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(Circulation. 1996;94:2410-2416.)
© 1996 American Heart Association, Inc.

Articles

Methylenetetrahydrofolate Reductase Polymorphism, Plasma Folate, Homocysteine, and Risk of Myocardial Infarction in US Physicians

Jing Ma, MD, PhD; Meir J. Stampfer, MD, DrPH; Charles H. Hennekens, MD, DrPH; Phyllis Frosst, MSc; Jacob Selhub, PhD; Jonathan Horsford, BSc; M. Rene Malinow, MD; Walter C. Willett, MD, DrPH; Rima Rozen, PhD

the Division of Preventive Medicine (C.H.H.) and Channing Laboratory (J.M., M.J.S., W.C.W.), Departments of Medicine and Ambulatory Care and Prevention (C.H.H.), Brigham and Women's Hospital and Harvard Medical School, the Departments of Epidemiology (M.J.S., C.H.H.) and Nutrition (M.J.S., W.C.W.), Harvard School of Public Health, and the Jean Mayer USDA Human Nutrition Center on Aging at Tufts University (J.S.), Boston, Mass; the Oregon Regional Primate Research Center (M.R.M.), Beaverton, Ore; and the Departments of Human Genetics, Pediatrics, and Biology, McGill University–Montreal Children's Hospital Research Institute (P.F., J.H., R.R.), Montreal, Canada.

Background Hyperhomocysteinemia appears to be an independent risk factor for coronary disease. Elevated levels of plasma total homocysteine (tHCY) can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for homocysteine metabolism. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate, which serves as a methyl donor for remethylation of homocysteine to methionine. A common mutation in MTHFR recently has been identified.

Methods and Results We assessed the polymorphism in MTHFR, plasma tHCY, and folate using baseline blood levels among 293 Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of follow-up and 290 control subjects. The frequency of the three genotypes was (-/-) (homozygous normal), 47%; (+/-) (heterozygous), 41%; and (+/+) (homozygous mutant), 12%, with a similar distribution among both MI case patients and control subjects. Compared with those with genotype (-/-), the relative risk (RR) of MI among those with (+/-) was 1.1 (95% CI, 0.8 to 1.5), and it was 0.8 (0.5 to 1.4) for the (+/+) genotype; none of these RRs were statistically significant. However, those with genotype (+/+) had an increased mean tHCY level (mean±SEM, 12.6±0.5 nmol/mL), compared with those with genotype (-/-) (10.6±0.3) (P<.01). This difference was most marked among men with low folate levels (the lowest quartile distribution of the control subjects): those with genotype (+/+) had tHCY levels of 16.0±1.1 nmol/mL, compared with 12.3±0.6 nmol/mL (P<.001) for genotype (-/-).

Conclusions In this population, MTHFR polymorphism was associated with higher homocysteine levels but not with risk of MI. A gene-environment interaction might increase the risk by elevating tHCY, especially when folate intake is low.

Key Words: folate • homocysteine • myocardial infarction • genetics • epidemiology

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				J. Chen, E. L. Giovannucci, and D. J. Hunter MTHFR Polymorphism, Methyl-Replete Diets and the Risk of Colorectal Carcinoma and Adenoma among U.S. Men and Women: An Example of Gene-Environment Interactions in Colorectal Tumorigenesis J. Nutr., February 1, 1999; 129(2): 560 - 560. [Abstract] [Full Text] [PDF]

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				K. Demuth, N. Moatti, O. Hanon, M. O. Benoit, M. Safar, and X. Girerd Opposite Effects of Plasma Homocysteine and the Methylenetetrahydrofolate Reductase C677T Mutation on Carotid Artery Geometry in Asymptomatic Adults Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1838 - 1843. [Abstract] [Full Text] [PDF]

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				P. Verhoef, E. B. Rimm, D. J. Hunter, J. Chen, W. C. Willett, K. Kelsey, and M. J. Stampfer A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men J. Am. Coll. Cardiol., August 1, 1998; 32(2): 353 - 359. [Abstract] [Full Text] [PDF]

				D. W. Jacobsen Homocysteine and vitamins in cardiovascular disease Clin. Chem., August 1, 1998; 44(8): 1833 - 1843. [Abstract] [Full Text] [PDF]

				A. R. Folsom, F. J. Nieto, P. G. McGovern, M. Y. Tsai, M. R. Malinow, J. H. Eckfeldt, D. L. Hess, and C. E. Davis Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins : The Atherosclerosis Risk in Communities (ARIC) Study Circulation, July 21, 1998; 98(3): 204 - 210. [Abstract] [Full Text] [PDF]

				J. H. Stein and P. E. McBride Hyperhomocysteinemia and Atherosclerotic Vascular Disease: Pathophysiology, Screening, and Treatment Arch Intern Med, June 22, 1998; 158(12): 1301 - 1306. [Abstract] [Full Text] [PDF]

				D. Girelli, S. Friso, E. Trabetti, O. Olivieri, C. Russo, R. Pessotto, G. Faccini, P. F. Pignatti, A. Mazzucco, and R. Corrocher Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction Blood, June 1, 1998; 91(11): 4158 - 4163. [Abstract] [Full Text] [PDF]

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				G. N. Welch and J. Loscalzo Homocysteine and Atherothrombosis N. Engl. J. Med., April 9, 1998; 338(15): 1042 - 1050. [Full Text] [PDF]

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				C. H. Hennekens Increasing Burden of Cardiovascular Disease : Current Knowledge and Future Directions for Research on Risk Factors Circulation, March 24, 1998; 97(11): 1095 - 1102. [Full Text] [PDF]

				L. A. J. Kluijtmans, J. J. P. Kastelein, J. Lindemans, G. H. J. Boers, S. G. Heil, A. V. G. Bruschke, J. W. Jukema, L. P. W. J. van den Heuvel, F. J. M. Trijbels, G. J. M. Boerma, et al. Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease Circulation, October 21, 1997; 96(8): 2573 - 2577. [Abstract] [Full Text]

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				S. M. Schwartz, D. S. Siscovick, M. R. Malinow, F. R. Rosendaal, R. K. Beverly, D. L. Hess, B. M. Psaty, W. T. Longstreth Jr, T. D. Koepsell, T. E. Raghunathan, et al. Myocardial Infarction in Young Women in Relation to Plasma Total Homocysteine, Folate, and a Common Variant in the Methylenetetrahydrofolate Reductase Gene Circulation, July 15, 1997; 96(2): 412 - 417. [Abstract] [Full Text]

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				P. M. Ridker, C. H. Hennekens, J. Selhub, J. P. Miletich, M. R. Malinow, and M. J. Stampfer Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism Circulation, April 1, 1997; 95(7): 1777 - 1782. [Abstract] [Full Text]

				J. L. Wiemels, R. N. Smith, G. M. Taylor, O. B. Eden, F. E. Alexander, M. F. Greaves, and United Kingdom Childhood Cancer Study Investigator Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia PNAS, March 27, 2001; 98(7): 4004 - 4009. [Abstract] [Full Text] [PDF]

				S. Friso, S.-W. Choi, D. Girelli, J. B. Mason, G. G. Dolnikowski, P. J. Bagley, O. Olivieri, P. F. Jacques, I. H. Rosenberg, R. Corrocher, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status PNAS, April 16, 2002; 99(8): 5606 - 5611. [Abstract] [Full Text] [PDF]