Abstract
Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.
Highlights
The lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure was demonstrated and quantified to be associated with a lower risk of cardio-cerebrovascular diseases (CVD) [1]
Studies showed that the residual risk can be partly attributed to triglyceride-rich lipoproteins [3]; insulin resistance (IR)-related glucose (GLU) and triglyceride (TG) were thought to play an important role in the development of CVD [4]
We derived two datasets according to the above procedure: dataset A enrolled 273,368 participants after excluding individuals with diabetes mellitus (DM) and disorders of lipoprotein metabolism (DLM) to avoid the potential effect of hypoglycemic drugs or lipid-lowering drugs on non-fasting GLU and TG levels; dataset B enrolled 347,076 participants, including those with DM/DLM to assess the performance of generalization
Summary
The lifelong genetic exposure to lower levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure was demonstrated and quantified to be associated with a lower risk of cardio-cerebrovascular diseases (CVD) [1]. Studies showed that the residual risk can be partly attributed to triglyceride-rich lipoproteins [3]; insulin resistance (IR)-related glucose (GLU) and triglyceride (TG) were thought to play an important role in the development of CVD [4]. To clarify these additional risk factors, researchers have committed to exploring the independent effect of circulating TG or GLU on some cardio-cerebrovascular metabolic outcomes [5,6,7,8,9]. The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking
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