Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

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.

Keywords: cardio-cerebrovascular diseases; causal association; glucose; triglyceride; triglyceride-glucose index.

Figure 1

The inclusion and exclusion criteria of study participants and the factorial study design.

Figure 2

Independent associations of 1-SD higher glucose and triglyceride with the risk of major CVD. CVD, cardiovascular and cerebrovascular metabolic diseases; IHD, ischemic heart diseases; CED, cerebrovascular diseases; GLU, glucose; TG, triglyceride. ΔGLU and Δlog TG: the difference of observed glucose level between the higher GLU genetic score group or the higher TG genetic score group and the reference group. The difference value and corresponding OR (95% CI) were scaled to the 1-SD difference (0.62 mmol/L or 0.50 log mmol/L).

Figure 3

Association of joint exposure to higher glucose and triglyceride with the risk of CVD. CVD, cardiovascular and cerebrovascular metabolic diseases; IHD, ischemic heart diseases; CED, cerebrovascular diseases; AP, angina pectoris; AMI, acute myocardial infarction; CIHD, chronic ischemic heart disease; HF, heart failure; HS, hemorrhagic stroke; IS, ischemic stroke; GLU, glucose; TG, triglyceride. ΔGLU and Δlog TG: the difference of observed glucose level and log converted TG level between the higher GLU/TG genetic score group and the reference group.

Figure 4

Association of the triglyceride–glucose index with the risk of CVD. CVD, cardiovascular and cerebrovascular metabolic diseases; IHD, ischemic heart diseases; CED, cerebrovascular diseases; AP, angina pectoris; AMI, acute myocardial infarction; CIHD, chronic ischemic heart disease; HF, heart failure; HS, hemorrhagic stroke; IS, ischemic stroke. ΔTyG: the difference of the observed triglyceride–glucose index level between the higher TyG index genetic score group (Q2–Q4) and the reference group (Q1).

Figure 5

Dose–response associations of meta-regression for combined glucose and triglyceride on the risk of CVD and IHD. CVD, cardiovascular and cerebrovascular metabolic diseases; IHD, ischemic heart diseases; iLTG, incremental log TG; iGLU, incremental GLU, iTyG, incremental TyG index. The combined TG and GLU subgroup linked the Q1–Q4 TG group and Q–Q4 GLU group. The 1-1 subgroup was set as the reference, and the incremental TG and GLU was the crude mean difference compared to the reference. The risk of CVD and IHD for each subgroup relative to the reference group is plotted and expressed as an increased proportional risk. The dashed line is the regression line of increased proportional risk.