title: Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1.
abstract: Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults. There is a 30-50-fold increased incidence of VUR in first-degree relatives of probands, compared with the general population. We report the results of the first genomewide search of VUR and RN; we studied seven European families whose members exhibit apparently dominant inheritance. We initially typed 387 polymorphic markers spaced, on average, at 10 cM throughout the genome; we used the GENEHUNTER program to provide parametric and nonparametric linkage analyses of affected individuals. The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16. Saturation with markers at 1-cM intervals increased the NPL to 5.94 (P=.00009). Hence, VUR maps to a locus on chromosome 1. There was evidence of genetic heterogeneity at the chromosome 1 locus, and 12 additional loci were identified genomewide, with P<.05. No significant linkage was found to 6p, where a renal and ureteric malformation locus has been reported, or to PAX2, mutations of which cause VUR in renal-coloboma syndrome. Our results support the hypothesis that VUR is a genetic disorder.
authors.affiliation: Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom. sfeather@ich.ucl.ac.uk
authors.forename: S A
authors.initials: SA
authors.lastname: Feather
authors.forename: S
authors.initials: S
authors.lastname: Malcolm
authors.forename: A S
authors.initials: AS
authors.lastname: Woolf
authors.forename: V
authors.initials: V
authors.lastname: Wright
authors.forename: D
authors.initials: D
authors.lastname: Blaydon
authors.forename: C J
authors.initials: CJ
authors.lastname: Reid
authors.forename: F A
authors.initials: FA
authors.lastname: Flinter
authors.forename: W
authors.initials: W
authors.lastname: Proesmans
authors.forename: K
authors.initials: K
authors.lastname: Devriendt
authors.forename: J
authors.initials: J
authors.lastname: Carter
authors.forename: P
authors.initials: P
authors.lastname: Warwicker
authors.forename: T H
authors.initials: TH
authors.lastname: Goodship
authors.forename: J A
authors.initials: JA
authors.lastname: Goodship
mesh_terms: D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005060:Europe; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D018740:Genetic Heterogeneity; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012984:Software; D018709:Statistics, Nonparametric; D013577:Syndrome; D014718:Vesico-Ureteral Reflux / Q000235:genetics* / Q000473:pathology*
chemical_list: D005819:Genetic Markers