This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verhoef, P. Articles by Stampfer, M. J. Search for Related Content PubMed PubMed Citation Articles by Verhoef, P. Articles by Stampfer, M. J.

CLINICAL STUDIES

A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men

Petra Verhoef, PhD^{* ¶}, Eric B. Rimm, SCD^{* ||}, David J. Hunter, MBBS ^||, Jia Chen, SCD ^||, Walter C. Willett, MD^{* ||}, Karl Kelsey, MD and Meir J. Stampfer, MD^{* ||}

^* Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts, USA
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
^|| Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, USA
^¶ Division of Human Nutrition and Epidemiology, Agricultural University, Wageningen, The Netherlands

Manuscript received August 13, 1997; revised manuscript received March 30, 1998, accepted April 16, 1998.

Address for correspondence: Dr. Eric B. Rimm, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115

Objectives. We examined the risk of coronary heart disease associated with homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene.

Background. The mutation increases plasma homocysteine levels by impairing its remethylation. Increased plasma homocysteine is an independent risk factor for cardiovascular disease.

Methods. This was a case-control study nested within the Health Professionals Follow-up Study. In 1986, 44,940 U.S. male health professionals, aged 40 to 75 years and free from diagnosed cardiovascular disease, provided detailed information on usual dietary intake, including intake of folate, vitamins B₂, B₆ and B₁₂, and methionine. Between 1993 and 1995, blood samples were provided by approximately 40% of the participants. We compared data from 500 men with nonfatal coronary heart disease, diagnosed between 1986 and 1992, with data from 500 age-matched control subjects who were free of diagnosed cardiovascular disease at the time of the matched case subject’s diagnosis.

Results. Frequencies of homozygosity (+/+) and heterozygosity (+/–) for the mutation were 12.2% and 41.8% in case subjects and 14.4% and 40.0% in control subjects. With subjects homozygous (–/–) or heterozygous (+/–) for the wildtype allele as a reference and matched by age, the odds ratio of coronary heart disease was 0.83 (95% confidence interval, 0.57 to 1.19) for +/+ subjects. The odds ratio was unchanged after adjustment for smoking and other risk factors for coronary heart disease. Odds ratios were also calculated within strata for intake of vitamins involved in homocysteine metabolism or methionine, the metabolic precursor of homocysteine. The +/+ genotype was not directly associated with risk of coronary heart disease among men with low (that is, within the lowest quartile) intake (<301 µg/d) of folate, the substrate for methylenetetrahydrofolate reductase; low intake (<1.8 mg/d) of vitamin B₂, the cofactor for methylenetetrahydrofolate reductase; low intake (<8.0 µg/d) of vitamin B₁₂, the cofactor for remethylation; low intake (<2.1 mg/d) of vitamin B₆, the cofactor in the catabolic pathway of homocysteine; or high intake (>2.4 g/d) of methionine.

Conclusions. In this generally well-nourished population, men with the +/+ genotype for the C677T mutation in the methylenetetrahydrofolate reductase gene have no increase in risk of coronary heart disease, even when intake of folate or other B vitamins is low.

Abbreviations and Acronyms   CABG = coronary artery bypass grafting   CHD = coronary heart disease   CI = confidence interval   CVD = cardiovascular disease   MTHFR = methylenetetrahydrofolate reductase   OR = odds ratio

This article has been cited by other articles:

				U. Lim, K. Peng, B. Shane, P. J. Stover, A. A. Litonjua, S. T. Weiss, J. M. Gaziano, R. L. Strawderman, F. Raiszadeh, J. Selhub, et al. Polymorphisms in Cytoplasmic Serine Hydroxymethyltransferase and Methylenetetrahydrofolate Reductase Affect the Risk of Cardiovascular Disease in Men J. Nutr., August 1, 2005; 135(8): 1989 - 1994. [Abstract] [Full Text] [PDF]

				D Castle Clinical challenges posed by new biotechnology Postgrad. Med. J., February 1, 2003; 79(928): 65 - 66. [Full Text] [PDF]

				M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]

				H. McNulty, M. C McKinley, B. Wilson, J. McPartlin, J. Strain, D. G Weir, and J. M Scott Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements Am. J. Clinical Nutrition, August 1, 2002; 76(2): 436 - 441. [Abstract] [Full Text] [PDF]

				S. Skoupy, M. Fodinger, M. Veitl, A. Perschl, H. Puttinger, C. Rohrer, K. Schindler, A. Vychytil, W. H. Horl, and G. Sunder-Plassmann Riboflavin Is a Determinant of Total Homocysteine Plasma Concentrations in End-Stage Renal Disease Patients J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1331 - 1337. [Abstract] [Full Text] [PDF]

				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]

				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]

				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. 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]