Genetic and molecular mechanisms of kidney stone disease

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Kidney stones are common and affect nearly 1 in 5 men in their lifetime. Around half of patients who develop a kidney stone will form another within 10 years. Unfortunately, the reasons why some people make kidney stones are poorly understood and the treatments available to prevent more stones forming are not very effective. It has been said that obesity increases the risk of kidney stones, but it is unclear exactly how or why. If we could better understand why some people form kidney stones, and the links between kidney stones and obesity, we could design improved treatments to prevent this problem. The UK Biobank is a study of nearly half a million people who have shared genetic data, physical measurements, medical records, and blood tests with researchers. I have used this data to show that people who carry more fat around their waist are more likely to get kidney stones, even if their body mass index is normal. This suggests that central fat distribution, not overall obesity, is a risk factor for developing kidney stones. We know from previous research that high blood calcium levels are a risk factor for kidney stones. Looking at the UK Biobank data, I found that people with more fat around their waist are also more likely to have an increased blood calcium level. This result partly, but not fully, explains why increased central fat distribution increases a person's risk of kidney stones. This study aims to improve our understanding of why people form kidney stones. I will investigate the reasons why high levels of central fat are linked to kidney stones and raised blood calcium levels. Using these findings, I will look for new treatments for patients with kidney stones. This project has three main stages and will be carried out at the University of Oxford, a world-leading centre for medical and genetic research. In the first stage of this project, I will use newly released genetic data from the UK Biobank. I will identify areas of DNA that increase an individual's risk of kidney stones by changing how proteins are made. This work will identify pathways that cause kidney stones that were not previously known. To confirm my findings are correct, I will undertake similar studies in other large datasets. In the second stage of the project, I will use the UK Biobank's data on blood biomarkers. Biomarkers are chemicals in the body that may have increased or decreased levels in certain conditions. I will look for blood biomarkers that are high or low in people with a high central fat distribution. I will then see if these are also altered in people with kidney stones or high blood calcium levels. Once I have identified biomarkers that look interesting, I will use a genetic technique called Mendelian randomisation to find out whether changes in the levels of these biomarkers are causally linked to the conditions I am studying. In stages one and two, I will identify pathways and biomarkers that are linked to an increased risk of kidney stones. In stage three, I will use genetic techniques to see if targeting these with medications may be helpful for treatment. I will look to see whether there are any existing medicines that affect these pathways and biomarkers and are used to treat other diseases. I will assess if these medicines could be used in patients with kidney stones. My studies will provide information about which new or current medications we should focus on developing to help treat people with kidney stones in the future.