Nicholas A Sumpter, Murray J Cadzow, Riku Takei, Megan P Leask, Angelo Gaffo, Alexander So, Richard J Reynolds, Tony R Merriman
Division of Clinical Immunology and Rheumatology, Department of Medicine, University Of Alabama At Birmingham, Alabama, United States; Department Of Biochemistry, University of Otago, Dunedin, New Zealand; Department of Medicine, Service of Rheumatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
Objectives: We aimed to investigate how gout risk factors interact to influence gout risk in a sex- and ethnicity-stratified setting, with a focus on disease burden (as measured by 12 common gout comorbidities), serum urate, genetic risk for gout, and age.
Methodology: This study included participants of European ancestry from the UK Biobank cohort (N = 402,264; 56.9 ± 8.0 years old; 46% male) and individuals of Black, White, Latinx, or Asian ethnicity from the All of Us cohort (NTOTAL = 342,960; 55.1 ± 17.0 years old; 38% male). Common gout comorbidities were defined using survey data, physical measurements, and electronic health record (EHR) codes. This included 12 total conditions: hypertension, type 2 diabetes, obesity, dyslipidemia, chronic kidney disease (CKD; stage 3, stage 4, and end-stage), liver disease, ischemic heart disease, heart failure, stroke, and sleep apnea. Individuals were categorized based on the number of different comorbidities that they had (0, 1, 2, 3, 4, 5, or 6+). A 27 variant gout polygenic risk score (PRS) was calculated in each individual based on a genome-wide association study for gout in the UK Biobank. Each comorbidity was tested for association with gout using logistic regression models. Both the gout PRS and serum urate level (excluding individuals on urate-lowering therapy) were tested for association with gout, with stratification based on disease burden. Mediation analyses were used to investigate whether the effect of either the gout PRS or disease burden on gout was mediated by serum urate. All models were adjusted for age and stratified by sex and ethnicity.
Findings: All comorbidities were at least twice as common in people with gout relative to non-gout controls, regardless of sex or ethnicity. Interestingly, all comorbidities had higher odds ratios for their association with gout in European/White women compared to men, with non-overlapping confidence intervals for 7 of the 12 conditions. However, the opposite was true in the All of Us Black population, with stronger associations in men for 8 of the 12 conditions, and no sex differences were noted in the Asian and Latinx populations. In European/White men, excluding non-comorbid gout cases, the effect of the PRS on gout was reduced as disease burden increased. In European/White women, those with non-comorbid gout displayed similar urate levels and gout genetic risk when compared to their non-gout counterparts. Disease burden was also more strongly associated with serum urate in European/White women, regardless of gout status. Inference in other populations was limited by small sample size. Mediation analyses suggested that gout genetic risk simultaneously influences gout directly and indirectly (via urate) in the European/White population. The indirect urate effect was similar in both sexes, though the direct effect was stronger in men. In Black and European/White populations, increased disease burden had both a direct and indirect effect (via urate) on gout, both of which had stronger effects in women.
Significance: Our study highlights how gout risk factors influence gout in each sex. Gout in women may result more from increased comorbidity burden, while gout in men may have a larger contribution of serum urate-independent genetic effects. Additionally, non-comorbid gout in women may be uncommon, and women with no comorbidities may be misdiagnosed. Importantly, these sex effects may differ between people of different ethnicities.