A986S polymorphism of the calcium-sensing receptor and circulating calciumconcentrations

Background The regulation of extracellular calcium concentration by parathy roid hormone is mediated by a calcium-sensing, G-protein-coupled cell-surfa ce receptor (CASR). Mutations of the CASR gene alter the set-point for extr acellular ionised calcium [Ca2+](o) and cause familial hypercalcaemia or hy pocalcaemia. The CASR missense polymorphism, A986S, is common in the genera l population and is, therefore, a prime candidate as a genetic determinant of extracellular calcium concentration. Methods We genotyped the CASR A986S variant (S allele frequency of 16.3%) i n 163 healthy adult women and tested samples of their serum for total calci um, albumin, total protein, creatinine, phosphate, pH, and parathyroid horm one. A prospectively generated, random subset of 84 of these women provided a whole blood sample for assay of [Ca2+](o). Findings The A986S genotype showed no association with total serum concentr ation of calcium, until corrected for albumin. In a multivariate regression model, biochemical and genetic variables accounted for 74% of the total va riation in calcium. The significant predictors of serum calcium were: album in (p<0.001), phosphate (p=0.02), parathyroid hormone (p=0.007), pH (p=0.00 1), and A986S genotype (p=0.009). Fasting whole-blood [Ca2+](o) also showed an independent positive association with the 986S variant (p=0.013). Interpretation The CASR A986S variant has a significant effect on extracell ular calcium. The CASR A986S polymorphism is a likely candidate locus for g enetic predisposition to various bone and mineral disorders in which extrac ellular calcium concentrations have a prominent part.