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Association of the Calcium-Sensing Receptor Gene with Blood Pressure and Urinary Calcium in African-Americans

Departments of Medical and Molecular Genetics (J.J., T.M.F., L.F.-W., H.J.E., S.-A.Z.), Medicine (G.J.E., J.H.P.), and Biochemistry and Molecular Biology (H.J.E., X.X.), Indiana University School of Medicine, and the Richard L. Roudebush Veterans Affairs Medical Center (J.H.P.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: J. Howard Pratt, M.D., Veterans Affairs Medical Center, 1481 West 10th Street, Indianapolis, Indiana 46202. E-mail: johpratt{at}iupui.edu.

Context: Calcium binding to the Ca-sensing receptor (CASR) expressed in thick ascending limb inhibits the Na,K,2Cl cotransporter, which decreases sodium reabsorption and secondarily decreases Ca reabsorption. CASR gene variants could influence blood pressure (BP) by affecting Na retention.

Objective: The objective of the study was to determine whether variations in CASR associated with BP in African-Americans, an ethnic group at high risk for hypertension.

Design: Population- and family-based association studies of single-nucleotide polymorphisms (SNPs) in CASR with BP measured over the age range 5.6–25 yr (14 biannual visits per subject on average) were carried out. In a cross-sectional study where urinary Ca excretion had been measured, Ca excretion was used as an additional phenotype of CASR influence on Na,K,2Cl cotransporter activity.

Participants: Subjects were normotensive. In the longitudinal study, there were 223 subjects (mean age 14 yr) and 123 families (one or both parents provided a DNA sample); in the cross-sectional study, there were 106 subjects (mean age 23 yr) and 88 families.

Results: Three SNPs in linkage disequilibrium associated with systolic BP at P < 0.005 (the significance threshold corrected for multiple comparisons) in the population-based longitudinal study. In the cross-sectional study, SNPs contained in the same linkage disequilibrium block associated with urinary Ca excretion in both population- and family-based association studies.

Conclusion: The findings suggest that in African-Americans, functional heterogeneity of the CASR in thick ascending limb may influence BP.