Description:
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<jats:title>Background and objectives</jats:title>
<jats:p>Claudin-16 and -19 are proteins forming pores for the paracellular reabsorption of divalent cations in the ascending limb of Henle loop; conversely, claudin-14 decreases ion permeability of these pores. Single-nucleotide polymorphisms in gene coding for <jats:italic toggle="yes">claudin-14</jats:italic> were associated with kidney stones and calcium excretion. This study aimed to explore the association of <jats:italic toggle="yes">claudin-14</jats:italic>, <jats:italic toggle="yes">claudin-16</jats:italic>, and <jats:italic toggle="yes">claudin-19</jats:italic> single-nucleotide polymorphisms with calcium excretion.</jats:p>
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<jats:title>Design, setting, participants, & measurements</jats:title>
<jats:p>We performed a retrospective observational study of 393 patients with hypertension who were naïve to antihypertensive drugs, in whom we measured 24-hour urine calcium excretion; history of kidney stones was ascertained by interview; 370 of these patients underwent an intravenous 0.9% sodium chloride infusion (2 L in 2 hours) to evaluate the response of calcium excretion in three different 2-hour urine samples collected before, during, and after saline infusion. Genotypes of <jats:italic toggle="yes">claudin-14</jats:italic>, <jats:italic toggle="yes">claudin-16</jats:italic>, and <jats:italic toggle="yes">claudin-19</jats:italic> were obtained from data of a previous genome-wide association study in the same patients.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>Thirty-one single-nucleotide polymorphisms of the 3′ region of the <jats:italic toggle="yes">claudin-14</jats:italic> gene were significantly associated with 24-hour calcium excretion and calcium excretion after saline infusion. The most significant associated single-nucleotide polymorphism was rs219755 (24-hour calcium excretion in GG, 225±124 mg/24 hours; 24-hour calcium excretion in GA, 194±100 mg/24 hours; 24-hour calcium excretion in AA, 124±73 mg/24 hours; <jats:italic toggle="yes">P</jats:italic><0.001; calcium excretion during saline infusion in GG, 30±21 mg/2 hours; calcium excretion during saline infusion in GA, 29±18 mg/2 hours; calcium excretion during saline infusion in AA, 17±11 mg/2 hours; <jats:italic toggle="yes">P</jats:italic>=0.03). No significant associations were found among <jats:italic toggle="yes">claudin-16</jats:italic> and <jats:italic toggle="yes">claudin-19</jats:italic> single-nucleotide polymorphisms and calcium excretion and between <jats:italic toggle="yes">claudin-14</jats:italic>, <jats:italic toggle="yes">claudin-16</jats:italic>, and <jats:italic toggle="yes">claudin-19</jats:italic> single-nucleotide polymorphisms and stones. Bioinformatic analysis showed that one single-nucleotide polymorphism at <jats:italic toggle="yes">claudin-14</jats:italic> among those associated with calcium excretion may potentially influence splicing of transcript.</jats:p>
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<jats:title>Conclusions</jats:title>
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<jats:italic toggle="yes">Claudin-14</jats:italic> genotype at the 3′ region is associated with calcium excretion in 24-hour urine and after the calciuretic stimulus of saline infusion.</jats:p>
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