Gout and Metabolic Disease: Investigation of Potential Relationship in the New Zealand Population

Abstract

Hyperuricaemia, pathologically defined as the presence of higher levels of serum urate, results from a compromise in the delicate balance between the production and excretion of urate primarily in the liver and the kidneys, respectively. Hyperuricaemia is a prerequisite for gout, a painful inflammatory arthritis. The symptoms of gout arise from the body’s immune response to monosodium urate crystals that accumulate in the synovial fluid of the joints. Hyperuricaemia and gout are complex traits. A number of genetic loci confer risk to develop hyperuricaemia. Genome-wide association studies (GWAS), an indispensable tool in population genetics, has identified at least twenty eight genomic loci that contain variants affecting serum urate concentration. Gene-environment interactions also play a significant role in this context. Exogenous factors such as the intake of purine-rich foods increase the frequency of gout flares. Population-specific genetic effects on gout are as evident, if not more, as for other complex phenotypes.

The prevalence of gout is much higher in the New Zealand Polynesian population compared to other populations. Approximately 7% of New Zealand Māori and Pacific Island people and 3% of New Zealand Europeans are affected by gout. The coexistence of metabolic conditions with gout, usually called gout-comorbidities, adds another level of complexity. However, not many studies have attempted to address the causal relationship between these traits. In fact, my research project was instigated as an attempt to study the causal associations between gout and its comorbidities and fill in some gap in the scientific literature. The research was, however, limited to three metabolic conditions/comorbidities of gout – imbalanced iron homeostasis, metabolic syndrome and disrupted lipid metabolism. My study shows an association between increased serum ferritin and the risk of gout and seeded an idea that the consumption of iron-rich diet may play a role in increasing the frequency and severity of gout flares. Genetic association analysis using two variants in the HFE gene was done to confirm the association between ferritin and urate, which showed positive association in a smaller dataset and provoked the idea to investigate the causality, if it exists, between gout and iron metabolism. Using the robust ‘Two-sample Mendelian randomisation’ approach and exploiting summary statistics data from two large GWA studies, I was able to find an evidence of a causal effect of iron on urate metabolism, but not urate on iron metabolism. In the context of the metabolic syndrome, the role of variants within/near the ADRB3, MC3R, MC4R and ADTRP genes were investigated. The positive effects identified for these variants supported the possible involvement of obesity and insulin resistance-related genes in gout pathophysiology. With the help of gene sequencing-based rare variant analyses, several novel population-specific association signals were found within the coding regions of two lipid-related genes, LRP2 and A1CF. Polynesian-specific novel genetic effects were identified to be predictive for gout for common variants within the LRP2 gene. Rare variants within the LRP2 gene were also identified and a higher prevalence of non-synonymous polymorphisms that can increase the risk of hyperuricaemia was observed in European individuals compared to Polynesians. These results indicated LRP2 to contribute to the difference in gout prevalence between Māori and Pacific Island individuals compared to the New Zealand European population. Collectively, my study reports a causal role of iron and ferritin in increasing serum urate concentration and the involvement of imbalanced iron homeostasis in hyperuricaemia. Also, positive genetic associations indicated that genes contributing to metabolic syndrome and lipid metabolism can increase the risk of gout, and also have population-specific effects for the Polynesian and European ancestral groups in New Zealand.