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Submitted on January 12, 2006
Accepted on March 12, 2007
Synlab Centre of Laboratory Diagnostics (W.M.), Heidelberg, Germany; the LURIC Study nonprofit LLC (U.S., B.W.), Freiburg, Germany; the Clinical Institute of Medical and Chemical Laboratory Diagnostics (B.T., W.R.) and the Division of Endocrinology, Department of Medicine (B.O.P.), Medical University of Graz, Austria; the Division of Endocrinology and Diabetes, Department of Medicine (B.O.B.), University Hospital, Ulm, Germany; the Department of Medicine (E.R.), University of Heidelberg, Germany; and the Division of Clinical Chemistry, Department of Medicine (M.M.H.), University of Freiburg, Germany
* To whom correspondence should be addressed. E-mail: maerz{at}synlab.de.
Background - Disorders of calcium homeostasis have been implicated in atherosclerosis. The calcium-sensing receptor (CASR) is crucial to the regulation of calcium metabolism. An alanine (A) to serine (S) polymorphism at codon 986 (A986S) of the CASR gene has been associated with higher calcium and osteoporosis; the association with coronary artery disease (CAD) has not been studied.
Methods and Results - We investigated this polymorphism in individuals with CAD (n=2561) including survivors of myocardial infarction (MI, n=1358) compared to 698 controls without angiographic CAD. Compared to AA homozygotes, the prevalence of CAD (multivariate OR 1.25; 95% CI: 1.02-1.54) and previous MI (multivariate OR 1.33; 95% CI: 1.06-1.68) was increased in carriers of at least one S-allele. With each S-allele the prevalence of CAD and MI increased 1.22-fold (95% CI: 1.02-1.47) and 1.30-fold (95% CI: 1.06-1.60), respectively. Fully adjusted hazard ratios for total and cardiovascular mortality per one S-allele were 1.24 (95% CI: 1.05-1.46) and 1.38 (95% CI: 1.13-1.67), respectively. In carriers of at least one S-allele the adjusted hazard ratios for all-cause and cardiovascular death were 1.25 (95% CI: 1.04-1.51), and 1.48 (95% CI: 1.18-1.86), respectively. These associations were independent of cardiovascular risk factors, calcium and phosphate. The S-allele was associated with higher calcium (P<0.001) and parathyroid hormone (P<0.02), and lower phosphate (P<0.003) in CAD patients and controls.
Conclusion - Serine at position 986 of CASR may be an independent genetic predictor of angiographic CAD, previous MI and cardiovascular mortality.
CONDENSED ABSTRACT
We examined an alanine to serine polymorphism at codon 986 of the calcium-sensing receptor (CASR) in relation to coronary artery disease (CAD), myocardial infarction (MI) and mortality from all causes. Serine at position 986 was associated with higher calcium and parathyroid hormone, and lower phosphate concentrations. Serine at position 986 also increased the risk of CAD, MI, total and cardiovascular mortality, independent of conventional risk factors and serum calcium or phosphate.
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| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
