Keele Research Repository

OBJECTIVE: To determine whether a gout polygenic risk score (PRS) associates with age at gout onset and tophaceous disease in European (EUR), East Polynesian (EP), and West Polynesian (WP) men/women with gout. METHODS: A 19-variant gout PRS was produced in seven European gout cohorts (NTOTAL = 4,016), two East Polynesian gout cohorts (NTOTAL = 682), and one West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at onset/tophaceous disease. RESULTS: The PRS associated with earlier age at gout onset in men (βEUR [95%-CI]: -3.61 [-4.32, -2.90] years per unit PRS; βEP : -6.35 [-8.91, -3.80]; βWP : -3.51 [-5.46, -1.57]) but not in women (βEUR : 0.07 [-2.32, 2.45]; βEP : 0.20 [-7.21, 7.62]; βWP : -3.33 [-9.28, 2.62]). The PRS showed a positive association with tophaceous disease in men (OREUR : 1.15 [1.00, 1.31]; OREP : 2.60 [1.66, 4.06]; ORWP : 1.53 [1.07, 2.19]) but not in women (OREUR : 0.68 [0.42, 1.10]; OREP : 1.45 [0.39, 5.36]). The age at onset association was robust to the removal of ABCG2 variants from the PRS in Europeans and East Polynesians but not West Polynesians (βEUR : -2.42 [-3.37, -1.46]; βEP : -6.80 [-10.06, -3.55]; βWP : -1.79 [-4.74, 1.16]). CONCLUSION: Gout risk variants also harbor risk for earlier age at 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 women, and that this genetic risk is shared across multiple ancestral groups.