Methylenetetrahydrofolate Reductase Mutation and Coronary Artery Disease
To the Editor:
The article by Kluijtmans and colleagues1 (Circulation, October 21, 1997) adds to the growing literature on the relationship between the common thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) and risk of vascular disease. In an angiographically assessed cohort of subjects with coronary artery disease (CAD) participating in a statin regression trial (REGRESS), significantly increased homocysteine concentrations were found in subjects homozygous (+/+) or heterozygous (+/−) for the thermolabile variant compared with those carrying only the normal variant (−/−). Median levels were 2.8 and 0.8 μmol/L higher in the +/+ and +/− subjects, respectively. Compared with population-based controls, there was trend toward higher risk of CAD in subjects carrying the thermolabile variant, but this did not reach significance (OR for +/+ versus −/−: 1.21 [0.87 to 1.68]; +/− versus −/−: 1.14 [0.94 to 1.38]). However, when the results were combined with those of 6 other studies, including our own,2 in a meta-analysis, there was a significant increase in relative risk in subjects with the +/+ genotype (OR, 1.22; 95% CI, 1.10 to 1.47).
The data of Kluijtmans et al in a large cohort of well-characterized CAD patients are welcome. However, I am concerned by their meta-analysis. They have pooled together data from studies that have examined different phenotypes. For example, in our study,2 we recruited subjects with myocardial infarction. Although there is, of course, a relationship between angiographic CAD and myocardial infarction, the 2 are not synonymous, and each has distinct determinants. This is likely to extend to genetic causes. Indeed, analysis of different phenotypes may explain at least some of the discrepancies that have been reported not only in relation to the thermolabile MTHFR mutation but also to other genetic factors. Meta-analysis, even when restricted to a single phenotype, has several well-recognized limitations.3 When added to by heterogeneity in the phenotype, its validity is highly questionable. The meta-analysis carried out by Kluijtmans et al adds little to their primary data. Although positive, it should not be interpreted as strong evidence in support of a role for the MTHFR thermolabile mutation as a determinant of coronary risk. As discussed by Wilcken et al4 in a detailed letter in the same issue of Circulation, the jury is still out on its relevance.
- Copyright © 1998 by American Heart Association
Kluijtmans LAJ, Kastelein JJP, Lindemans J, Boers GHJ, Heil SG, Bruschke AVG, Jukema JW, van den Heuvel LPWJ, Trijbels FJM, Boerma GJM, Verheugt FWA, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1997;96:2573–2577.
Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM. 1996;89:437–444.
Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation. 1996;94:708–712.
Wilcken DEL, Wang XL, Wilcken B. Methylenetetrahydrofolate Reductase (MTHFR) mutation, homocyst(e)ine, and coronary artery disease. Circulation. 1997;96:2738–2740.
Since the characterization of the common 677C→T variant in the methylenetetrahydrofolate reductase (MTHFR) gene, many efforts have been made to study its contribution to hyperhomocysteinemia and to the risk of various forms of vascular disease.
In our study published in the October 21, 1997, issue of Circulation,R1 we analyzed the frequency of this mutation in angiographically proven coronary artery disease (CAD) patients selected from the Dutch Regression Growth Evaluation Statin Study (REGRESS) and in a meta-analysis in which we combined 8 studies to estimate the relative risk of the homozygous (+/+) genotype in CAD. In REGRESS, a study that included patients with clinical evidence of CAD severe enough to be a reason for invasive analysis, we were able to demonstrate that homozygotes and heterozygotes for this 677C→T variant had significantly elevated homocysteine concentrations. Furthermore, the relative risk for this MTHFR variant equaled the risk that could be calculated on the basis of differences in homocysteine concentrations between MTHFR genotypes. Thus, the thermolabile MTHFR variant most likely exerts its proarteriosclerotic effects via an elevation of plasma homocysteine. In the meta-analysis, patients with either CAD or myocardial infarction were included. As correctly indicated by Dr Samani, CAD and myocardial infarction are not identical and may have their distinct determinants, but both phenotypes are strongly correlated. In almost every patient, myocardial infarction originates from a progressively extended coronary arteriosclerosis. Because mild hyperhomocysteinemia has been identified as a risk factor for both CADR2 R3 and myocardial infarction,R4 R5 the combination of both phenotypes to study the effects of this MTHFR variant in the risk of coronary heart disease seems to be justified.
Kluijtmans LAJ, Kastelein JJP, Lindemans J, Boers GHJ, Heil SG, Bruschke AVG, Jukema JW, Van den Heuvel LPWJ, Trijbels JMF, Boerma GJM, Verheugt FWA, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation.. 1997;96:2573–2577.
Kang S-S, Wong PWK, Cook H, Norusis M, Messer JV. Protein-bound homocyst(e)ine: a possible risk factor for coronary artery disease. J Clin Invest.. 1986;77:1482–1486.
Dr Samani makes relevant comments about the article by Kluijtmans and colleagues.R6 He points out that it remains unresolved whether or not mild elevation of circulating homocyst(e)ine, which is frequently associated with the presence of vascular disease, contributes independently to cardiovascular risk or is, as discussed in our previous letter,R7 “a fellow traveler.”
In their carefully studied patients, Kluijtmans et al show that those homozygous and heterozygous for the 677C→T mutation in the MTHFR gene have increases in median homocyst(e)ine levels; but the increases are indeed small (2.8 and 0.8 μmol/L, respectively). And, for the reasons set out in Dr Samani’s letter, their meta-analysis, which includes a limited number of studies, does not provide convincing evidence that homozygosity for the MTHFR mutation increases coronary risk.
The somewhat lower MTHFR (+/+) prevalence in the Netherlands compared with that of other white populations is also perhaps worth noting. Kluijtmans et alR6 comment that this may vary between different populations, but in other white populations in which substantial numbers of subjects have been assessed, the population prevalence has been about 11.5%.R7 R8 Thus, the 9.5% in patients and 8.5% in controls in the Dutch study may reflect a lower prevalence of the genotype in Holland.
Kluijtmans LAJ, Kastelein JJP, Lindemans J, Boers GHJ, Heil SG, Bruschke AVG, Jukema JW, van den Heuvel LPWJ, Trijbels FJM, Boerma GJM, Verheugt FWA, Willems F, Blom HJ. Thermolabile reductase in coronary artery disease. Circulation. 1997;96:2573–2577.
Wilcken DEL, Wang XL, Wilcken B. Methylenetetrahydrofolate reductase (MTHFR) mutation, homocyst(e)ine, and coronary artery disease. Circulation. 1997;96:2738–2740. Letter.