A prospective study of plasma homocyst(e)ine and risk of ischemic stroke

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Stroke. 1994;25:1924-1930

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A prospective study of plasma homocyst(e)ine and risk of ischemic stroke

P Verhoef, CH Hennekens, MR Malinow, FJ Kok, WC Willett and MJ Stampfer
Department of Epidemiology and Public Health, Agricultural University, Wageningen, Netherlands.

BACKGROUND AND PURPOSE: Several studies have reported elevated circulating homocyst(e)ine levels in subjects with cerebral atherosclerosis. We assessed prospectively whether high plasma levels of homocyst(e)ine affect risk of ischemic stroke and evaluated whether high blood pressure modifies any such effect. METHODS: The study sample was drawn from the Physicians' Health Study, a randomized, double- blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 US male physicians. A total of 14,916 subjects 40 to 84 years old with no prior history of stroke, transient ischemic attack, or myocardial infarction provided blood samples at baseline and were followed for 5 years, with 99.7% morbidity and 100% mortality follow-up. Using a nested case-control design, we assayed homocyst(e)ine in samples from 109 subjects who subsequently developed ischemic stroke and 427 control subjects. RESULTS: The mean plasma concentration of homocyst(e)ine was slightly higher in subjects with stroke (11.1 +/- 4.0 [+/- SD] nmol/mL) than in control subjects (10.6 +/- 3.4 nmol/mL), but the difference was not statistically significant (P = .12). The crude odds ratio of ischemic stroke for subjects in the upper 20% (> 12.7 nmol/mL) compared with those in the bottom 80% of homocyst(e)ine levels was 1.4 (95% confidence interval, 0.8 to 2.2). The odds ratio was 1.2 (95% confidence interval, 0.7 to 2.0) after controlling for several risk factors and other potential confounders. In subgroup analyses, elevated homocyst(e)ine levels appeared to be more strongly predictive of ischemic stroke in normotensive subjects and in men 60 years or younger. Although not statistically significant, in these subgroups increases in risks of 100% and 70%, respectively, were observed for men in the upper 20% of homocyst(e)ine values. CONCLUSIONS: In this study, the data were compatible with a small but nonsignificant association between elevated plasma homocyst(e)ine and risk of ischemic stroke. However, since the sample size is small and the confidence intervals are wide, either no association or a moderate increase in risk cannot be excluded, particularly in subgroups otherwise at low risk, eg, younger men and those with normal blood pressure.

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				S. Cronin, K. L. Furie, and P. J. Kelly Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke: Evidence From a Cumulative Meta-Analysis Stroke, July 1, 2005; 36(7): 1581 - 1587. [Abstract] [Full Text] [PDF]

				Y. Sato, Y. Honda, J. Iwamoto, T. Kanoko, and K. Satoh Effect of Folate and Mecobalamin on Hip Fractures in Patients With Stroke: A Randomized Controlled Trial JAMA, March 2, 2005; 293(9): 1082 - 1088. [Abstract] [Full Text] [PDF]

				A. B. Sobol, E. Bald, and J. Loba Fractions of Total Plasma Homocysteine in Patients with Ischemic Stroke Before the Age of 55 Years Angiology, March 1, 2005; 56(2): 201 - 209. [Abstract] [PDF]

				R. L. Sacco, K. Anand, H.-S. Lee, B. Boden-Albala, S. Stabler, R. Allen, and M. C. Paik Homocysteine and the Risk of Ischemic Stroke in a Triethnic Cohort: The Northern Manhattan Study Stroke, October 1, 2004; 35(10): 2263 - 2269. [Abstract] [Full Text] [PDF]

				H. Iso, Y. Moriyama, S. Sato, A. Kitamura, T. Tanigawa, K. Yamagishi, H. Imano, T. Ohira, T. Okamura, Y. Naito, et al. Serum Total Homocysteine Concentrations and Risk of Stroke and Its Subtypes in Japanese Circulation, June 8, 2004; 109(22): 2766 - 2772. [Abstract] [Full Text] [PDF]

				W. K. Al-Delaimy, K. M. Rexrode, F. B. Hu, C. M. Albert, M. J. Stampfer, W. C. Willett, and J. E. Manson Folate Intake and Risk of Stroke Among Women Stroke, June 1, 2004; 35(6): 1259 - 1263. [Abstract] [Full Text] [PDF]

				J. F. Toole, M. R. Malinow, L. E. Chambless, J. D. Spence, L. C. Pettigrew, V. J. Howard, E. G. Sides, C.-H. Wang, and M. Stampfer Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death: The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial JAMA, February 4, 2004; 291(5): 565 - 575. [Abstract] [Full Text] [PDF]

