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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. 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]

				R. Diaz-Arrastia Homocysteine and Neurologic Disease Arch Neurol, October 1, 2000; 57(10): 1422 - 1427. [Abstract] [Full Text] [PDF]

				M. L. Watkins, J. D. Erickson, M. J. Thun, J. Mulinare, and C. W. Heath Jr. Multivitamin Use and Mortality in a Large Prospective Study Am. J. Epidemiol., July 15, 2000; 152(2): 149 - 162. [Full Text] [PDF]

				C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Lack of Association between the C677T MTHFR Polymorphism and Colorectal Hyperplastic Polyps Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 427 - 433. [Abstract] [Full Text]

H. H. Yu, R. Joubran, M. Asmi, T. Law, A. Spencer, M. Jouma, and N. Rifai Agreement among Four Homocysteine Assays and Results in Patients with Coronary Atherosclerosis and Controls Clin. Chem., February 1, 2000; 46(2): 258 - 264. [Abstract] [Full Text] [PDF]