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Cited by 2,059Folate and B Vitamins ResearchMetabolism and Genetic DisordersNutritional Studies and Diet

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

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Homocysteine Studies Collaboration·2002·JAMA
DOI 10.1001/jama.288.16.2015
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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 micromol/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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  • Hyperhomocysteinemia can induce vascular endothelial injury and is one of the main risk factors for cardiovascular diseases.

    “Hyperhomocysteinemia (HHcy) can induces vascular endothelial injury, and has been determined to be one of the main risk factors for cardiovascular diseases,2, 3”

    From Picroside <scp>II</scp> attenuates hyperhomocysteinemia‐induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis (2019) · cites this paper as [2]

    The Comment section reports a modest association between homocysteine levels and ischemic heart disease and stroke risk, but says causality remains uncertain. The paper does not establish homocysteine as a main cardiovascular risk factor or show that it induces vascular endothelial injury (searched for endothelial injury and related mechanisms). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The elevation of homocysteine concentration in the blood is a risk factor not just for CAD but also for stroke and PAD.

    “The elevation of homocysteine concentration in the blood has been reported to be a risk factor not just for CAD but also for stroke and PAD287–289).”

    From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [287]

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Research works printed but not linked: 18

  1. B. Fowler, PhD; M. A. Mansoor, MD; M. R. Malinow, MD, P. Ducimetiere, MD; O. Nygard, MD, H. Ref- sum, 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. Robin- son, MD, D. W. Jacobsen, PhD; S. M. Schwartz, PhD; D. S. Siscovick, MD; M. J. Stampfer, MD, C. H. Hen- nekens, MD; E. J. M. Feskens, D. Kromhout, PhD; J. Ubbink, MD, P. Elwood, MD, J. Pickering, MSc; P. Ver- hoef, 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. Sher- liker, BSc; P. Linksted, MSc; and G. Davey Smith. Author Contributions of the author members of the Ho- mocysteine Studies Collaboration are listed online at: http://jama.ama-assn.org/issues/v288n16/rfull /jma20003.html. Additional Collaborators of the Homocysteine Stud- ies Collaboration: J. C. M. Witteman; B. Israelsson; G. Sexton; L. L. Wu; R. Joubran; B. Norrving, B. Hult- berg, A. Andersson, B. B. Johansson; C. Bergmark, A. M. Svardal; A. E. Evans; N. Pancharuniti, C. A. Lewis; R. Holman, I. Stratton, C. Johnston; and J. Morris. REFERENCES 1. McCully KS. Vascular pathology of homocystein- emia. Am J Pathol. 1969;56:111-128.
  2. Clarke R, Daly L, Robinson K, et al. Hyperhomo- cysteinemia. N Engl J Med. 1991;324:1149-1155.
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  17. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, and the MTHFR Studies Collaboration. MTHFR C677C→T polymorphism and risk of coro- nary heart disease: a meta-analysis. JAMA. 2002;288: 2023-2031.
  18. Clarke R, Collins R. Can dietary supplements with folic acid or vitamin B6 reduce cardiovascular risk? J Cardiovasc Risk. 1998;5:249-255. Acquisition of data: Clarke, Alfthan, Tuomilehto, Arnesen, Bonaa, Blacher, Boers, Bots, Grobbee, Bratt- stro ¨m, Breteler, Hofman, Chambers, Kooner, Coull, Evans, Evers, Folsom, Freyburger, Parrot, Genest Jr, Dalery, Graham, Hoogeveen, Stehouwer, Hopkins, Jacques, Selhub, Luft, Jungers, Lindgren, Lolin, Loe- hrer, Fowler, Mansoor, Malinow, Ducimetiere, Ny- gard, Refsum, Ueland, Omenn, Roseman, Parving, Gall, Perry, Ebrahim, Shaper, Robinson, Jacobsen, Schwartz, Siscovick, Stampfer, Hennekens, Feskens, Krom- hout, Ubbink, Elwood, Verhoef, von Eckardstein, Schulte, Assmann, Wald, Whincup, Wilcken, Sher- liker, Linksted, Davey Smith, Silberberg. Analysis and interpretation of data: Clarke, Collins, Lewington, Donald, Alfthan, Bostom, Brattstro ¨m, Kuller, Daly, Kostense, Stehouwer, Jacques, Lindgren, Fowler, Vollset, Omenn, Schwartz, Siscovick, Hennekens, Feskens, Kromhout, Pickering, Wald, Law, Silberberg. Drafting of the manuscript: Clarke, Collins, Lewing- ton, Donald, Bostom, Evans, Genest Jr, Sherliker, Linksted. Critical revision of the manuscript for important intellectual content: Clarke, Collins, Lewington, Alfthan, Tuomilehto, Bonaa, Blacher, Boers, Bots, Grobbee, Brattstro ¨m, Breteler, Hofman, Kooner, Coull, Kuller, Evers, Folsom, Freyburger, Parrot, Genest Jr, Graham, Daly, Hoogeveen, Kostense, Ste- houwer, Hopkins, Jacques, Selhub, Jungers, Lindgren, Lolin, Loehrer, Fowler, Mansoor, Malinow, Ducime- tiere, Nygard, Refsum, Vollset, Ueland, Omenn, Beresford, Roseman, Parving, Gall, Perry, Ebrahim, Shaper, Robinson, Jacobsen, Schwartz, Siscovick, Stampfer, Hennekens, Feskens, Kromhout, Pickering, Verhoef, von Eckardstein, Schulte, Assmann, Wald, Law, Whincup, Wilcken, Davey Smith. Statistical expertise: Clarke, Collins, Lewington, Don- ald, Bots, Daly, Hoogeveen, Kostense, Hopkins, Jacques, Ducimetiere, Vollset, Stampfer, Hennekens, Feskens, Pickering, Verhoef, Wald, Sherliker, Silberberg. Obtained funding: Tuomilehto, Blacher, Bots, Grobbee, Genest Jr, Loehrer, Roseman, Ebrahim, Feskens, Krom- hout, Whincup. Administrative, technical, or material support: Clarke, Tuomilehto, Hofman, Evans, Evers, Genest Jr, Dalery, Hopkins, Luft, Lolin, Refsum, Ueland, Omenn, Parv- ing, Perry, Ebrahim, Stampfer, Hennekens, Feskens, von Eckardstein, Schulte, Assmann, Linksted. Study supervision: Clarke, Collins, Lewington, Alfthan, Brattstro ¨m, Hofman, Stehouwer, Luft, Loehrer, Nygard, Kromhout, Whincup, Linksted.

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Authors
Homocysteine Studies Collaboration
Corresponding author
Homocysteine Studies Collaboration
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2002-10-23
Volume
288
Issue
16
Pages
2015
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.288.16.2015
OpenAlex
W2230430502
Cited by
2,059
References
65
Citations by year
2026: 25 · 2025: 56 · 2024: 42 · 2023: 50 · 2022: 56 · 2021: 66 · 2020: 61 · 2019: 70 · 2018: 64 · 2017: 68 · 2016: 75 · 2015: 68 · 2014: 89 · 2013: 94 · 2012: 88
FWCI
19.80
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
Funders
  • British Heart Foundation
  • European Commission
  • Medical Research Council
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
homocysteine, ischemic heart disease, stroke, cardiovascular risk factors, regression dilution bias, methionine loading test, genetic variants, hyperhomocysteinemia
MeSH terms
Adult, Aged, Cardiovascular Diseases, Female, Homocysteine, Humans, Male, Middle Aged, Prospective Studies, Retrospective Studies, Risk Factors, Myocardial Ischemia, Stroke

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