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(Circulation. 2000;101:e171.)
© 2000 American Heart Association, Inc.

Circulation Electronic Pages

Hyperhomocysteinemia, MTHFR, and Risk of Vascular Disease

Dr Henk J. Blom

Department of Pediatrics University Hospital Nijmegen, Nijmegen, The Netherlands

Dr Petra Verhoef

Wageningen Centre for Food Sciences and, Wageningen University, Division of Human Nutrition and Epidemiology, Wageningen, The Netherlands

	Introduction

 
To the Editor:

In contrast to data derived from many epidemiological studies,¹ Brattström et al² conclude that mild hyperhomocysteinemia is not causally related to the pathogenesis of vascular disease. Their conclusion is based on a meta-analysis of 23 studies in which they observed no significant increased risk of vascular disease among subjects with the TT genotype for the MTHFR C677T polymorphism (a common mutation that raises total homocysteine [tHcy] in plasma) compared with those with the CC genotype.

In our opinion, the authors have overlooked several crucial aspects:

1. They calculated that subjects with the MTHFR TT genotype have plasma tHcy concentrations 2.6 µmol/L higher than those with the CC genotype. Presuming that an increase in plasma tHcy of 1 µmol/L is associated with approximately a 10% increase in risk of vascular disease,¹ the expected odds ratio (OR) for the TT genotype compared with the CC genotype is 1.26. This is well within the 95% CI Brattström et al calculated (OR 1.12 [95% CI 0.92 to 1.37]). Therefore, their study does not prove or disprove whether TT genotype is associated with increased risk of vascular disease.

2. MTHFR regulates availability of 1-carbon units of folate not only for remethylation of homocysteine, but also for synthesis of thymidine and purines. Reduced MTHFR activity will hamper homocysteine remethylation but lead to higher availability of folate for DNA synthesis.^{3 4} The latter may be beneficial during cell division, eg, during repair of endothelial damage. Indeed, endothelial cells with the TT genotype in culture grow . . . [Full Text of this Article]