Elsevier

Mayo Clinic Proceedings

Volume 83, Issue 11, November 2008, Pages 1203-1212
Mayo Clinic Proceedings

ORIGINAL ARTICLE
Homocysteine Level and Coronary Heart Disease Incidence: A Systematic Review and Meta-analysis

https://doi.org/10.4065/83.11.1203Get rights and content

OBJECTIVE

To determine whether an elevated homocysteine level is an independent risk factor for the development of coronary heart disease (CHD) to aid the US Preventive Services Task Force in its evaluation of novel risk factors for incident CHD.

METHODS

Studies of homocysteine and CHD were identified by searching MEDLINE (1966 through March 2006). We obtained additional articles by reviewing reference lists from prior reviews, original studies, editorials, and Web sites and by consulting experts. We included prospective cohort studies that measured homocysteine and Framingham risk factors and the incidence of CHD in the general adult population without known CHD. Each study was quality rated using criteria developed by the US Preventive Services Task Force. We conducted a meta-analysis using a random-effects model to determine summary estimates of the risk of major CHD associated with each 5-μmol/L increase in homocysteine level. The systematic review and meta-analysis were conducted between January 25, 2005, and September 17, 2007.

RESULTS

We identified 26 articles of good or fair quality. Most studies found elevations of 20% to 50% in CHD risk for each increase of 5 μmol/L in homocysteine level. Meta-analysis yielded a combined risk ratio for coronary events of 1.18 (95% confidence interval, 1.10-1.26) for each increase of 5 μmol/L in homocysteine level. The association between homocysteine and CHD was similar when analyzed by sex, length of follow-up, outcome, study quality, and study design.

CONCLUSION

Each increase of 5 μmol/L in homocysteine level increases the risk of CHD events by approximately 20%, independently of traditional CHD risk factors.

Section snippets

METHODS

We reviewed the MEDLINE and Cochrane Controlled Trials Register Database (1966 through March 2006) using the following keywords: cohort studies, cardiovascular diseases, homocysteine, hyperhomocysteinemia, and cystathionine beta-synthase. To ensure complete ascertainment, we reviewed the bibliographies of reviews, editorials, book chapters, and letters that discussed the association between homocysteine and CHD outcomes. We sought primary prevention trials and studies that evaluated the risk

RESULTS

A total of 603 abstracts were identified from our literature searches, and 163 articles were reviewed for inclusion. Of the 31 studies (articles) from 24 cohorts representing populations from North America and Europe that were included (Table 2), 23 were nested case-control studies,27, 28, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 58 and 8 were cohort studies.29, 51, 52, 53, 54, 55, 56, 57 Of the 23 nested case-control studies, 12 studies were rated good

DISCUSSION

Our review shows an association between elevated homocysteine levels and CHD that is independent of Framingham risk factors. In the overall analysis, the risk of any CHD event increased approximately 20% for each increase of 5 μmol/L of homocysteine. Because some studies reported only CVD events and because statistically these events are dominated by CHD events, we think that the overall estimate of 1.18 for all good and fair studies combined gives an accurate measure of the risk of CHD.

To our

CONCLUSION

Elevated homocysteine levels independently and moderately increase the risk of developing CHD either in a causal manner or as a risk marker by approximately 20%. The prevalence of above-normal homocysteine levels in the United States has been shown to be higher than 5% to 10% in several population-based cohorts, even after widespread fortification of food with folic acid. Thus, if primary prevention treatment studies were to show benefit among persons with elevated homocysteine levels, many CHD

Acknowledgments

We thank Miranda Walker, BA, David Buckley, MD, and Craig Fleming, MD, for their contributions on this project and Andrew Hamilton, MLS, MS, for conducting the literature searches.

REFERENCES (65)

  • SE Vollset et al.

    Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study

    Am J Clin Nutr

    (2001)
  • S Voutilainen et al.

    Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study

    Am J Clin Nutr

    (2004)
  • PF Jacques et al.

    Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort

    Am J Clin Nutr

    (2001)
  • AG Bostom et al.

    Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes

    Kidney Int

    (1997)
  • KC Ferdinand

    Coronary artery disease in minority racial and ethnic groups in the United States

    Am J Cardiol

    (2006 Jan 16)
  • PW Wilson et al.

    Prediction of coronary heart disease using risk factor categories

    Circulation

    (1998)
  • National Cholesterol Education Program (NCEP) Expert Panel

    Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report

    Circulation

    (2002)
  • HC McGill et al.

    Effects of serum lipoproteins and smoking on atherosclerosis in young men and women

    Arterioscler Thromb Vasc Biol

    (1997)
  • SC Smith

    Current and future directions of cardiovascular risk prediction

    Am J Cardiol

    (2006 Jan 16)
  • KS McCully

    Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis

    Am J Pathol

    (1969)
  • DE Wilcken et al.

    The pathogenesis of coronary artery disease: a possible role for methionine metabolism

    J Clin Invest

    (1976)
  • SH Mudd et al.

    The natural history of homocystinuria due to cystathionine β-synthase deficiency

    Am J Hum Genet

    (1985)
  • SR Lentz et al.

    Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia

    J Clin Invest

    (1996)
  • JW Yarnell et al.

    Lifestyle and hemostatic risk factors for ischemic heart disease: the Caerphilly Study

    Arterioscler Thromb Vasc Biol

    (2000)
  • PF Jacques et al.

    The effect of folic acid fortification on plasma folate and total homocysteine concentrations

    N Engl J Med

    (1999)
  • J Selhub et al.

    Vitamin status and intake as primary determinants of homocysteinemia in an elderly population

    JAMA

    (1993)
  • TG Bentley et al.

    Population-level changes in folate intake by age, gender, and race/ethnicity after folic acid fortification

    Am J Public Health

    (2006 Nov)
  • Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis

    JAMA

    (2002)
  • KH Bonaa et al.

    Homocysteine lowering and cardiovascular events after acute myocardial infarction

    N Engl J Med

    (2006 Apr 13)
  • E Lonn et al.

    Homocysteine lowering with folic acid and B vitamins in vascular disease [published correction appears in N Engl J Med. 2006; 355(7):746]

    N Engl J Med

    (2006 Apr 13)
  • B Jancin

    Homocysteine hypothesis of CV disease is ‘dead': lowering plasma levels may be dangerous

    Internal Medicine News

    (October 1, 2005)
  • CJ Boushey et al.

    A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes

    JAMA

    (1995)
  • Cited by (0)

    This research was funded by the Agency for Healthcare Research and Quality to support the work of the US Preventive Services Task Force under contract 290-02-0024, task order 2, Rockville, MD.

    View full text