Decoding the lipid etiology of atherogenic index of plasma and gout: establishing the causal role of triglycerides through NHANES, Mendelian randomization, and network pharmacology.

backgroundAlthough a cross-sectional relation between the atherogenic index of plasma (AIP) and gout has been well documented, the causal roles of its principal components, TG and HDL-C, have not yet been clearly established. Therefore, this study sought to explicate the causal relations between AIP, its individual constituents, and the risk of gout, as well as to investigate the potential molecular mechanisms underlying these associations.

methodsWe adopted an integrated analytical pipeline. First, mediation and cross-sectional analyses were carried out to quantify the phenotypic associations of TG, HDL-C, and AIP with gout. Second, both multivariable and univariable Mendelian randomization (MR) analyses were applied to assess causal directions. Finally, a network pharmacology approach was applied to construct interaction networks linking lipid-related factors with gout, and subsequent enrichment analyses were done to identify the main biological pathways involved and key genes were identified using the Icelandic database's pQTLs.

resultsAIP showed a significant positive link with gout prevalence (OR = 1.700, p = 0.010), with this relationship being mediated mainly by HDL-C (45.19%), rather than TG or LDL-C. Univariable MR analyses indicated that TG exerted a substantial causal effect on gout risk (OR = 1.0058, p < 0.001). Although univariable MR showed a nominally protective association for HDLC (OR = 0.623, 95% CI: 0.399-0.974, p = 0.042), this effect was attenuated and became statistically nonsignificant after multivariable adjustment for other lipid traits (p > 0.05). After adjustment for genetic correlations in multivariable MR analyses, TG remained the sole lipid trait with a robust and independent causal effect on gout (OR = 1.0077, p < 0.001), whereas neither HDL-C nor LDL-C reached statistical significance. The TG-specific gout-associated gene set (Group B) was significantly enriched in T-cell receptor and NF-κB signaling pathways, with hub genes including PTPRC, MYD88, and LCK, supporting a direct lipid-immune axis. By contrast, the combined TG/HDL-C gene set (Group F) showed predominant enrichment in PI3K-Akt and cytokine-cytokine receptor pathways, whereas genes uniquely shared between HDL-C and gout (Group C) were mainly enriched in fundamental cellular processes without marked inflammatory pathway involvement.

conclusionsAIP exhibits a non-linear positive association with gout, but this association is primarily mediated by HDL‑C, which itself has no independent causal protective effect. TG may play an independent causal role in gout, potentially involving T‑cell receptor/NF‑κB signaling pathways. However, these findings are exploratory and require further validation.