Familial calcium stone disease: TaqI polymorphism and the vitamin D receptor

Background and Objective: Calcium nephrolithiasis has a strong familial com ponent. However, to date, no specific genetic abnormality has been identifi ed. Allelic variation in the vitamin D receptor (VDR) gene has been suggest ed as a partial explanation of differential calcium absorption or excretion in these patients. Polymorphism of this gene has been associated with alte red vitamin D activity and has been implicated in osteoporosis and prostate cancer, We propose that a similar association may be found between familia l hypercalciuric stone disease and the VDR, Subjects and Methods: Genomic DNA was isolated from 37 controls and 19 pati ents with hypercalciuria (>250 mg/24 hours) and a family history of nephrol ithiasis, A 740-basepair segment of the VDR gene was amplified by polymeras e chain reaction, digested with TaqI endonuclease, and resolved by gel elec trophoresis. Alleles were classified as "T" if only one TaqI site was prese nt and "t" if two were present. A simplified strength of family history sco re (FHS) was computed by adding 2 and 1 points, respectively, for each firs t- and second-degree relative affected by stone disease, Results: No difference in allelic or genotypic frequencies between the stud y and control groups was present, In the stone group, a significant associa tion was found between the strength of the family history and the TI genoty pe, Patients with this genotype had an average FHS of 4.0, whereas the mean FHS for the Tt and tt genotypes was 2.0 and 1.8, respectively (P < 0.05), Nonsignificant trends of the TT genotype toward a higher number of stone ep isodes (19 v 13 and 3) and higher 24-hour urine calcium excretion (408 v 29 7 and 353 mg) were also noted in the study group, Conclusion: The results suggest that the TT genotype is associated with mor e aggressive stone disease, both within families and with respect to recurr ence. Quantifying the risk of calcium stone disease through DNA markers has potential application in determining the risk of a patient's family member s for nephrolithiasis or a patient's risk of recurrence, This information m ay have therapeutic implications with regard to the rigor of medical therap y and frequency of follow-up.