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Familial Vesicoureteral Reflux: Testing Replication of Linkage in Seven New Multigenerational Kindreds

Simone Sanna-Cherchi^*,, Adam Reese^*,, Terry Hensle, Gianluca Caridi, Claudia Izzi^||, You Yeun Kim^*, Anita Konka^*, Luisa Murer^¶, Francesco Scolari^||, Roberto Ravazzolo^**,, Gian Marco Ghiggeri and Ali G. Gharavi^*

^* Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York; Department of Clinical Medicine, Nephrology, and Health Science, University of Parma, Italy; Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York; Laboratory on Pathophysiology of Uremia, G. Gaslini Institute, Genoa, Italy; ^|| Division and Chair of Nephrology, Spedali Civili, University of Brescia, Italy; ^¶ Department of Pediatrics, University of Padua, Italy; ^** Laboratory of Molecular Genetics, G. Gaslini Institute; and Department of Pediatrics and CEBR, University of Genoa, Italy

Address correspondence to: Dr. Ali G. Gharavi, Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, 630 W 168th Street, P&S 10-432 New York, NY 10032. Phone: 212-342-1277; Fax: 212-305-3475; E-mail: ag2239{at}columbia.edu

Received for publication December 2, 2004. Accepted for publication March 5, 2005.

Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.

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