Prospective association of the triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol ratio with anxiety risk in a community-based cohort: a UK Biobank study

OBJECTIVE: To investigate whether the triglyceride-glucose (TyG) index and the triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio, as clinical surrogates of insulin resistance, predict the risk of anxiety, and to examine the potential mediating role of plasma proteins. DESIGN: Prospective cohort study. SETTING: Community-based population cohort in the United Kingdom. PARTICIPANTS: A total of 412 767 participants aged 40-69 years without anxiety at baseline and with available data on TyG index and TG/HDL-C ratio were included. Among them, 43 991 participants had proteomic data with 2923 unique plasma proteins measured. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the incidence of first-episode anxiety. The main exposures were TyG index and TG/HDL-C ratio. Mediation analysis was conducted to assess the contribution of plasma proteins. RESULTS: During a median follow-up of 13.8 years, 21 616 cases of first-episode anxiety were identified. Higher quintiles of TyG index and TG/HDL-C ratio were significantly associated with increased anxiety risk (p trend <0.001). Each one SD increase in TyG index and TG/HDL-C ratio was associated with an 8% and 9% higher risk of anxiety, respectively. Mediation analysis showed that 36 proteins jointly explained 64.0% and 74.9% of the associations of TyG index and TG/HDL-C ratio with anxiety, respectively, with asialoglycoprotein receptor 1 (ASGR1) and protease serine 8 (PRSS8) identified as key mediators. CONCLUSIONS: Elevated baseline TyG index and TG/HDL-C ratio are associated with an increased risk of anxiety, and this association may be mediated by ASGR1 and PRSS8.