Exploring metabolic changes in gout - Insights from a genetic study

Gout is the most common inflammatory joint disease caused by the crystallization of urate inside the joints. Patients with gout typically have abnormal blood lipid and sugar levels, which are associated with cardiovascular diseases. However, the relationship between gout and metabolic changes is unclear. Our goal was two-fold: to identify new gout risk factors using genome-wide association analysis and subsequently to investigate the effects of the identified risk alleles on metabolic measures in the bloodstream. We performed a genome-wide meta-analysis for gout in the FinnGen project, the Estonian Biobank, and the UK Biobank, encompassing a total of 992,583 individuals, including 17,972 gout cases. Given that gout is commonly recognized as a disease affecting the elderly, and males specifically, we further explored age- and sex-stratified genetic associations in FinnGen (10,885 cases and 366,392 controls). Finally, we determined the metabolomic consequences of the gout risk-increasing alleles using data from a large metabolomics GWAS. In the meta-analysis, we observed 32 genome-wide significant (P<5x10-8) loci, one of which was novel. In the age- and sex-stratified analyses, we additionally identified one novel gout-associated locus in the male subgroup. The metabolomic findings suggested that the majority of the gout risk alleles primarily affected urate concentration in the bloodstream but not the concentrations of lipids and other metabolites. Therefore, it appears that the associations between gout and metabolic factors at the population level are likely explained by shared lifestyle risk factors. In conclusion, our study sheds new light on the genetic architecture of gout and adds to the growing body of evidence supporting the role of urate, but not other metabolic measures, including lipoprotein lipids and glucose, as a key risk factor for developing gout.