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The thiazide-sensitive Na-Cl cotransporter (TSC) is the principal modulator of Na⁺ and Cl^– reabsorption in the distal convoluted tubule of the kidney and it indirectly influences renal Ca²⁺ handling. Sequence changes in the TSC gene influence blood pressure regulation and urinary calcium excretion. Alterations in calcium metabolism and hypercalciuria are associated with hypertension, leading to our hypothesis that the TSC gene may play a role in certain types of essential hypertension associated with hypercalciuria. To study the role of the TSC gene in hypertension susceptibility we tested for linkage between hypertension or hypercalciuria and the TSC gene locus. We collected families in whom the probands were under the age of 50 years, and had increased urinary excretion of calcium (Ca²⁺³ 0.314 mmol per mmol creatinine). Five polymorphic microsatellite markers over a region of 10 cM spanning the TSC gene locus on chromosome 16q13 were used for genotyping the families. Affection was defined as the presence of hypercalciuria or drug treated hypertension. Data were analyzed using non-parametric allele-sharing method with the Genehunter software package. Analysis of 49 informative families with a family history of hypertension (more than 20% of first degree relatives of the proband having hypertension) resulted in a peak NPL score of 2.28 (p<0.013) at marker D16S3253 flanking the TSC gene locus. Analyzing only Caucasian families (n=43) the maximum NPL score was 2.98 (p<0.002). Analysis of families in whom there was no family history of hypertension (n=29) resulted in scores near 0 with a peak score of –0.31. To test the null hypothesis that there is equal identity-by-descent allele sharing among pairs of affected relatives in families with a positive or negative family history of hypertension we applied a permutation test to compare differences in the mean NPL score between family history positive and negative families. There was significant heterogeneity of NPL scores at marker D16S3253 (p=0.04 for all families, p=0.01 for Caucasian families). Our results suggest the importance of this genetic region in essential hypertension associated with increased urinary calcium excretion in families with a positive family history of hypertension.