(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
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
(677C
T) 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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I. P Fohr, R. Prinz-Langenohl, A. Bronstrup, A. M Bohlmann, H. Nau, H. K Berthold, and K. Pietrzik 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women Am. J. Clinical Nutrition, February 1, 2002; 75(2): 275 - 282. [Abstract] [Full Text] [PDF]
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M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 6 - 13. [Abstract] [Full Text] [PDF]
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R. Butler, A. D. Morris, and A. D. Struthers The T Allele of The C677T 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism May Protect Endothelial Function in Young, Normal Subjects Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 193 - 194. [Full Text] [PDF]
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P. Madonna, V. de Stefano, A. Coppola, F. Cirillo, A. M. Cerbone, G. Orefice, and G. Di Minno Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke Stroke, January 1, 2002; 33(1): 51 - 56. [Abstract] [Full Text] [PDF]
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 C. H. Pullin, P. A. L. Ashfield-Watt, M. L. Burr, Z. E. Clark, M. J. Lewis, S. J. Moat, R. G. Newcombe, H. J. Powers, J. M. Whiting, and I. F. W. McDowell Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1799 - 1805. [Abstract] [Full Text] [PDF]
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 G. Schnyder, M. Roffi, R. Pin, Y. Flammer, H. Lange, F. R. Eberli, B. Meier, Z. G. Turi, and O. M. Hess Decreased Rate of Coronary Restenosis after Lowering of Plasma Homocysteine Levels N. Engl. J. Med., November 29, 2001; 345(22): 1593 - 1600. [Abstract] [Full Text] [PDF]
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H. Markus, Z. Kapozsta, R. Ditrich, C. Wolfe, N. Ali, J. Powell, M. Mendell, and M. Cullinane Increased Common Carotid Intima-Media Thickness in UK African Caribbeans and Its Relation to Chronic Inflammation and Vascular Candidate Gene Polymorphisms Stroke, November 1, 2001; 32(11): 2465 - 2471. [Abstract] [Full Text] [PDF]
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S. Lopaciuk, K. Bykowska, H. Kwiecinski, A. Mickielewicz, A. Czlcankawska, T. Mendel, A. Kuczynska-Zardzewialy, D. Szelagowska, J. Windyga, W. Schroder, et al. Factor V Leiden, Prothrombin Gene G20210A Variant, and Methylenetetrahydrofolate Reductase C677T Genotype in Young Adults With Ischemic Stroke Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 346 - 350. [Abstract] [PDF]
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J. Thambyrajah, M. J. Landray, H. J. Jones, F. J. McGlynn, D. C. Wheeler, and J. N. Townend A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1858 - 1863. [Abstract] [Full Text] [PDF]
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 M. S. Williams and P. F. Bray Genetics of Arterial Prothrombotic Risk States Experimental Biology and Medicine, May 1, 2001; 226(5): 409 - 419. [Abstract] [Full Text]
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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]
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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]
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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]
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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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S.-M. Saw, J.-M. Yuan, C.-N. Ong, K. Arakawa, H.-P. Lee, G. A Coetzee, and M. C Yu Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore Am. J. Clinical Nutrition, February 1, 2001; 73(2): 232 - 239. [Abstract] [Full Text] [PDF]
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D. J. Meiklejohn, M. A. Vickers, R. Dijkhuisen, and M. Greaves Plasma Homocysteine Concentrations in the Acute and Convalescent Periods of Atherothrombotic Stroke Stroke, January 1, 2001; 32(1): 57 - 62. [Abstract] [Full Text] [PDF]
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E. E Delvin, R. Rozen, A. Merouani, J. Genest Jr, and M. Lambert Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children Am. J. Clinical Nutrition, December 1, 2000; 72(6): 1469 - 1473. [Abstract] [Full Text] [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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 A. Hassan and H. S. Markus Genetics and ischaemic stroke Brain, September 1, 2000; 123(9): 1784 - 1812. [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]
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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]
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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]
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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]
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 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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H. KIMURA, F. GEJYO, S. SUZUKI, and R. MIYAZAKI The C677T Methylenetetrahydrofolate Reductase Gene Mutation in Hemodialysis Patients J. Am. Soc. Nephrol., May 1, 2000; 11(5): 885 - 893. [Abstract] [Full Text]
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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]
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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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A. Mager, P. Tiqva, D. L. Brattstrom, L. Brudin, P. D. E.L. Wilcken, and J. Ohrvik Methylenetetrahydrofolate Reductase Gene and Coronary Artery Disease Response Circulation, April 25, 2000; 101 (16): e172 - e173. [Full Text] [PDF]
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M. A. Mansoor, C. Bergmark, S. J. Haswell, I. F. Savage, P. H. Evans, R. K. Berge, A. M. Svardal, and O. Kristensen Correlation between Plasma Total Homocysteine and Copper in Patients with Peripheral Vascular Disease Clin. Chem., March 1, 2000; 46(3): 385 - 391. [Abstract] [Full Text] [PDF]
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S. E. Vollset, O. Nygard, H. Refsum, and P. M. Ueland Coffee and homocysteine1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 403 - 404. [Full Text] [PDF]
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 K. ROBINSON Homocysteine, B vitamins, and risk of cardiovascular disease Heart, February 1, 2000; 83(2): 127 - 130. [Full Text]
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 B. N. Ames Cancer prevention and diet: Help from single nucleotide polymorphisms PNAS, October 26, 1999; 96(22): 12216 - 12218. [Full Text] [PDF]
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 J. D. Kark, J. Selhub, B. Adler, J. Gofin, J. H. Abramson, G. Friedman, and I. H. Rosenberg Nonfasting Plasma Total Homocysteine Level and Mortality in Middle-Aged and Elderly Men and Women in Jerusalem Ann Intern Med, September 7, 1999; 131(5): 321 - 330. [Abstract] [Full Text] [PDF]
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A. G. Bostom, I. H. Rosenberg, H. Silbershatz, P. F. Jacques, J. Selhub, R. B. D'Agostino, P. W.F. Wilson, and P. A. Wolf Nonfasting Plasma Total Homocysteine Levels and Stroke Incidence in Elderly Persons: The Framingham Study Ann Intern Med, September 7, 1999; 131(5): 352 - 355. [Abstract] [Full Text] [PDF]
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J. W. Eikelboom, E. Lonn, J. Genest Jr., G. Hankey, and S. Yusuf Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence Ann Intern Med, September 7, 1999; 131(5): 363 - 375. [Abstract] [Full Text] [PDF]
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S. N. Doshi, J. Goodfellow, M. J. Lewis, and I. F.W. McDowell Homocysteine and endothelial function Cardiovasc Res, June 1, 1999; 42(3): 578 - 582. [Full Text] [PDF]
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P. M. Ridker, J. E. Manson, J. E. Buring, J. Shih, M. Matias, and C. H. Hennekens Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women JAMA, May 19, 1999; 281(19): 1817 - 1821. [Abstract] [Full Text] [PDF]
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A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]
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