Exclusion mapping of major crystallization inhibitors in idiopathic calcium urolithiasis

Purpose: We determined whether genetic variation at 3 loci coding for putat ive crystallization inhibitors is linked to calcium urolithiasis. Materials and Methods: We studied a cohort of 64 French-Canadian sibships i ncluding multiple recurrent calcium stone formers, comprising 154 independe nt pairs of siblings with at least 1 stone episode. Physical and meiotic ma pping of the genes coding for osteopontin and uromodulin (Tamm-Horsfall pro tein) as well as the osteocalcin related gene (ORG or putative nephrocalcin ) was performed and microsatellite markers were identified. We used nonpara metric linkage analysis in the whole affected sib pair cohort as well as in affected pairs without hypercalciuria, that is concordant for 24-hour urin e calcium excretion in the first quartile (mean plus or minus standard devi ation 0.053 +/- 0.020 mmol./kg. or 3.4 +/- 1.3 mmol. daily), and in the fir st and second quartiles (mean 0.064 +/- 0.027 mmol./kg. or 4.9 +/- 2.1 mmol . daily, respectively). Results: Lod scores were less than 0.3 for all 3 loci using these affection statuses. Further analysis enabled the exclusion of uromodulin at (relativ e risk or lambda = 3.9 and 2.5), osteopontin (A = 2.7 and 1.6) and ORG (lam bda = 5.5 and 3.7) for affected sib pairs concordant for urine calcium excr etion in the lowest and 2 lowest quartiles, respectively. Conclusions: Loci encoding 3 crystallization inhibitors are unlikely to be major genes involved in calcium stone formation in our population.