Circulating Inflammatory Cytokines, Lipoprotein Particles, and Gestational Diabetes Risk: A Mendelian Randomization Study

To explore the causal associations between inflammatory cytokines and lipoprotein particles and analyze the possible mediating role of lipoprotein particles. Independent single nucleotide polymorphisms (SNPs) were employed as instrumental variables (IVs). We employed Two-Sample Mendelian Randomization (TSMR) to examine the effects of 41 inflammatory cytokines and 17 lipoprotein particles on gestational diabetes mellitus (GDM) risk, with additional evaluation of lipoprotein particles' potential mediating effects. Our primary analysis utilized inverse variance weighted (IVW) estimation, complemented by secondary methods including weighted median and MR-Egger regression to verify result robustness. Inverse variance weighting (IVW) estimates revealed that genetically predicted lower levels of GROA (OR = 0.901 [95% CI: 0.831, 0.977], p = 0.011), VEGF (OR = 0.941 [95% CI: 0.891, 0.996], p = 0.034), IL_12_P70 (OR = 0.927 [95% CI: 0.862, 0.997], and p = 0.037), and CTACK (OR = 0.901 [95% CI: 0.831, 0.977], p = 0.011) with an increased risk of gestational diabetes mellitus (GDM). Conversely, higher levels of IL-1β (OR = 1.134 [95% CI: 1.006, 1.277], and p = 0.039) and HGF (OR = 1.292 [95% CI: 1.102, 1.515], p = 0.002) were associated with an elevated risk of GDM. Additionally, our study indicated a relationship between three HDL particles and GDM (p < 0.05). Furthermore, mediation analysis revealed that very large high-density lipoprotein (VLHDL) particles partially mediated the association between hepatocyte growth factor (HGF) and GDM, accounting for 1.29% of the total effect. The results of two-step Mendelian randomization analysis suggested a causal relationship between circulating inflammatory cytokines and lipoprotein particles and an increased risk of GDM.