Abstract
BACKGROUND: Tumor necrosis factor (TNF) is a potent inflammatory cytokine that has been causally associated with coronary artery disease (CAD) and ischemic stroke (IS), implying opportunities for disease prevention by anti-TNF therapeutics. METHODS: Leveraging summary statistics of several genome-wide association studies (GWAS), we assessed the repurposing potential of TNF inhibitors for CAD and IS using drug-target Mendelian randomization (MR) design. Pharmacologic blockade of the pro-inflammatory TNF signalling mediated by TNF receptor 1 (TNFR1) was instrumented by four validated variants. Causal effects of TNF/TNFR1 blockade on CAD (N(case/control) upto 122,733/424,528) and IS (N(case/control) upto 60,341/454,450) were then estimated via various MR estimators using circulating C-reactive protein (CRP; N(GWAS)=204,402) as downstream biomarker to reflect treatment effect. Associations of a functional variant, rs1800693, with CRP, CAD and IS were also examined. FINDINGS: No protective effect of TNF/TNFR1 inhibition on CAD or IS was observed. For every 10% decrease of circulating CRP achieved by TNF/TNFR1 blockade, odds ratio was 0.98 (95% confidence interval [CI]: 0.60-1.60) for CAD and 0.77 (95% CI: 0.36-1.63) for IS. Findings remained null in all supplement analyses. INTERPRETATION: Our findings do not support TNFR1 as a promising target for CAD or IS prevention among the general population. Future research is warranted to investigate whether the detrimental effect of circulating TNF on CAD and IS might be counteracted by modulating other relevant drug targets. FUNDING: No.