Rationale: The calcium-sensing receptor (CaSR) regulates serum calcium concentrations and common single nucleotide polymorphisms (SNPs) in a carboxyl terminal tri-locus haplotype block contribute to serum calcium variance in the general population. Altered serum calcium concentrations are associated with coronary artery disease (CAD), but direct role for CaSR in CAD remains to be determined. Methods: We evaluated the associations of serum calcium and common CASR SNPs or the tri-locus haplotype block with major diseases including CAD in 51,289 patients from the DiscovEHR cohort derived from a single US health care system. Results: Serum calcium concentrations were positively associated with the risk of CAD, and this risk was modified by common CASR SNPs. The Ala986Ser SNP was positively associated with hypercalcemia. Carriers of Ala986Ser had a significantly increased CAD risk whereas Arg990Gly carriers had a reduced risk relative to the reference SNP, for those with albumin-corrected serum calcium from 8.5-9.5 mg/dL. In the context of the tri-locus haplotype, the reduced CAD risk conferred by Arg990Gly remained significant. Analysis of the association of common CASR SNPs with CAD risk factors showed Arg990Gly was negatively associated with the CAD risk factor of chronic kidney disease, but independent of alterations in lipids, hemoglobin A1c, or blood pressure. Conclusions: This study compares the common approach of single SNP analysis with the impact of a common variant haplotype block and refocuses attention on the CaSR Arg990Gly SNP which reduces the risk of CAD over a specific range of median albumin-corrected calcium concentrations.

Calcium Sensing Receptor Common Variants Influence the Effects of Serum Calcium on Coronary Artery Disease Risks