From the Division of Epidemiology, School of Public Health (A.R.F.,
P.G.M.) and Department of Laboratory Medicine and Pathology (M.Y.T., J.H.E.),
University of Minnesota, Minneapolis; Department of Epidemiology, School of
Hygiene and Public Health (F.J.N.), Johns Hopkins University, Baltimore, Md;
Laboratory of Cardiovascular Diseases, Oregon Regional Primate Research Center
(M.R.M., D.L.H.), Beaverton, Ore; and Collaborative Studies Coordinating
Center (C.E.D.), Chapel Hill, NC.
Background—Elevated plasma total
homocysteine (tHcy), low B-vitamin intake, and genetic
polymorphisms related to tHcy metabolism may play roles
in coronary heart disease (CHD). More prospective studies
are needed.
Methods and Results—We used a prospective case-cohort design to
determine whether tHcy-related factors are associated with incidence of
CHD over an average of 3.3 years of follow-up in a biracial sample of
middle-aged men and women. Age-, race-, and field center–adjusted CHD
incidence was associated positively (P<0.05) with tHcy
in women but not men, and CHD was associated negatively
(P<0.05) with plasma folate (women only), plasma
pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women
only). However, after accounting for other risk factors, only plasma
pyridoxal 5'-phosphate was associated with CHD incidence; the relative
risk for the highest versus lowest quintile of pyridoxal 5'-phosphate
was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the
C677T mutation of the
methylenetetrahydrofolate reductase
gene or with 3 mutations of the cystathionine ß-synthase gene.
Conclusions—Our prospective findings add uncertainty to
conclusions derived mostly from cross-sectional studies that tHcy is a
major, independent, causative risk factor for CHD. Our findings point
more strongly to the possibility that vitamin B6 offers
independent protection. Randomized trials, some of which are under way,
are needed to better clarify the interrelationships of tHcy, B
vitamins, and cardiovascular disease.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
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
Key Words: : coronary disease • vitamins • homocysteine • polymorphism (genetics)
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S. Friso, P. F. Jacques, P. W.F. Wilson, I. H. Rosenberg, and J. Selhub Low Circulating Vitamin B6 Is Associated With Elevation of the Inflammation Marker C-Reactive Protein Independently of Plasma Homocysteine Levels Circulation, June 12, 2001; 103(23): 2788 - 2791. [Abstract] [Full Text] [PDF]
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S. Voutilainen, T. H. Rissanen, J. Virtanen, T. A. Lakka, and J. T. Salonen Low Dietary Folate Intake Is Associated With an Excess Incidence of Acute Coronary Events : The Kuopio Ischemic Heart Disease Risk Factor Study Circulation, June 5, 2001; 103(22): 2674 - 2680. [Abstract] [Full Text] [PDF]
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K. K. A. Witte, A. L. Clark, and J. G. F. Cleland Chronic heart failure and micronutrients J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1765 - 1774. [Abstract] [Full Text] [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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 S. Bleich, K. Bleich, S. Kropp, H.-J. Bittermann, D. Degner, W. Sperling, E. Ruther, and J. Kornhuber Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the 'French Paradox'? Alcohol Alcohol., May 1, 2001; 36(3): 189 - 192. [Abstract] [Full Text] [PDF]
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K. M Koehler, R. N Baumgartner, P. J Garry, R. H Allen, S. P Stabler, and E. B Rimm Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use Am. J. Clinical Nutrition, March 1, 2001; 73(3): 628 - 637. [Abstract] [Full Text] [PDF]
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 U B Fallon, P Elwood, Y Ben-Shlomo, J B Ubbink, R Greenwood, and G D. Smith Homocysteine and ischaemic stroke in men: the Caerphilly study J Epidemiol Community Health, February 1, 2001; 55(2): 91 - 96. [Abstract] [Full Text]
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U B Fallon, Y Ben-Shlomo, P Elwood, J B Ubbink, and G D. Smith Homocysteine and coronary heart disease in the Caerphilly cohort: a 10 year follow up Heart, February 1, 2001; 85(2): 153 - 158. [Abstract] [Full Text]
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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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R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Scientific Statement: AHA Dietary Guidelines: Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association J. Nutr., January 1, 2001; 131(1): 132 - 146. [Full Text]
