THE 1-ALPHA-HYDROXYLASE LOCUS IS NOT LINKED TO CALCIUM STONE FORMATION OR CALCIURIC PHENOTYPES IN FRENCH-CANADIAN FAMILIES

Calcium urolithiasis is often associated with increased intestinal abs orption and urine excretion of calcium, and has been suggested to resu lt from increased vitamin D production. The role of the enzyme 1 alpha -hydroxylase, the rate-limiting step in active vitamin D production, w as evaluated in 36 families, including 28 sibships with at least a pai r of affected sibs, using qualitative and quantitative trait linkage a nalyses. Sibs with a verified calcium urolithiasis passage (n = 117) h ad higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)(2) vitamin D levels (P = 0.02) compared with non-stone-forming sibs (n = 120). Markers fro m a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 1 2q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (1 46 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (greater than or equal to 3 episod es) stone forming sibs. Two-point and multipoint analyses did not reve al excess in alleles shared among affected sibs at the VDD1 locus. Lin kage of stone formation to the VDD1 locus could be excluded, respectiv ely, with a lambda(d) of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed n o evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)( 2) vitamin D levels, and Ca/cr ratios. This study shows absence of lin kage of the putative 1 alpha-hydroxylase locus to calcium stone format ion or to quantitative traits associated with idiopathic hypercalciuri a. In addition, there is coaggregation of calciuric and oxaluric pheno types with stone formation.