Insights into Causal Associations of Lipid Traits and Lipid-modifying Drug Targets with Uric Acid and Risk of Gout

Emerging lipid-modifying agents show potential but lack evidence for the management of uric acid and gout. We aimed to explore the causal effects of lipid traits, lipid-modifying drugs on uric acid levels and risk of gout. Two-sample MR analyses were performed to investigate the associations of genetically predicted lipid traits (LDL-C, HDL-C and TG) and lipid-modifying drug targets (PCSK9, HMGCR, NPC1L1, CETP, ABCG5/G8, APOB, LDLR, LPL, ANGPTL3, and APOC3) with uric acid levels and gout risk. Validation analyses were performed using the independent cohort of the UK Biobank. Summary-data-based MR was further conducted to estimate the associations of the expression of drug target genes with the outcomes. Genetically predicted lower HDL-C and higher TG were significantly associated with elevated uric acid levels (beta (95% CI): -0.11 [-0.18, -0.04], p = 0.001 for HDL-C; 0.18 [0.09, 0.27], p < 0.001 for TG) and increased risk of gout (OR (95% CI): 0.83 [0.71, 0.97], p = 0.017 for HDL-C; 1.54 [1.25, 1.91], p < 0.001 for TG). Notably, LPL activation among lipid-modifying drug targets demonstrated significant associations with both reduced uric acid levels (beta [95% CI]: -0.13 [-0.16, -0.10], p < 0.001) and decreased risk of gout (OR 95% CI: 0.84 [0.76, 0.93], p = 0.001). These findings were corroborated in the UK Biobank dataset. Furthermore, the expression of LPL was significantly associated with lower uric acid levels (beta [95% CI]: -0.03 [-0.04, -0.01], p = 0.002). Our results suggest that LPL activation, which reduces TG levels, holds promise as a candidate drug for the treatment and prevention of hyperuricemia and gout.