Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene

Serum calcium is under tight physiological control, but it is also a quanti tative trait with substantial genetic regulation. Mutations of the CASR gen e cause familial hypocalciuric hypercalcemia or autosomal dominant hypopara thyroidism, depending on whether they decrease or increase, respectively, l igand binding to the receptor protein. We described an association between ionized calcium and a common polymorphism (A986S) found in the cytoplasmic tail of this G protein-coupled receptor. We report here on an independent s tudy of 387 healthy young women. Genotyping was performed by allele-specifi c amplification and serum chemistries were measured by automated clinical a ssay. Frequencies of SS, AS, and AA genotypes were 6, 107, and 274, respect ively, yielding a 986S allele frequency of 15.4%. Mean total serum calcium (Ca-T) was significantly higher in the SS (9.88 +/- 0.29 mg/dL, P = 0.015) and AS groups (9.45 +/- 0.05 mg/dL, P = 0.002), than in the AA group (9.23 +/- 0.04 mg/dL). In multiple regression modeling, the A986S genotype remain ed an independently significant predictor of Ca-T (P < 0.0001) when serum a lbumin, globulin, inorganic phosphate, and creatinine covariates were inclu ded. These data are the first to show significant association between a com mon polymorphism and concentrations of a serum electrolyte. The A986S polym orphism is also a potential predisposing factor in disorders of bone and mi neral metabolism. (C) 2001 Academic Press.