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Alanine to Serine Polymorphism at Position 986 of the Calcium-Sensing Receptor Associated with Coronary Heart Disease, Myocardial Infarction, All-Cause, and Cardiovascular Mortality

Synlab Centre of Laboratory Diagnostics (W.M.), D-69037 Heidelberg, Germany; Ludwigshafen Risk and Cardiovascular Health Study Nonprofit LLC (U.S., B.W.), D-79098 Freiburg, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics (B.T., W.R.), and Division of Endocrinology, Department of Medicine (B.O.-P.), Medical University of Graz, A-8036 Graz, Austria; Division of Endocrinology and Diabetes, Department of Medicine (B.O.B.), University Hospital, D-89081 Ulm, Germany; Department of Medicine (E.R.), University of Heidelberg, D-69115 Heidelberg, Germany; and Division of Clinical Chemistry, Department of Medicine (M.M.H.), University of Freiburg, D-79106 Freiburg, Germany

Address all correspondence and requests for reprints to: Winfried März, M.D., Synlab Center of Laboratory Diagnostics Heidelberg, P.O. Box 10 47 80, D-69037 Heidelberg, Germany. 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 odds ratio 1.25; 95% confidence interval (CI) 1.02–1.54] and previous MI (multivariate odds ratio 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 PTH (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.