiology, and Medicine (R.R.T.), Royal Perth Hospital, Western Australia.

Correspondence to Frank M. van Bockxmeer, PhD, Department of Biochemistry, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6001.

	Abstract

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Background Hyperhomocysteinemia has been substantiated as a risk factor for occlusive vascular disease. A common mutation (nucleotide 677 CT) has been described recently in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which results in a valine for alanine substitution, a thermolabile enzyme, and a tendency to elevate plasma homocysteine levels and which has been proposed to contribute importantly to coronary artery disease.

Methods and Results To study the potential influence of the mutation on ischemic heart disease, we screened 555 whites with angiographically documented coronary artery disease and 143 unrelated control subjects without a history of angina or myocardial infarction randomly selected from the community. The patients were in two groups: group 1 comprised 358 prospectively recruited individuals younger than 50 years, and group 2, 197 patients investigated prospectively for restenosis 6 months after coronary angioplasty. The frequency of homozygosity for the mutation was 10.5% in control subjects, 10.6% in group 1, and 9.1% in group 2 patients. There was no relationship between MTHFR genotype and number of coronary vessels with >50% diameter obstruction, prior myocardial infarction, or restenosis after coronary angioplasty. Plasma folate concentrations in control subjects (n=90) and patients (n=208) showed closely similar distributions.

Conclusions Although it is accepted that moderate hyperhomocysteinemia significantly increases the risk for coronary, cerebrovascular, and peripheral vascular diseases, our data suggest that a mutation of the MTHFR gene, which has been associated with a thermolabile form of the enzyme and with hyperhomocysteinemia in subjects with plasma folate below the median, does not appear to be significantly associated with risk for premature coronary artery disease or for restenosis after coronary angioplasty.

Key Words: homocysteine • genes • cardiovascular diseases • restenosis

	Introduction

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In accordance with early suggestions,^{1 2} there is now firm evidence that an elevated plasma homocysteine level is an independent risk factor for vascular disease, including coronary artery disease, as recently reviewed and submitted to meta-analysis.³ A functionally important and common mutation (nucleotide [nt] 677 CT) in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), which is involved in the remethylation of homocysteine to methionine, has now been described.⁴ In individuals homozygous for the mutation, constituting 12% of a French-Canadian population studied, specific MTHFR enzyme activity was reduced to approximately one third, was more thermolabile than the normal isoform, and was associated with near doubling of the plasma homocysteine level.⁴ It was suggested that the mutation could represent an important and previously unrecognized genetic risk factor for vascular disease. However, a very recent study⁵ of a US population found that homozygosity for the mutation increased total plasma homocysteine 20% in subjects with plasma folate levels below the median but did not increase homocysteine levels in those with higher folate levels. Heterozygosity did not increase homocysteine in either folate-level group. There is, therefore, considerable doubt whether this mutation is important in the genesis of vascular disease; although the mutation could be important in contributing to vascular disease in certain groups, such as those with nutritional deficiency, it remains unclear whether it would be important more generally. We examined the prevalence of the nt 677 CT mutation of the MTHFR gene in patients with premature coronary heart disease, another group subsequent to coronary angioplasty, and a control group selected randomly from a well-nourished Australian population.⁶

	Methods

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Subjects and Protocol
Control subjects and patients were unrelated whites, the large majority being residents of metropolitan Perth, Western Australia. The first patient group (group 1) consisted of 358 subjects younger than 50 years presenting with symptomatic coronary heart disease. They were prospectively documented for risk factors and genetic studies. To qualify for inclusion, they were required to have at least one obstruction of a major coronary artery 50% diameter at angiography with or without prior myocardial infarction with historical, ECG, and enzyme documentation. In these patients, the extent of obstructive disease was categorized as involving one, two, or three of the major vessels. The second patient group (group 2) comprised 197 subjects aged 56±8 years (mean±SD) who had previous coronary balloon angioplasty, with and without restenosis documented angiographically at 6 months, as described in a previous report.⁷ The control group comprised 143 unrelated subjects younger than 50 years, randomly selected from the electoral roll, and who did not have a history of angina or myocardial infarction.⁷ The study protocol was approved by the Ethics Committee of Royal Perth Hospital.

