Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis

R. Clarke, R. Collins, S. Lewington, A. Donald, G. Alfthan, J. Tuomilehto, E. Arnesen, K. Bonaa, J. Blacher, G. H J Boers, A. Bostom, M. L. Bots, D. E. Grobbee, L. Brattström, M. M B Breteler, A. Hofman, J. C. Chambers, J. S. Kooner, Bruce M Coull, R. W. EvansL. H. Kuller, S. Evers, A. R. Folsom, G. Freyburger, F. Parrot, J. Genest, K. Dalery, I. M. Graham, L. Daly, E. K. Hoogeveen, P. J. Kostense, C. D A Stehouwer, P. N. Hopkins, P. Jacques, J. Selhub, F. C. Luft, P. Jungers, A. Lindgren, Y. I. Lolin, F. Loehrer, B. Fowler, M. A. Mansoor, M. R. Malinow, P. Ducimetiere, O. Nygard, H. Refsum, S. E. Vollset, P. M. Ueland, G. S. Omenn, S. A A Beresford, J. M. Roseman, H. H. Parving, M. A. Gall, I. J. Perry, S. B. Ebrahim, A. G. Shaper, K. Robinson, D. W. Jacobsen, S. M. Schwartz, D. S. Siscovick, M. J. Stampfer, C. H. Hennekens, E. J M Feskens, D. Kromhout, J. Ubbink, P. Elwood, J. Pickering, P. Verhoef, A. Von Eckardstein, H. Schulte, G. Assmann, N. Wald, M. R. Law, P. H. Whincup, D. E L Wilcken, P. Sherliker, P. Linksted, G. Davey Smith

Research output: Contribution to journalArticle

1699 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2015-2022
Number of pages8
JournalJournal of the American Medical Association
Volume288
Issue number16
StatePublished - Oct 23 2002
Externally publishedYes

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Homocysteine
Myocardial Ischemia
Meta-Analysis
Stroke
Odds Ratio
Prospective Studies
Vascular Diseases
Observational Studies
Retrospective Studies
Confidence Intervals
Inborn Genetic Diseases
Information Storage and Retrieval
Vitamins
MEDLINE
Methionine
Cardiovascular Diseases
Logistic Models
Communication
Research Personnel

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Clarke, R., Collins, R., Lewington, S., Donald, A., Alfthan, G., Tuomilehto, J., ... Smith, G. D. (2002). Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. Journal of the American Medical Association, 288(16), 2015-2022.

Homocysteine and risk of ischemic heart disease and stroke : A meta-analysis. / Clarke, R.; Collins, R.; Lewington, S.; Donald, A.; Alfthan, G.; Tuomilehto, J.; Arnesen, E.; Bonaa, K.; Blacher, J.; Boers, G. H J; Bostom, A.; Bots, M. L.; Grobbee, D. E.; Brattström, L.; Breteler, M. M B; Hofman, A.; Chambers, J. C.; Kooner, J. S.; Coull, Bruce M; Evans, R. W.; Kuller, L. H.; Evers, S.; Folsom, A. R.; Freyburger, G.; Parrot, F.; Genest, J.; Dalery, K.; Graham, I. M.; Daly, L.; Hoogeveen, E. K.; Kostense, P. J.; Stehouwer, C. D A; Hopkins, P. N.; Jacques, P.; Selhub, J.; Luft, F. C.; Jungers, P.; Lindgren, A.; Lolin, Y. I.; Loehrer, F.; Fowler, B.; Mansoor, M. A.; Malinow, M. R.; Ducimetiere, P.; Nygard, O.; Refsum, H.; Vollset, S. E.; Ueland, P. M.; Omenn, G. S.; Beresford, S. A A; Roseman, J. M.; Parving, H. H.; Gall, M. A.; Perry, I. J.; Ebrahim, S. B.; Shaper, A. G.; Robinson, K.; Jacobsen, D. W.; Schwartz, S. M.; Siscovick, D. S.; Stampfer, M. J.; Hennekens, C. H.; Feskens, E. J M; Kromhout, D.; Ubbink, J.; Elwood, P.; Pickering, J.; Verhoef, P.; Von Eckardstein, A.; Schulte, H.; Assmann, G.; Wald, N.; Law, M. R.; Whincup, P. H.; Wilcken, D. E L; Sherliker, P.; Linksted, P.; Smith, G. Davey.

In: Journal of the American Medical Association, Vol. 288, No. 16, 23.10.2002, p. 2015-2022.

