Association Between PNPLA3 Inhibition and Gout: A Drug Target Mendelian Randomization Study

Aims: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) plays a crucial role in metabolic dysfunction-related steatotic liver disease. ARO-PNPLA3 is a therapeutic agent designed to target PNPLA3, but its long-term effects remain uncertain. The objective of this study was to ascertain the impact of PNPLA3 inhibition on the risk of gout through Mendelian randomization. Methods: Mendelian randomization analysis was conducted by choosing single nucleotide polymorphisms (SNPs) in proximity to the PNPLA3 gene, which were significantly associated with the percentage of hepatic fat, to represent PNPLA3 suppression. Nonalcoholic fatty liver disease and hepatic fibrosis served as positive controls, while urate and gout were the outcomes. Results: Genetically predicted PNPLA3 inhibition significantly increased the risk of gout (OR: 1.83, 95% CI: 1.49 to 2.26, p = 1.44 × 10^-8), idiopathic gout (OR: 2.42, 95% CI: 1.60 to 3.65, p = 2.81 × 10^-5) and urate (OR: 1.12, 95% CI: 1.01 to 1.23, p = 2.56 × 10^-2), but not with gout due to impairment of renal function (OR: 1.25, 95% CI: 0.37 to 4.22, p = 7.23 × 10^-1). Conclusions: This study found that PNPLA3 inhibition increased the risk of high urate level and gout. In addition, PNPLA3 inhibition also increased triglyceride (TG) levels, which partially mediate the relationship between PNPLA3 inhibition and gout. Trial Registration: ClinicalTrials.gov identifier: NCT04844450.