EXCLUSION MAPPING OF MAJOR CRYSTALLIZATION INHIBITORS IN IDIOPATHIC CALCIUM UROLITHIASIS

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Abstract
We determined whether genetic variation at 3 loci coding for putative crystallization inhibitors is linked to calcium urolithiasis. We studied a cohort of 64 French-Canadian sibships including multiple recurrent calcium stone formers, comprising 154 independent pairs of siblings with at least 1 stone episode. Physical and meiotic mapping of the genes coding for osteopontin and uromodulin (Tamm-Horsfall protein) as well as the osteocalcin related gene (ORG or putative nephrocalcin) was performed and microsatellite markers were identified. We used nonparametric linkage analysis in the whole affected sib pair cohort as well as in affected pairs without hypercalciuria, that is concordant for 24-hour urine calcium excretion in the first quartile (mean plus or minus standard deviation 0.053 +/- 0.020 mmol./kg. or 3.4 +/- 1.3 mmol. daily), and in the first and second quartiles (mean 0.064 +/- 0.027 mmol./kg. or 4.9 +/- 2.1 mmol. daily, respectively). Lod scores were less than 0.3 for all 3 loci using these affection statuses. Further analysis enabled the exclusion of uromodulin at (relative risk or lambda = 3.9 and 2.5), osteopontin (lambda = 2.7 and 1.6) and ORG (lambda = 5.5 and 3.7) for affected sib pairs concordant for urine calcium excretion in the lowest and 2 lowest quartiles, respectively. Loci encoding 3 crystallization inhibitors are unlikely to be major genes involved in calcium stone formation in our population.

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