Identification of a new candidate locus for uric acid nephrolithiasis

Renal stone formation is a common multifactorial disorder, of unknown etiol ogy, with an established genetic contribution. Lifetime risk for nephrolith iasis is similar to 10% in Western populations, and uric acid stones accoun t for 5%-10% of all stones, depending on climatic, dietary, and ethnic diff erences. We studied a small, isolated founder population in Sardinia, chara cterized by an increased prevalence of uric acid stones, and performed a ge nomewide search in a deep-rooted pedigree comprising many members who forme d uric acid renal stones. The pedigree was created by tracing common ancest ors of affected individuals through a genealogical database based on archiv al records kept by the parish church since 1640. This genealogical informat ion was used as the basis for the study strategy, involving screening for a lleles shared among affected individuals, originating from common ancestors , and utilization of large pedigrees to obtain greater power for linkage de tection. We performed multistep linkage and allele-sharing analyses. In the initial stage, 382 markers were typed in 14 closely related affected subje cts; interesting regions were subsequently investigated in the whole sample . We identified two chromosomal regions that may harbor loci with susceptib ility genes for uric acid stones. The strongest evidence was observed on 10 q21-q22, where a LOD score of 3.07 was obtained for D10S1652 under an affec ted-only dominant model, and a LOD score of 3.90 was obtained using a domin ant pseudomarker assignment. The localization was supported also by multipo int allele-sharing statistics and by haplotype analysis of familial cases a nd of unrelated affected subjects collected from the isolate. In the second region on 20q13.1-13.3, multipoint nonparametric scores yielded suggestive evidence in a similar to 20-cM region, and further analysis is needed to c onfirm and fine-map this putative locus. Replication studies are required t o investigate the involvement of these regions in the genetic contribution to uric acid stone formation.