A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations

Lancet. 1999 Jan 9;353(9147):112-5. doi: 10.1016/s0140-6736(98)06434-4.


Background: The regulation of extracellular calcium concentration by parathyroid hormone is mediated by a calcium-sensing, G-protein-coupled cell-surface receptor (CASR). Mutations of the CASR gene alter the set-point for extracellular ionised calcium [Ca2+]o and cause familial hypercalcaemia or hypocalcaemia. The CASR missense polymorphism, A986S, is common in the general 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%) in 163 healthy adult women and tested samples of their serum for total calcium, albumin, total protein, creatinine, phosphate, pH, and parathyroid hormone. 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 concentration of calcium, until corrected for albumin. In a multivariate regression model, biochemical and genetic variables accounted for 74% of the total variation in calcium. The significant predictors of serum calcium were: albumin (p<0.001), phosphate (p=0.02), parathyroid hormone (p=0.007), pH (p=0.001), 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 extracellular calcium. The CASR A986S polymorphism is a likely candidate locus for genetic predisposition to various bone and mineral disorders in which extracellular calcium concentrations have a prominent part.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Calcium / blood*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation
  • Genotype
  • Humans
  • Hypercalcemia / blood
  • Hypercalcemia / genetics
  • Hypocalcemia / blood
  • Hypocalcemia / genetics
  • Linkage Disequilibrium / genetics
  • Polymorphism, Genetic / genetics*
  • Prospective Studies
  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface / genetics*


  • Receptors, Calcium-Sensing
  • Receptors, Cell Surface
  • Calcium