All ETDs from UAB

Advisory Committee Chair

Tony Merriman

Advisory Committee Members

Angelo Gaffo

M Ryan Irvin

Richard Reynolds

Alex Szalai

Hemant Tiwari

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Gout is a common inflammatory arthritis that is increasing in prevalence globally. It has clear sex differences, being more common among men, though comorbidities appear to be more common among women. It also varies in prevalence between populations, driven by a combination of genetic and socioeconomic factors. Genetic studies have identified gout-associated genetic variants, several of which are shared between different populations. Here, I combined gout-associated genetic variants into a gout polygenic risk score. This score was then used to elucidate the genetic underpinning of gout severity and presence of comorbidities, comparing its effects in different sexes and populations. I found that increased gout genetic risk reduced the age at onset for gout in men, but not women, of both European and Polynesian ancestry. I also identified genetic associations with tophaceous disease that were partially independent of the genetic effects on age at gout onset. These differences highlight the role of genetics in gout risk for men, though gout in women appears to be under less genetic control. I then used this polygenic risk score to highlight a flaw in existing methodology for identifying genetic variants that associate with the progression from hyperuricemia to gout. By testing the association of the polygenic risk score with gout at various thresholds of hyperuricemic controls in men and women separately, I was able to show that any identified genetic effects were likely due to residual association of the genetic variants with serum urate. This highlighted a likely role of serum urate in gout risk beyond hyperuricemia, and further showed evidence for a serum urate-independent genetic effect on gout in men but not women. Finally, I applied this polygenic risk score to improve understanding of the role of comorbidities in gout. Initially, this study highlighted ethnicity-dependent sex interactions for the association of gout with comorbidities. I then showed that the effect of the polygenic risk score and serum urate on gout were both dependent on the number of comorbidities that a person with gout has. Finally, I highlighted sex differences in the direct and indirect effects of gout genetic risk, serum urate, and comorbidity burden.

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