MTHFR Genotyping
Genomic DNA was isolated from nucleated blood cells by use of a Triton X-100 method, and the prevalence of the nt 677 CT mutation was determined by polymerase chain reaction (PCR) and HinfI restriction enzyme digestion as described by Frosst et al.⁴ Conditions during the latter process included DNA amplification at 1.5 mmol/L MgCl₂ and 1 U Thermus thermophilus (Tth) polymerase in a final volume of 25 µL exposed to 1 cycle of 95°C for 5 minutes and 35 cycles of 97°C for 10 seconds, 94°C for 30 seconds, 64°C for 40 seconds, and extension at 72°C for 2 minutes. HinfI digestion (1.5 U/reaction mixture) was performed directly in the PCR tube at 37°C for 4 hours before analysis by PAGE (12% T, 3.3% C). Plasma folate was determined by a microbiological assay that used Lactobacillus casei.

	Results

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The figure illustrates a polyacrylamide gel electropherogram of PCR digestion products from 8 subjects. A 175-bp fragment is indicative of those individuals homozygous for the thermolabile enzyme variant; those homozygous for the normal gene have a 198-bp fragment, whereas heterozygotes demonstrate both. There was no statistical difference in the prevalence of homozygosity for the mutation in the patient and control groups (normal approximation of the binomial distribution, one-tailed test). On the basis of the relatively small number of control subjects studied, there would have been an 80% power to detect a difference of 10%. Homozygotes for the mutation made up 10.5% of the control population (15 of 143 subjects), 10.6% of group 1 patients <50 years of age (38 of 358), and 9.1% (18 of 197) of group 2 angioplasty patients. Five of 83 subjects who developed restenosis were homozygous for the mutation compared with 13 of 114 who did not (P=NS).

View larger version (61K): [in this window] [in a new window]   Figure 1. Methylenetetrahydrofolate reductase (MTHFR) genotype by PCR analysis. One hundred ninety-eight–base pair and 175-bp fragments are distinguished on 12% polyacrylamide gel. -/- represents an individual homozygous for the normal allele (nucleotide 677=CAla); +/+, an individual homozygous for the thermolabile variant (nucleotide 677=TVal); and +/-, a heterozygous individual.

Table 1 compares the MTHFR genotypes and common coronary risk factors for 212 consecutive group 1 patients, categorized according to whether or not they had prior myocardial infarction. No relation between the mutation and risk factors or infarction was present; most relevantly, 11.7% of patients having a first-degree relative aged <60 years with coronary heart disease were homozygous for the mutation compared with 10.2% without a family history (P=NS). Table 2 presents the extent of coronary obstructive disease related to genotype in all 358 group 1 patients. There was clearly no relation; for example, 7 (18%) of 38 patients homozygous for the mutation had triple-vessel disease whereas 38 (23%) of 167 homozygous for the normal allele did so, and allele frequencies were nearly identical in subgroups categorized by the extent of disease.

View this table: [in this window] [in a new window]   Table 1. Distribution by MTHFR Genotype of Risk Factors in Group 1 Patients*

View this table: [in this window] [in a new window]   Table 2. Angiographic Occlusive Disease by MTHFR Genotype in Group 1 Patients*

Because folate status can critically influence hyperhomocysteinemia in individuals homozygous for the thermolabile mutation,⁵ plasma folate concentrations were measured in control subjects (n=90) and group 1 patients (n=208). These showed nearly identical skewed distributions, with a median value of 7.6 µmol/L for control subjects and 6.4 µmol/L for the patients. If the coexistence of homozygosity for the mutation and low plasma folate was an important determinant of premature CAD, an overrepresentation of homozygotes would be expected in those patients with plasma folate below the median. Of the 208 patients, 125 had plasma folate values below the normal median and 83 had values above; 16 of the former (12.8%) and 7 of the latter (8.4%) were homozygous for the mutation (P=NS).

