Osteoprotegerin and Soluble Receptor Activator of Nuclear Factor-&kgr;B Ligand and Risk for Coronary Events: A Nested Case–Control Approach in the Prospective EPIC-Norfolk Population Study 1993–2003

Objective—The purpose of this study was to examine the association between serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor-&kgr;B ligand (RANKL) and future coronary artery disease (CAD) in apparently healthy individuals. The identification of OPG as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. Methods and Results—Serum levels of OPG and RANKL were analyzed in a prospective case–control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a cohort study of 25 663 men and women, where 951 apparently healthy individuals who developed a coronary event during 6 years’ follow-up were matched by sex and age with 1705 healthy controls. Baseline OPG, but not RANKL, was higher in cases than in controls, and OPG was higher in women than in men. Both men and women in the highest OPG quartile had a higher risk for future CAD. These associations were independent of established cardiovascular risk factors, and when using OPG as a continuous variable, also after adjustment for CRP. In contrast, RANKL showed no association with coronary events. Conclusion—OPG is associated with the risk of future CAD in apparently healthy men and women, independent of established cardiovascular risk factors.

[1]  P. D’Amelio,et al.  The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. , 2009, Journal of endocrinological investigation.

[2]  J. Herlitz,et al.  Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. , 2008, Journal of the American College of Cardiology.

[3]  Qingbo Xu,et al.  Soluble Receptor Activator of Nuclear Factor-&kgr;B Ligand and Risk for Cardiovascular Disease , 2007, Circulation.

[4]  A. Khera,et al.  Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study). , 2007, The American journal of cardiology.

[5]  W. Fraser,et al.  The circadian rhythm of osteoprotegerin and its association with parathyroid hormone secretion. , 2005, The Journal of clinical endocrinology and metabolism.

[6]  N. Rifai.  C-reactive protein and coronary heart disease , 2007, Cardiovascular Toxicology.

[7]  R. Peters,et al.  C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993-2003. , 2006, Atherosclerosis.

[8]  G. Hansson,et al.  Enhanced T-Cell Expression of RANK Ligand in Acute Coronary Syndrome: Possible Role in Plaque Destabilization , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[9]  E. Minar,et al.  Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease. , 2005, Atherosclerosis.

[10]  J. Patsch,et al.  Syndecan-1 is involved in osteoprotegerin-induced chemotaxis in human peripheral blood monocytes. , 2005, The Journal of clinical endocrinology and metabolism.

[11]  K. Dickstein,et al.  Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. , 2004, Journal of the American College of Cardiology.

[12]  R. Peters,et al.  Macrophage migration inhibitory factor and the risk of myocardial infarction or death due to coronary artery disease in adults without prior myocardial infarction or stroke: the EPIC-Norfolk Prospective Population study. , 2004, The American journal of medicine.

[13]  R. Peters,et al.  Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The Prospective EPIC (European Prospective Investigation into Cancer and nutrition)–Norfolk Population Study , 2004, Circulation.

[14]  JonathanGolledge,et al.  Osteoprotegerin and Osteopontin Are Expressed at High Concentrations Within Symptomatic Carotid Atherosclerosis , 2004 .

[15]  W. Poewe,et al.  Osteoprotegerin Is a Risk Factor for Progressive Atherosclerosis and Cardiovascular Disease , 2004, Circulation.

[16]  Vilmundur Gudnason,et al.  C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. , 2004, The New England journal of medicine.

[17]  H. Melhus,et al.  A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima‐media thickness of the carotid artery in hypertensive patients. The Swedish irbesartan left ventricular hypertrophy investigation vs atenolol (SILVHIA) , 2004, Blood pressure.

[18]  K. Nitta,et al.  The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[19]  L. Hofbauer,et al.  Increased osteoprotegerin serum levels in men with coronary artery disease. , 2003, The Journal of clinical endocrinology and metabolism.

[20]  Y. Ikari,et al.  Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease , 2002, Circulation.

[21]  K. Godang,et al.  Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess--possible role in bone homeostasis. , 2001, European journal of endocrinology.

[22]  L. Hofbauer,et al.  Osteoprotegerin: a link between osteoporosis and arterial calcification? , 2001, The Lancet.

[23]  S. Cummings,et al.  Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. , 2001, The Journal of clinical endocrinology and metabolism.

[24]  B. Riggs,et al.  Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. , 2001, Biochemical and biophysical research communications.

[25]  E. Clark,et al.  Osteoprotegerin Is an αvβ3-induced, NF-κB-dependent Survival Factor for Endothelial Cells* , 2000, The Journal of Biological Chemistry.

[26]  E. Clark,et al.  Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. , 2000, The Journal of biological chemistry.

[27]  N. Day,et al.  EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. , 1999, British journal of cancer.

[28]  J. Rumberger,et al.  Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. , 1995, Circulation.

[29]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.