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Osteoprotegerin Gene Polymorphisms in Men with Coronary Artery Disease

Departments of Internal Medicine and Cardiology (M.So., M.Sc., A.M.S., M.H., B.M., J.R.S.), and Gastroenterology, Endocrinology, and Metabolism (L.C.H.), Philipps University, D-35033 Marburg, Germany

Address all correspondence and requests for reprints to: Dr. Michael Schoppet, Department of Internal Medicine and Cardiology, Philipps University, Baldingerstrasse, D-35033 Marburg, Germany. E-mail: schoppet{at}mailer.uni-marburg.de.

Osteoprotegerin (OPG) antagonizes receptor activator of nuclear factor-B ligand (RANKL), the principal regulator of osteoclasts. Of note, OPG-deficient mice display osteoporosis and arterial calcification. Recently, OPG gene polymorphisms have been associated with osteoporosis and early predictors of cardiovascular disease. In this study, we examined OPG gene polymorphisms in 468 men who had absence of coronary artery disease (CAD) or single-, double-, or triple-vessel disease on coronary angiography. Denaturing gradient gel electrophoresis followed by DNA sequencing revealed nucleotide substitutions 149 TC, 163 AG, 209 GA, 245 TG, 950 TC (all promoter), 1181 GC (exon 1), and 6890 AC (intron 4), respectively. Although single polymorphisms were not associated with CAD, linkage of polymorphisms 950 and 1181 revealed that haplotypes were overrepresented in men with CAD (² = 17.05; P = 0.03) with an increased risk of CAD in carriers of genotypes 950 TC/1181 GC and 950 CC/1181 CC (odds ratio, 1.67; 95% confidence interval, 1.02–2.72; P = 0.04). Furthermore, serum OPG levels were correlated with the presence of a C allele at position 950 (P = 0.02). In summary, linkage of genetic variations of the OPG gene at positions 950 and 1181 may confer an increased risk of CAD in Caucasian men.

This work was supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft (to L.C.H.; Ho 1875/3-1 and Ho 1875/4-1).

M.So. and M.Sc. contributed equally to this work.

Abbreviations: CAD, Coronary artery disease; CI, confidence interval; DGGE, denaturing gradient gel electrophoresis; LDL, low-density lipoprotein; OPG, osteoprotegerin; OR, odds ratio; RANK, receptor activator of nuclear factor-B; RANKL, RANK ligand.

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