GENETIC DETERMINANTS OF VESICOURETERAL REFLUX

Vesicoureteral reflux (VUR) is a condition characterized by retrograde flow of urine from the bladder into the ureters and kidneys during micturation. The diagnosis is most commonly made by Voiding Cystourethrogram in a child who presents with urinary tract infection. It occurs in 1% of live births and accounts for up to 25% of pediatric end-stage renal disease. The biological basis of this disorder is poorly understood, but increased familial aggregation suggests that genetic factors are important in its pathogenesis. These data motivate genetic approaches to elucidate the biological basis of VUR. To accomplish this goal, we have recruited a unique cohort of large families with VUR to investigate the genetic determinants of this disease. Three are the aims of this project: 1) recruit patients with familial and sporadic forms of VUR to enable execution of clinical and genetic studies; 2) perform a genome wide analysis of linkage to localize gene(s) underlying VUR; 3) identify and characterize the causative gene(s) and its function. The reduced penetrance and the possible resolution of VUR with age, made difficult the ascertainment of pedigrees tractable for linkage. To date, we have recruited 10 large kindreds with VUR. The pattern of inheritance is consistent with autosomal dominant inheritance with incomplete penetrance. We have excluded linkage to known genes and loci for VUR in these kindreds. Power analyses indicate that we will already have ample power to detect linkage. Moreover, three of these kindreds can each provide LOD scores >3 and are therefore sufficiently large to identify a locus on their own. We will perform a genome-wide screen to obtain chromosomal localization of VUR susceptibility genes and next proceed with identification of the underlying gene(s) by functional and sequence analysis of positional candidates. The discovery of genes causing VUR will have potential for diagnosis and therapy of patients with VUR and other chronic renal diseases.