Research output: Contribution to journalArticle

Clarke, R, Collins, R, Lewington, S, Donald, A, Alfthan, G, Tuomilehto, J, Arnesen, E, Bonaa, K, Blacher, J, Boers, GHJ, Bostom, A, Bots, ML, Grobbee, DE, Brattström, L, Breteler, MMB, Hofman, A, Chambers, JC, Kooner, JS, Coull, BM, Evans, RW, Kuller, LH, Evers, S, Folsom, AR, Freyburger, G, Parrot, F, Genest, J, Dalery, K, Graham, IM, Daly, L, Hoogeveen, EK, Kostense, PJ, Stehouwer, CDA, Hopkins, PN, Jacques, P, Selhub, J, Luft, FC, Jungers, P, Lindgren, A, Lolin, YI, Loehrer, F, Fowler, B, Mansoor, MA, Malinow, MR, Ducimetiere, P, Nygard, O, Refsum, H, Vollset, SE, Ueland, PM, Omenn, GS, Beresford, SAA, Roseman, JM, Parving, HH, Gall, MA, Perry, IJ, Ebrahim, SB, Shaper, AG, Robinson, K, Jacobsen, DW, Schwartz, SM, Siscovick, DS, Stampfer, MJ, Hennekens, CH, Feskens, EJM, Kromhout, D, Ubbink, J, Elwood, P, Pickering, J, Verhoef, P, Von Eckardstein, A, Schulte, H, Assmann, G, Wald, N, Law, MR, Whincup, PH, Wilcken, DEL, Sherliker, P, Linksted, P & Smith, GD 2002, 'Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis', Journal of the American Medical Association, vol. 288, no. 16, pp. 2015-2022.
Clarke R, Collins R, Lewington S, Donald A, Alfthan G, Tuomilehto J et al. Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis. Journal of the American Medical Association. 2002 Oct 23;288(16):2015-2022.
Clarke, R. ; Collins, R. ; Lewington, S. ; Donald, A. ; Alfthan, G. ; Tuomilehto, J. ; Arnesen, E. ; Bonaa, K. ; Blacher, J. ; Boers, G. H J ; Bostom, A. ; Bots, M. L. ; Grobbee, D. E. ; Brattström, L. ; Breteler, M. M B ; Hofman, A. ; Chambers, J. C. ; Kooner, J. S. ; Coull, Bruce M ; Evans, R. W. ; Kuller, L. H. ; Evers, S. ; Folsom, A. R. ; Freyburger, G. ; Parrot, F. ; Genest, J. ; Dalery, K. ; Graham, I. M. ; Daly, L. ; Hoogeveen, E. K. ; Kostense, P. J. ; Stehouwer, C. D A ; Hopkins, P. N. ; Jacques, P. ; Selhub, J. ; Luft, F. C. ; Jungers, P. ; Lindgren, A. ; Lolin, Y. I. ; Loehrer, F. ; Fowler, B. ; Mansoor, M. A. ; Malinow, M. R. ; Ducimetiere, P. ; Nygard, O. ; Refsum, H. ; Vollset, S. E. ; Ueland, P. M. ; Omenn, G. S. ; Beresford, S. A A ; Roseman, J. M. ; Parving, H. H. ; Gall, M. A. ; Perry, I. J. ; Ebrahim, S. B. ; Shaper, A. G. ; Robinson, K. ; Jacobsen, D. W. ; Schwartz, S. M. ; Siscovick, D. S. ; Stampfer, M. J. ; Hennekens, C. H. ; Feskens, E. J M ; Kromhout, D. ; Ubbink, J. ; Elwood, P. ; Pickering, J. ; Verhoef, P. ; Von Eckardstein, A. ; Schulte, H. ; Assmann, G. ; Wald, N. ; Law, M. R. ; Whincup, P. H. ; Wilcken, D. E L ; Sherliker, P. ; Linksted, P. ; Smith, G. Davey. / Homocysteine and risk of ischemic heart disease and stroke : A meta-analysis. In: Journal of the American Medical Association. 2002 ; Vol. 288, No. 16. pp. 2015-2022.
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abstract = "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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month = "10",
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TY - JOUR

T1 - Homocysteine and risk of ischemic heart disease and stroke

T2 - A meta-analysis

AU - Clarke, R.

AU - Collins, R.

AU - Lewington, S.

AU - Donald, A.

AU - Alfthan, G.

AU - Tuomilehto, J.

AU - Arnesen, E.

AU - Bonaa, K.

AU - Blacher, J.

AU - Boers, G. H J

AU - Bostom, A.

AU - Bots, M. L.

AU - Grobbee, D. E.

AU - Brattström, L.

AU - Breteler, M. M B

AU - Hofman, A.

AU - Chambers, J. C.

AU - Kooner, J. S.

AU - Coull, Bruce M

AU - Evans, R. W.

AU - Kuller, L. H.

AU - Evers, S.

AU - Folsom, A. R.

AU - Freyburger, G.

AU - Parrot, F.

AU - Genest, J.

AU - Dalery, K.

AU - Graham, I. M.

AU - Daly, L.

AU - Hoogeveen, E. K.

AU - Kostense, P. J.

AU - Stehouwer, C. D A

AU - Hopkins, P. N.

AU - Jacques, P.

AU - Selhub, J.

AU - Luft, F. C.

AU - Jungers, P.

AU - Lindgren, A.

AU - Lolin, Y. I.

AU - Loehrer, F.

AU - Fowler, B.

AU - Mansoor, M. A.

AU - Malinow, M. R.

AU - Ducimetiere, P.

AU - Nygard, O.

AU - Refsum, H.

AU - Vollset, S. E.

AU - Ueland, P. M.

AU - Omenn, G. S.

AU - Beresford, S. A A

AU - Roseman, J. M.

AU - Parving, H. H.

AU - Gall, M. A.

AU - Perry, I. J.

AU - Ebrahim, S. B.

AU - Shaper, A. G.

AU - Robinson, K.

AU - Jacobsen, D. W.

AU - Schwartz, S. M.

AU - Siscovick, D. S.

AU - Stampfer, M. J.

AU - Hennekens, C. H.

AU - Feskens, E. J M

AU - Kromhout, D.

AU - Ubbink, J.

AU - Elwood, P.

AU - Pickering, J.

AU - Verhoef, P.

AU - Von Eckardstein, A.

AU - Schulte, H.

AU - Assmann, G.

AU - Wald, N.

AU - Law, M. R.

AU - Whincup, P. H.

AU - Wilcken, D. E L

AU - Sherliker, P.

AU - Linksted, P.

AU - Smith, G. Davey

PY - 2002/10/23

Y1 - 2002/10/23

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=0037164104&partnerID=8YFLogxK

M3 - Article

C2 - 12387654

AN - SCOPUS:0037164104

VL - 288

SP - 2015

EP - 2022

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 16

ER -