Triglyceride-glucose index and its additive interaction with <i>ABCG2/SLC2A9</i> polygenic risk score on hyperuricemia in middle age and older adults: findings from the DLCC and BHMC study

We aim to investigate the joint effect of triglyceride-glucose (TyG) index and polygenic risk scores (PRS) of urate transporter genes <i>ABCG2</i> and <i>SLC2A9</i> on hyperuricemia. Baseline data from two prospective population-based cohort studies, including 30,453 individuals aged 50 years or older, were used to analyze the association between TyG index and hyperuricemia. A case-control study was then designed from the cohorts to investigate the interaction between genetic predisposition and TyG index on hyperuricemia among 595 matched pairs. PRS was constructed using 14 single nucleotide polymorphisms located in the <i>ABCG2</i> and <i>SLCA29</i> genes. In both sexes, higher TyG index levels were correlated with elevated serum urate (SUA) levels (<i>p</i> values in both sexes &lt; 0.001). In men, per unit increase of TyG was associated with a 1.44-fold (95% confidence interval [CI]: 1.35–1.55) higher risk of hyperuricemia after adjusted for covariates. In women, this estimate was 1.69 (1.51–1.89). Demonstrated by the restrict cubic spline model, TyG index was both linearly and non-linearly associated with elevated SUA (both <i>p</i> values &lt; 0.001). Association between TyG index and hyperuricemia was stronger among people with higher genetic risk, and vice versa. Compared to people with TyG &lt; 9 and PRS &lt; 2, the odds ratios (ORs) (95% CIs) for hyperuricemia in the TyG &lt;9 but PRS ≥2, TyG ≥9 but PRS &lt; 2, TyG ≥9 and PRS ≥2 groups were 3.30 (1.53–7.14), 3.16 (1.23–8.11) and 7.55 (2.76–20.65), respectively. Additive interaction was also significant, with 57.5% (30.5%–84.4%) of the excess risk attributable to the additive gene-TyG index interaction. The impact of genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index. Over 50% of the increased risk can be attributed to the interaction, indicating a crucial synergy between genetic factors and TyG index when estimating hyperuricemia risk. There are both linear and non-linear relationships between TyG index and serum urates.Genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index.Over 50% of the increased risk of hyperuricemia can be attributed to the genetic-phenotype interaction. There are both linear and non-linear relationships between TyG index and serum urates. Genetic predisposition on hyperuricemia was significantly greater among individuals with a higher TyG index. Over 50% of the increased risk of hyperuricemia can be attributed to the genetic-phenotype interaction.