AbstractBackground: 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.