	Discussion

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Despite background information suggesting that the common nt 677 CT mutation of the gene for the enzyme MTHFR might be important in predisposing individuals to vascular disease, including CAD, the question has not been systematically studied, and we found no influence in our patient groups.

In 1988, a thermolabile variant of the enzyme was described, and more recently, the same investigators⁸ reported 18% of patients with angiographically significant obstructive coronary artery disease to have this variant compared with 8% of those without angiographic disease and 5% of a previously documented normal population. Plasma homocysteine levels averaged almost twice the normal levels in those with the variant enzyme. In another study⁹ of families with coronary artery disease in whom a significant association with hyperhomocysteinemia was found, 18% of cases had plasma levels of homocysteine over the 95th percentile for control subjects, and furthermore, the distribution of plasma homocysteine levels was bimodal. The authors concluded that this phenomenon was related to a major genetic influence, almost certainly the C to T substitution at nt 677 of the MTHFR gene now found to correlate closely with enzyme thermolability and raised plasma homocysteine levels.⁴

In the present study, we found the frequency of homozygosity for the mutation to be 10.5% in our normal Western Australian, predominantly white population, whereas a frequency of 12% was recently reported in a French-Canadian population.⁴ The frequency was similar in the substantial number of our prospectively documented patients with premature coronary artery disease. There was no relation to the presence or absence of other well-recognized risk factors, including a family history of coronary heart disease, nor with prior myocardial infarction or the extent of coronary obstructive disease. Because the negative finding in relatively young patients could have related to their pathophysiology, such as a greater frequency of rupture of unstable plaques or less diffuse coronary artery disease than in older patients, we studied a second group. In this group of older patients who had submitted to coronary angioplasty, there was no excess of individuals with the mutation, and there was no influence on restenosis. We examined restenosis because there is evidence that homocysteine stimulates proliferation of rat smooth muscle cells,¹⁰ and restenosis after balloon angioplasty is essentially due to myointimal hyperplasia. Our findings imply that the disruptive influence on folate and homocysteine metabolism of the thermolabile MTHFR gene mutation is, at a population level, not importantly associated with premature coronary heart disease or the major problem of restenosis after successful balloon coronary angioplasty. The very recent finding⁵ that homozygosity for the mutation is only associated with elevated plasma homocysteine levels in those with plasma folate levels below the median helps explain our results. Our community is generally well nourished, and the plasma folate levels of our patients were not significantly different from those of our control population. Optimally, we would have liked to measure plasma homocysteine levels and relate them to genotype and plasma folate levels, but the valid measurement of plasma homocysteine requires the immediate separation of plasma, which was not done in the present study. However, the major aim of the present study was to determine whether the MTHFR mutation is important in the genesis of coronary artery disease, and it clearly does not have a significant impact in our community, which is no doubt similar to many living under satisfactory socioeconomic circumstances. The influence of the homocysteine-related metabolic system might also vary between vascular beds. Although moderate elevation of plasma homocysteine has been estimated to increase the risk of coronary and cerebrovascular diseases 1.4- to 2-fold, its contribution to peripheral vascular disease seems to be several times greater.³ It is therefore possible that the importance of the MTHFR gene mutation will be found to be greater in the peripheral vascular bed or to depend on age and interaction with other risk factors, especially dietary factors.

	Acknowledgments

 
We are grateful to the Medical Research Fund of Western Australia and Len Buckeridge for financial support, Konrad Jamrozik for recruitment of control subjects, and Stacy Cartwright for technical assistance.

Received July 11, 1996; revision received October 17, 1996; accepted October 28, 1996.

	References

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