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(Circulation. 1998;98:2520-2526.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease

The Result of a Meta-Analysis

Lars Brattström, MD, PhD; David E. L. Wilcken, MD, FRCP, FRACP; John Öhrvik, PhD; Lars Brudin, MD, PhD

From the Departments of Medicine (L. Brattström) and Clinical Physiology (L. Brudin), County Hospital, Kalmar, Sweden; Department of Cardiovascular Medicine (D.E.L.W.), University of New South Wales, The Prince Henry and Prince of Wales Hospitals, Sydney, Australia; and Department of Statistics (J.Ö.), The Swedish University of Agricultural Sciences, Uppsala, Sweden.

Correspondence to Assoc Prof Lars Brattström, Department of Medicine, Kalmar Hospital, S-391 85 Kalmar, Sweden. E-mail lars.brattstrom{at}alinks.se

Background—The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677CT) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute 12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis.

Methods and Results—We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 µmol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37).

Conclusions—We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.

Key Words: homocysteine • methylenetetrahydrofolate reductase • risk factors • coronary disease

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				C. Song, D. Xing, W. Tan, Q. Wei, and D. Lin Methylenetetrahydrofolate Reductase Polymorphisms Increase Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population Cancer Res., April 1, 2001; 61(8): 3272 - 3275. [Abstract] [Full Text]

				M. Roest, Y. T. van der Schouw, D. E. Grobbee, M. J. Tempelman, P. G. de Groot, J. J. Sixma, and J. D. Banga Methylenetetrahydrofolate Reductase 677 C/T Genotype and Cardiovascular Disease Mortality in Postmenopausal Women Am. J. Epidemiol., April 1, 2001; 153(7): 673 - 679. [Abstract] [Full Text] [PDF]

				B. Keavney and H. Watkins Evolution of genetic analysis strategies in coronary heart disease: a case of unnatural selection? Eur. Heart J., February 2, 2001; 22(4): 271 - 273. [PDF]

				L.A.J Kluijtmans and A.S Whitehead Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease. Evidence that all three MTHFR C677T genotypes confer different levels of risk Eur. Heart J., February 2, 2001; 22(4): 294 - 299. [Abstract] [PDF]

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				J. C. Chambers, H. Ireland, E. Thompson, P. Reilly, O. A. Obeid, H. Refsum, P. Ueland, D. A. Lane, and J. S. Kooner Methylenetetrahydrofolate Reductase 677 C->T Mutation and Coronary Heart Disease Risk in UK Indian Asians Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2448 - 2452. [Abstract] [Full Text] [PDF]

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				L. L. Stern, J. B. Mason, J. Selhub, and S.-W. Choi Genomic DNA Hypomethylation, a Characteristic of Most Cancers, Is Present in Peripheral Leukocytes of Individuals Who Are Homozygous for the C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene Cancer Epidemiol. Biomarkers Prev., August 1, 2000; 9(8): 849 - 853. [Abstract] [Full Text]

				L. Brattstrom and D. E. Wilcken Homocysteine and cardiovascular disease: cause or effect? Am. J. Clinical Nutrition, August 1, 2000; 72(2): 315 - 323. [Abstract] [Full Text] [PDF]

				P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset The controversy over homocysteine and cardiovascular risk Am. J. Clinical Nutrition, August 1, 2000; 72(2): 324 - 332. [Abstract] [Full Text] [PDF]

				S. Hustad, P. M. Ueland, S. E. Vollset, Y. Zhang, A. L. Bjorke-Monsen, and J. Schneede Riboflavin as a Determinant of Plasma Total Homocysteine: Effect Modification by the Methylenetetrahydrofolate Reductase C677T Polymorphism Clin. Chem., August 1, 2000; 46(8): 1065 - 1071. [Abstract] [Full Text] [PDF]

				G. L. Booth, E. E.L. Wang, and with the Canadian Task Force on Preventive Health Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events Can. Med. Assoc. J., July 1, 2000; 163(1): 21 - 29. [Abstract] [Full Text] [PDF]

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				J. W. Eikelboom, G. J. Hankey, S. S. Anand, E. Lofthouse, N. Staples, and R. I. Baker Association Between High Homocyst(e)ine and Ischemic Stroke due to Large- and Small-Artery Disease but Not Other Etiologic Subtypes of Ischemic Stroke Stroke, May 1, 2000; 31(5): 1069 - 1075. [Abstract] [Full Text] [PDF]

				D. H. J. Blom and D. P. Verhoef Hyperhomocysteinemia, MTHFR, and Risk of Vascular Disease Circulation, April 25, 2000; 101 (16): e171 - e171. [Full Text] [PDF]

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				E. J. Topol, J. McCarthy, S. Gabriel, D. J. Moliterno, W. J. Rogers, L. K. Newby, M. Freedman, J. Metivier, R. Cannata, C. J. O'Donnell, et al. Single Nucleotide Polymorphisms in Multiple Novel Thrombospondin Genes May Be Associated With Familial Premature Myocardial Infarction Circulation, November 27, 2001; 104(22): 2641 - 2644. [Abstract] [Full Text] [PDF]