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.本研究旨在探讨甘油三酯-葡萄糖（triglyceride-glucose, TyG）指数与尿酸转运蛋白基因*ABCG2*和*SLCA29*的多基因风险评分（polygenic risk scores, PRS）对高尿酸血症的联合影响。本研究采用两项基于人群的前瞻性队列研究的基线数据，共纳入30453名50岁及以上受试者，分析TyG指数与高尿酸血症的关联。随后从上述队列中构建病例对照研究亚群，纳入595对匹配受试者，探究遗传易感性与TyG指数对高尿酸血症的交互作用。本研究基于*ABCG2*和*SLCA29*基因上的14个单核苷酸多态性（single nucleotide polymorphism, SNP）构建PRS。在两性群体中，更高的TyG指数水平均与血清尿酸（serum urate, SUA）水平升高显著相关（两性的*p*值均<0.001）。调整协变量后，男性群体中TyG指数每升高1个单位，高尿酸血症的发病风险升高1.44倍（95%置信区间（confidence interval, CI）：1.35~1.55）；女性群体中该风险比值为1.69（95%CI：1.51~1.89）。限制性立方样条模型分析显示，TyG指数与血清尿酸水平升高呈线性及非线性关联（两者*p*值均<0.001）。TyG指数与高尿酸血症的关联在遗传风险更高的人群中更为显著，反之亦然。与TyG<9且PRS<2的受试者相比，TyG<9但PRS≥2、TyG≥9但PRS<2、TyG≥9且PRS≥2组受试者的高尿酸血症比值比（odds ratio, OR）及95%CI分别为3.30（1.53~7.14）、3.16（1.23~8.11）和7.55（2.76~20.65）。相加交互作用分析亦具有统计学意义，遗传易感性与TyG指数的相加交互作用可解释57.5%（30.5%~84.4%）的超额发病风险。高TyG指数人群中，遗传易感性对高尿酸血症的影响显著更强，超过50%的发病风险增量可归因于遗传-表型交互作用，表明在评估高尿酸血症发病风险时，遗传因素与TyG指数存在重要的协同效应。