SNP based sib-pair linkage study to identify loci contributing to Vesicoureteric Reflux and its associated nephropathy

Vesicoureteric reflux (VUR) is the term used for the abnormal passage of urine back up the ureters towards the kidneys. Urine is made by the kidneys and passes from each kidney down a tube called the ureter to the bladder. When someone goes to the toilet, urine leaves the bladder via the urethra and should not re-enter the ureters. Kidney damage associated with VUR accounts for end stage kidney failure (i.e. needing dialysis or transplant) in 3,000 people in the UK. VUR is found in 20-50% of brothers and sisters of affected individuals indicating that there are genetic factors contributing to this abnormality. We have collected blood samples from a large number of brothers and sisters with VUR and their parents and extracted DNA from these samples. We are using normal genetic variation to find DNA variants associated with the condition. This is the first step towards identifying the genetic causes of VUR. We hope that identifying the causes of VUR will lead to better screening tests so that people with VUR can be identified and treated before their kidneys are damaged. We also hope that a better understanding of the causes will lead to new treatment strategies.

Vesicoureteric reflux (VUR) is the retrograde passage of urine from bladder into the upper urinary tract; it represents a congenital malformation of the ureterovesical junction. It is termed primary when outflow obstruction is excluded. Primary VUR occurs in 1% of young children. Reflux nephropathy occurs in a proportion of individuals with primary VUR and accounts for 7-20% of children and 5-10% of adults with end-stage renal failure. As there is a significant heritable component (lamda s 20-50) to primary VUR, a genetic approach should identify loci and ultimately the genes harbouring mutations and polymorphic variants that contribute to VUR. Such information may lead to non-invasive screening strategies and new therapeutic approaches. To this end we have made DNA collections from primary VUR families in the UK and Slovenia. Strict diagnostic criteria have been applied for enrolment and details of both reflux and renal damage have been recorded in a database. The majority of the families comprise two affected siblings and their parents, some families have more than two affected siblings. We have 172 UK VUR families (230 sib pairs) and 150 Slovenian VUR families (187 sib pairs) making this the largest collection of VUR families. This application is for a SNP based genome-wide linkage study of these samples and statistical analysis of the resulting data.