The impact of cardiovascular disease risk factors and treatments on the development of gout

Objective. The goal of this dissertation is to fill the knowledge gap of the role of obesity, hypertension, diuretic use, and urate genes on the development of gout.;Methods. This dissertation utilized two longitudinal cohorts: CLUE and ARIC. Incident gout was the outcome of interest. The association of obesity and gout was estimated using a Poisson regression for cumulative incidence ratios (RR). Multivariate Cox Proportional analysis estimated the Hazard Rate Ratio (HR) to test the association of gout with hypertension and diuretic use (among hypertensive participants). The gene-by-diuretic interaction was tested using a logistic regression model and estimated Odds Ratios (OR). We tested the direct effect of urate genes on gout after accounting for biological variability in serum urate using a Cox Proportional model with regression calibration. All models were adjusted for confounders.;Results. Self-reported gout status was reliable (kappa=0.73) and sensitive (84%). The 18-year RR of gout in obese participants compared to non-obese participants was 1.92 (95% Confidence Interval (CI): 1.55, 2.37); the onset of gout was 3.1 years (95% CI: 0.3, 5.8) earlier in those who were obese at baseline and 11.0 years earlier (95% CI: 5.8, 16.1) in those obese at age 21. Hypertension (HR= 2.18; 95% CI: 1.68, 2.83), diuretic use (HR=1.48, 95% CI: 1.11, 1.98), thiazide diuretic use (HR=1.44, 95% CI: 1.00, 2.10), and loop diuretic use (HR=2.31, 95% CI: 1.36, 3.91) were all associated with gout. Serum urate mediated these associations. Use of a thiazide or loop diuretic was associated with gout for those with a genetic score above the median, OR 2.18 (95% CI: 1.31, 3.64) but not among those with a genetic mate score below the median, OR 0.37 (95% CI: 0.13, 1.03); p-value for interaction=0.003. Finally, the association of urate genes with incident gout was almost completely explained by serum urate level once long term variation was taken into account (HR=6.50, 95% CI: 2.69, 15.70 dropped to 2.45; 95% CI: 0.96, 6.22; p-value=0.06), suggesting full mediation by serum urate level.;Conclusions. This dissertation confirms and extends the association of known gout risk factors, obesity, hypertension, and diuretic use. We identified novel subpopulations at increased gout risk due to genetic and environmental exposures.