				S. Gottlieb More evidence that folic acid reduces risk of ischaemic stroke BMJ, January 31, 2004; 328(7434): 247 - 247. [Full Text] [PDF]

				K. He, A. Merchant, E. B. Rimm, B. A. Rosner, M. J. Stampfer, W. C. Willett, and A. Ascherio Folate, Vitamin B6, and B12 Intakes in Relation to Risk of Stroke Among Men Stroke, January 1, 2004; 35(1): 169 - 174. [Abstract] [Full Text] [PDF]

				Z. Li, L. Sun, H. Zhang, Y. Liao, D. Wang, B. Zhao, Z. Zhu, J. Zhao, A. Ma, Y. Han, et al. Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China Stroke, September 1, 2003; 34(9): 2085 - 2090. [Abstract] [Full Text] [PDF]

				U. B. Fallon, J. Virtamo, I. Young, D. McMaster, Y. Ben-Shlomo, N. Wood, A. S. Whitehead, and G. D. Smith Homocysteine and Cerebral Infarction in Finnish Male Smokers Stroke, June 1, 2003; 34(6): 1359 - 1363. [Abstract] [Full Text] [PDF]

				D. Tanne, M. Haim, U. Goldbourt, V. Boyko, R. Doolman, Y. Adler, D. Brunner, S. Behar, and B.-A. Sela Prospective Study of Serum Homocysteine and Risk of Ischemic Stroke Among Patients With Preexisting Coronary Heart Disease Stroke, March 1, 2003; 34(3): 632 - 636. [Abstract] [Full Text] [PDF]

				U. Lim and P. A. Cassano Homocysteine and Blood Pressure in the Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., December 15, 2002; 156(12): 1105 - 1113. [Abstract] [Full Text] [PDF]

				A. De Bree, W. M. Verschuren, D. Kromhout, L. I Mennen, H. J Blom, E. S Ford, S J. Smith, D. F Stroup, K. K Steinberg, P. W Mueller, et al. Homocysteine and coronary heart disease: the importance of a distinction between low and high risk subjects Int. J. Epidemiol., December 1, 2002; 31(6): 1268 - 1272. [Full Text] [PDF]

				C. D. Bushnell and L. B. Goldstein Homocysteine testing in patients with acute ischemic stroke Neurology, November 26, 2002; 59(10): 1541 - 1546. [Abstract] [Full Text] [PDF]

				Homocysteine Studies Collaboration Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis JAMA, October 23, 2002; 288(16): 2015 - 2022. [Abstract] [Full Text] [PDF]

				P. O'Callaghan, R. Meleady, T. Fitzgerald, I. Graham, and European COMAC group Smoking and plasma homocysteine Eur. Heart J., October 2, 2002; 23(20): 1580 - 1586. [Abstract] [Full Text] [PDF]

				P. J. Kelly, J. Rosand, J. P. Kistler, V. E. Shih, S. Silveira, A. Plomaritoglou, and K. L. Furie Homocysteine, MTHFR 677C->T polymorphism, and risk of ischemic stroke: Results of a meta-analysis Neurology, August 27, 2002; 59(4): 529 - 536. [Abstract] [Full Text] [PDF]

				N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]

				N. C.-K. Tan, N. Venketasubramanian, S.-M. Saw, and H. T.-L. Tjia Hyperhomocyst(e)inemia and Risk of Ischemic Stroke Among Young Asian Adults Stroke, August 1, 2002; 33(8): 1956 - 1962. [Abstract] [Full Text] [PDF]

				T. Sasaki, M. Watanabe, Y. Nagai, T. Hoshi, M. Takasawa, M. Nukata, A. Taguchi, K. Kitagawa, N. Kinoshita, and M. Matsumoto Association of Plasma Homocysteine Concentration With Atherosclerotic Carotid Plaques and Lacunar Infarction Stroke, June 1, 2002; 33(6): 1493 - 1496. [Abstract] [Full Text] [PDF]

				P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]

				E. S Ford, S J. Smith, D. F Stroup, K. K Steinberg, P. W Mueller, and S. B Thacker Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies Int. J. Epidemiol., February 1, 2002; 31(1): 59 - 70. [Abstract] [Full Text] [PDF]

				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]

				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]

				E. Rizos and D. P Mikhailidis Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res, November 1, 2001; 52(2): 199 - 207. [Abstract] [Full Text] [PDF]

				J. A. Tice, E. Ross, P. G. Coxson, I. Rosenberg, M. C. Weinstein, M. G. M. Hunink, P. A. Goldman, L. Williams, and L. Goldman Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease: Effect of Grain Fortification and Beyond JAMA, August 22, 2001; 286(8): 936 - 943. [Abstract] [Full Text] [PDF]