Background and purpose: Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation. Methods: Summary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect. Results: Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10 −5). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke. Conclusions: Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients.

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.

Background: Available data about the effects of circulating polyunsaturated fatty acids (PUFAs) on ischemic stroke (IS) and its main risk factors remains limited and conflicting. Therefore, we conducted Mendelian randomization (MR) to assess whether genetically predicted PUFA affected IS, lipids and blood pressure (BP). Methods: Genetic instruments associated with IS were derived from ISGC Consortium (n = 29,633), with lipids were derived from GLGC(n = 188,577), with BP were derived from Neale Lab(n = 337,000). The inverse-variance weighted method was the main analysis to estimate the effect of exposure on outcome. Sensitivity analyses included principal components analysis, MR-Egger, weighted median, and weighted mode. Results: Per SD increases in serum α-linolenic acid (ALA) were associated with lower IS risk, with odd ratio (OR) of 0.867(0.782,0.961), arachidonic acid (AA) were associated with higher IS risk (OR: 1.053(1.014,1.094)). Likewise, Per SD increases in ALA were associated with the lower-level low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) (β:-0.122(− 0.144, − 0.101), − 0.159(− 0.182, − 0.135), − 0.148(− 0.171, − 0.126), respectively), AA were associated with the higher-level of LDL-C, HDL-C and TC (β

Background: Although observational studies have shown an association between sex hormone-binding globulin (SHBG), testosterone (T) and cardiovascular diseases (CVD), controversy remains. In this study, we aim to explore the causal effects of SHBG and T on Coronary heart disease (CHD). Methods: We used univariable, network and multivariable mendelian randomization (MR) analysis to investigate the causal effect of SHBG and T on CHD. We performed inverse variance weighted (IVW) MR as the primary analysis, with the robustness of this approach further tested by other methods in sensitivity analysis. The SHBG and T were collected from the UK Biobank data, about 180,000 men aged 40 to 69 years. CHD was collected from CARDIoGRAMplusC4D 1000 Genomes-based GWAS, which was a meta-analysis including 48 studies and involving 60,801 CHD cases and 123,504 controls. Results: Using univariable MR-IVW, the results suggested that a one standard deviation (SD) increase in SHBG, the risk of CHD decreased by approximately 14% (OR (95% CI): 0.86(0.76,0.97)), and that a SD increase in total testosterone (TT), the risk also decreased, approximately 8% (OR (95% CI): 0.92(0.85,0.99)). Multivariable MR showed that both SHBG and TT had no direct causal effect with CHD (a SD increase in SHBG: OR (95% CI):0.75 (0.57,1.00), P = 0.053; a SD increase in TT: OR (95% CI): 1.05(0.90,1.22), P = 0.53). In the network MR analysis, the results suggested that TT might act as mediator in the causal pathway from SHBG to CHD and account for 93% of the total effect of SHBG on CHD, and that SHBG might be a mediator in the causal pathway from TT to CHD and account for 67% of the total effect of TT on CHD. Conclusions: Genetically predicted SHBG and TT were negatively correlated with CHD in both univariable and network MR, which may provide a causal explanation behind the observed conclusion. In addition, TT and SHBG had a bidirectional causal effect. Further work is required to disentangle the downstream effects of SHBG/TT on CHD and the molecular pathways involved, as the simultaneous regulation of SHBG and TT may make it a viable strategy for the prevention or treatment of CHD.

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