Author Members of the Homocysteine Studies Collaboration: R. Clarke, MD, R. Collins, MB, S. Lewington, DPhil, A. Donald, PhD; G. Alfthan, MD, J. Tuomilehto, MD; E. Arnesen, MD, K. Bonaa, MD; J. Blacher, MD; G. H. J. Boers, MD; A. Bostom, MD; M. L. Bots, MD, D. E. Grobbee, MD; L. Brattström, MD; M. M. B. Breteler, MD, A. Hofman, MD; J. C. Chambers, MRCP, J. S. Kooner, FRCP; B. M. Coull, MD; R. W. Evans, PhD, L. H. Kuller; S. Evers, MD; A. R. Folsom, MD; G. Freyburger, MD, F. Parrot, MD; J. Genest Jr, MD, K. Dalery, MD; I. M. Graham, MD, L. Daly, PhD; E. K. Hoogeveen, MD, P. J. Kostense, PhD, C. D. A. Stehouwer, MD; P. N. Hopkins, MD; P. Jacques, ScD, J. Selhub, PhD; F. C. Luft, MD; P. Jungers, MD; A. Lindgren, MD; Y. I. Lolin, MD; F. Loehrer, MD, B. Fowler, PhD; M. A. Mansoor, MD; M. R. Malinow, MD, P. Ducimetiere, MD; O. Nygard, MD, H. Refsum, MD, S. E. Vollset, MD, P. M. Ueland, MD; G. S. Omenn, MD, S. A. A. Beresford, PhD; J. M. Roseman, MD; H. H. Parving, MD, M. A. Gall, MD; I. J. Perry, MD, S. B. Ebrahim, MD, A. G. Shaper, MD; K. Robinson, MD, D. W. Jacobsen, PhD; S. M. Schwartz, PhD; D. S. Siscovick, MD; M. J. Stampfer, MD, C. H. Hennekens, MD; E. J. M. Feskens, D. Kromhout, PhD; J. Ubbink, MD, P. Elwood, MD, J. Pickering, MSc; P. Verhoef, PhD; A. von Eckardstein, MD, H. Schulte, PhD, G. Assmann, MD; N. Wald, FRCP, M. R. Law, FRCP; P. H. Whincup, FRCP; D. E. L. Wilcken, MD; P. Sherliker, BSc; P. Linksted, MSc; and G. Davey Smith.
Context It has been suggested that total blood homocysteine concentrations are
associated with the risk of ischemic heart disease (IHD) and stroke.
Objective To assess the relationship of homocysteine concentrations with vascular
Data Sources MEDLINE was searched for articles published from January 1966 to January
1999. Relevant studies were identified by systematic searches of the literature
for all reported observational studies of associations between IHD or stroke
risk and homocysteine concentrations. Additional studies were identified by
a hand search of references of original articles or review articles and by
personal communication with relevant investigators.
Study Selection Studies were included if they had data available by January 1999 on
total blood homocysteine concentrations, sex, and age at event. Studies were
excluded if they measured only blood concentrations of free homocysteine or
of homocysteine after a methionine-loading test or if relevant clinical data
were unavailable or incomplete.
Data Extraction Data from 30 prospective or retrospective studies involving a total
of 5073 IHD events and 1113 stroke events were included in a meta-analysis
of individual participant data, with allowance made for differences between
studies, for confounding by known cardiovascular risk factors, and for regression
dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke
with blood homocysteine concentrations were obtained by using conditional
Data Synthesis Stronger associations were observed in retrospective studies of homocysteine
measured in blood collected after the onset of disease than in prospective
studies among individuals who had no history of cardiovascular disease when
blood was collected. After adjustment for known cardiovascular risk factors
and regression dilution bias in the prospective studies, a 25% lower usual
(corrected for regression dilution bias) homocysteine level (about 3 µmol/L
[0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval
[CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower
Conclusions This meta-analysis of observational studies suggests that elevated homocysteine
is at most a modest independent predictor of IHD and stroke risk in healthy
populations. Studies of the impact on disease risk of genetic variants that
affect blood homocysteine concentrations will help determine whether homocysteine
is causally related to vascular disease, as may large randomized trials of
the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine
Homocysteine Studies Collaboration. Homocysteine and Risk of Ischemic Heart Disease and Stroke: A Meta-analysis. JAMA. 2002;288(16):2015–2022. doi:10.1001/jama.288.16.2015
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