Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout

Objective: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. Methods: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. Results: The PRS was associated with earlier age at gout onset in men (β = –3.61 in years per unit PRS [95% confidence interval (95% CI) –4.32, –2.90] in European men; β = –6.35 [95% CI –8.91, –3.80] in East Polynesian men; β = –3.51 [95% CI –5.46, –1.57] in West Polynesian men) but not in women (β = 0.07 [95% CI –2.32, 2.45] in European women; β = 0.20 [95% CI –7.21, 7.62] in East Polynesian women; β –3.33 [95% CI –9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (β = –2.42 [95% CI –3.37, –1.46] and β = –6.80 [95% CI –10.06, –3.55], respectively) but not in West Polynesian men (β = –1.79 [95% CI –4.74, 1.16]). Conclusion: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups