Title: Establishing the domestic cat as a novel model of spontaneous nephrolithiasis by investigation of the genetic basis of disease
Funder: The Academy of Medical Sciences

Abstract: Aims and objectives: The aims of this project are: 1) To use whole genome sequencing (WGS) to identify genetic variants associated with feline calcium oxalate nephrolithiasis. 2) To establish the alternate allele frequency of nephrolith-associated variants in a larger population of kidney stone-formers and non-stone-formers. 3) To begin functional follow-up of selected novel variants to identify potential mechanisms by which they contribute to nephrolithiasis, with the objective of revealing new treatment targets. Calcium oxalate nephrolithiasis is a common and painful problem in both humans and cats, leading to substantial morbidity. The heritability of genetic variants associated with the condition is well-established in humans, but it is estimated that only 20% of the genes associated with nephrolithiasis have been identified. Despite the relatively high incidence of the condition in cats, the genetics of feline nephrolithiasis are currently unexplored. I hypothesise that young cats with kidney stones will share one or more rare genetic variants of high or moderate impact. The genes in which these variants are found may offer new therapeutic targets for treatment or prevention of feline and / or human nephrolithiasis. Using WGS, I will identify candidate variants associated with feline nephrolithiasis and will use variant data from the Feline 99 Lives consortium, as well as a follow-up array, to establish alternate allele frequencies in a larger feline population. I will select one or more variants in genes with a plausible effect on renal handling of calcium or oxalate to explore their functional impact in an in vitro model.

Lay abstract: Kidney stones are a common problem and can be extremely painful. Approximately 10-20% of people will have a kidney stone at some point during their lifetime and some people suffer from them recurrently. Cats also commonly suffer from kidney stones, causing pain and potentially fatal obstructions between their kidneys and bladder. The most common type of kidney stone is the same in both humans and cats, made of a substance called calcium oxalate. In humans, genetics play a big part in an individual’s risk of kidney stone formation, but currently we do not know all the genes that are involved. Improved identification of the important genes in kidney stone formation has the potential to reveal targets for new treatments. The genetics of feline kidney stones has never been investigated. Identification of genetic mutations in cats that form kidney stones spontaneously at a very young age, will help with the discovery of new kidney stone genes, potentially improving our understanding and management of kidney stones in people. All cats enrolled in this study will be veterinary patients being treated for kidney stones or other conditions at the Royal Veterinary College. This study will use technology called whole genome sequencing to examine the genetic differences between stone-forming cats and cats that reach a healthy old age without forming stones. The most promising genetic differences will then be checked in a larger group of affected and unaffected cats, allowing prioritisation of the genes for more in-depth study to develop new treatments.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;DISPUTED AETIOLOGY AND OTHER