Multi-omics combined to investigate potential druggable therapeutic targets for stroke: A systematic Mendelian randomization study and transcriptome verification.

OBJECTIVE: Stroke is a highly prevalent and disabling disease whose disease mechanisms are not fully understood. The discovery of disease-associated proteins with genetic evidence of pathogenicity provides an opportunity to identify new therapeutic targets. METHOD: We examined the observed and causal associations of thousands of plasma and inflammatory proteins that were measured using affinity-based proteomic assays. First, we pooled >3000 relevant proteins using a fixed-effects meta-analysis of 2 population-based studies involving 48,383 participants, then investigated the causal effects of stroke and its subtype-associated proteins by forward Mendelian randomization using cis-protein quantitative locus genetic tools identified from genome-wide association studies of these >48,000 individuals. To improve the accuracy of causal estimation, we implemented a systematic Mendelian randomization model that accounts for cascading imbalances between instruments and tested the robustness of causal estimation through multi-method analyses. To further validate the hypothesis that ginsenoside Rg1 monomer acts on the five protein targets screened for drug-targeted regulation, we conducted a comparative analysis of the mRNA (gene) expression levels of a limited number of genes in the brain tissues of different groups of SD rats. The druggability of the candidate proteins was investigated and the mechanism of action and potential targeting side effects were explored by Phenome-wide MR. RESULTS: Six circulating proteins were identified to have a significant genetic association with stroke (PFDR < 0.05). For example, in patients with cardioembolic stroke, higher genetically predicted APRT was associated with a lower risk of cardioembolic stroke (ORivw [95 % CI] = 0.641 [0.517, 0.795]; P = 5.25 × 10-5, ORSMR [95 % CI] = 0.572, [0.397, 0.825], PSMR = 0.003). Mediation analyses suggested that atrial fibrillation, angina pectoris, and heart failure may mediate the association of CD40L, LIFR, and UPA with stroke. Molecular docking revealed promising interactions between the identified proteins and glycosides. Transcriptomic sequencing in animal models indicated that ginsenoside Rg1 may act through APRT, IL15RA, and VSIR pathways, with APRT showing significant variability in mRNA sequencing expression. Phenome-wide MR of the six target proteins showed an overwhelming predominance of PFDR > 0.05, indicating less toxicity. CONCLUSIONS: The present study provides genetic evidence to support the potential efficacy of targeting the three druggable protein targets for the treatment of stroke. This is achieved by triangulating population genomic and proteomic data. Furthermore, the study validates the pathway mechanisms by which APRT, IL15RA, and VSIR dock ginsenoside Rg1 in animal models. This will help to prioritize stroke drug development.

Genetically Predicted Apolipoprotein E Levels with the Risk of Panvascular Diseases: A Mendelian Randomization Study.

The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10-3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10-4] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10-2]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10-2]. (Bonferroni threshold p < 0.0026, PFDR < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.