Genetics of serum urate regulation in human health and disease

Abstract

Uric acid, the end product of purine catabolism in humans, is a biologically active molecule that plays a role in oxidative stress, inflammation, and the regulation of blood pressure. Excessively high serum urate levels (hyperuricaemia) are associated with a wide range of diseases. With the exception of gout, where monosodium urate crystals are known to trigger a painful inflammatory response, both the causality and the underlying mechanisms linking hyperuricaemia and disease are unclear. To better understand the link between uric acid and cardiometabolic disease, I have investigated the correlation between serum urate and 266 Olink protein biomarkers associated with cardiovascular disease and inflammation and 191 lipid species. Using partial correlation and lasso regression, I have identified and replicated 11 protein biomarkers whose serum levels covary with urate independently of the other biomarkers. The associated proteins are involved in diverse processes including phosphate metabolism and bone development, glucose metabolism, adipocyte function and blood pressure regulation. I have additionally identified 15 lipids, some of which have a potential link with cognitive function. To approach the question of uric acid from a regulation perspective, I have run genome-wide association scans, first in our own cohorts, with a sample exceeding 10,000 individuals imputed to the Haplotype Reference Consortium reference panel, the first GWAS of serum urate levels to be run on this panel. Then, as part of the CKDGen consortium, I co-lead a transethnic meta-analysis of over 450,000 individuals, the largest GWAS of serum urate to date. Our work identified 183 urate-associated loci, of which 147 were novel. These loci can be used to create a genetic risk score for urate that has considerable predictive potential for gout, assessed in the UK Biobank.