The A986S polymorphism of the calcium-sensing receptor (CASR) gene is a significant contributor to inter-individual variability of serum calcium

Abstract

Serum calcium is under tight physiological control, but it is also a quantitative trait with a substantial genetic component. Mutations of the CASR gene cause familial hypocalciuric hypercalcemia and autosomal dominant hypoparathyroidism, depending on whether they decrease or increase, respectively, the activity of the protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor (Lancet 1999;353:112). We report here on an independent study of 387 healthy young women. Genotyping was performed by allele-specific amplification and serum chemistries were measured by automated clinical assay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respectively, yielding a 986S allele frequency of 15%. Mean total serum calcium (Ca_r) was significantly higher in the SS (9.88 ± 0.29 mg/dL, p=.015) and AS groups (9.45 ± 0.05 mg/dL, p=.002), than in the AA group (9.23 ± 0.04 mg/dL). In multiple regression modelling, the A986S genotype remained an independently significant predictor of Ca_r (p<.0001) when serum total protein, albumin, phosphate, magnesium, and creatinine covariates were included. These data are among the first to show significant association between a common polymorphism and a serum electrolyte assay. The A986S polymorphism is also a potential predisposing factor in disorders of bone and mineral metabolism.