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B. K. Nallamothu, A. M. Fendrick, M. Rubenfire, S. Saint, R. R. Bandekar, and G. S. Omenn Potential Clinical and Economic Effects of Homocyst(e)ine Lowering Arch Intern Med, December 11, 2000; 160(22): 3406 - 3412. [Abstract] [Full Text] [PDF]
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M. S. Morris, P. F. Jacques, I. H. Rosenberg, J. Selhub, B. A. Bowman, E. W. Gunter, J. D. Wright, and C. L. Johnson Serum Total Homocysteine Concentration Is Related to Self-Reported Heart Attack or Stroke History among Men and Women in the NHANES III J. Nutr., December 1, 2000; 130(12): 3073 - 3076. [Abstract] [Full Text] [PDF]
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C. M. Loria, D. D. Ingram, J. J. Feldman, J. D. Wright, and J. H. Madans Serum Folate and Cardiovascular Disease Mortality Among US Men and Women Arch Intern Med, November 27, 2000; 160(21): 3258 - 3262. [Abstract] [Full Text] [PDF]
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R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Dietary Guidelines : Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association Stroke, November 1, 2000; 31(11): 2751 - 2766. [Full Text] [PDF]
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R. M. Krauss, R. H. Eckel, B. Howard, L. J. Appel, S. R. Daniels, R. J. Deckelbaum, J. W. Erdman Jr, P. Kris-Etherton, I. J. Goldberg, T. A. Kotchen, et al. AHA Dietary Guidelines : Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association Circulation, October 31, 2000; 102(18): 2284 - 2299. [Full Text] [PDF]
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N. Aleksic, H. Juneja, A. R. Folsom, C. Ahn, E. Boerwinkle, L. E. Chambless, and K. K. Wu Platelet PlA2 Allele and Incidence of Coronary Heart Disease : Results From the Atherosclerosis Risk In Communities (ARIC) Study Circulation, October 17, 2000; 102(16): 1901 - 1905. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, J. J. Genest Jr, and B. A. Nassar Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease J. Am. Coll. Cardiol., September 1, 2000; 36(3): 758 - 765. [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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N. K Fukagawa, J. M Martin, A. Wurthmann, A. H Prue, D. Ebenstein, and B. O'Rourke Sex-related differences in methionine metabolism and plasma homocysteine concentrations Am. J. Clinical Nutrition, July 1, 2000; 72(1): 22 - 29. [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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T. Omland, A. Samuelsson, M. Hartford, J. Herlitz, T. Karlsson, B. Christensen, and K. Caidahl Serum Homocysteine Concentration as an Indicator of Survival in Patients With Acute Coronary Syndromes Arch Intern Med, June 26, 2000; 160(12): 1834 - 1840. [Abstract] [Full Text] [PDF]
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J Thambyrajah and J.N Townend Homocysteine and atherothrombosis--mechanisms for injury Eur. Heart J., June 2, 2000; 21(12): 967 - 974. [PDF]
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E. K. Hoogeveen, P. J. Kostense, C. Jakobs, J. M. Dekker, G. Nijpels, R. J. Heine, L. M. Bouter, and C. D. A. Stehouwer Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes : 5-Year Follow-Up of the Hoorn Study Circulation, April 4, 2000; 101(13): 1506 - 1511. [Abstract] [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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W. G. Christen, U. A. Ajani, R. J. Glynn, and C. H. Hennekens Blood Levels of Homocysteine and Increased Risks of Cardiovascular Disease: Causal or Casual? Arch Intern Med, February 28, 2000; 160(4): 422 - 434. [Abstract] [Full Text] [PDF]
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J. M. Foody, J. A. Milberg, K. Robinson, G. L. Pearce, D. W. Jacobsen, and D. L. Sprecher Homocysteine and Lipoprotein(a) Interact to Increase CAD Risk in Young Men and Women Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 493 - 499. [Abstract] [Full Text] [PDF]
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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]
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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. W. Walsh, S. Paul, R. A. Wild, R. A. Dean, R. P. Tracy, D. A. Cox, and P. W. Anderson The Effects of Hormone Replacement Therapy and Raloxifene on C-Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 214 - 218. [Abstract] [Full Text]
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 V. Fonseca, S. C. Guba, and L. M. Fink Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis Endocr. Rev., October 1, 1999; 20(5): 738 - 759. [Abstract] [Full Text]
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