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Homocysteine and Risk of Ischemic Heart Disease and Stroke A Meta-analysis

Homocysteine Studies Collaboration
JAMA. 2002;288(16):2015-2022. doi:10.1001/jama.288.16.2015.
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Published online

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 disease risk.

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 logistic regression.

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 stroke risk.

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 concentrations.

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Figure 1. Odds Ratios of Ischemic Heart Disease for a 25% Lower Usual Homocysteine Level in Individual Studies
Graphic Jump Location
Data were adjusted for study, sex, and age at enrollment and were corrected for regression dilution. The size of the square is inversely proportional to the variance of the log odds ratio (OR). The horizontal lines represent the 95% confidence intervals (CIs). The combined ORs in the subtotals for each study design and their 95% CIs are indicated by the diamonds.
Figure 2. Odds Ratios of Ischemic Heart Disease for a 25% Lower Usual Homocysteine Level Among People in Prospective Studies
Graphic Jump Location
Data were adjusted for study, sex, and age at enrollment. Studies are grouped by age at event, sex, smoking, and quintiles of systolic blood pressure and total cholesterol level. A global test for heterogeneity between all of these subgroups was not significant (χ216 = 14; P = .60). Symbols and conventions are as for Figure 1. To convert cholesterol to mmol/L, multiply by 0.02586. OR indicates odds ratio; CI, confidence interval.
Figure 3. Odds Ratios of Stroke for a 25% Lower Homocysteine Level in Individual Studies
Graphic Jump Location
Data were adjusted for study, sex, and age at enrollment and were corrected for regression dilution. Symbols and conventions are as for Figure 1. OR indicates odds ratio; CI, confidence interval.

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