OBJECTIVE: There is still disagreement about whether anti-tumor necrosis factor (TNF) therapy is beneficial or detrimental to cardiovascular conditions. This two-sample Mendelian randomization (MR) study aimed to evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on cardiovascular diseases (CVDs) and cardiometabolic risk factors via genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) and TNF. MATERIALS AND METHODS: Two genetic instruments were examined to mimic the long-term effect of TNF inhibitors. The first were single-nucleotide polymorphisms (SNPs) within or nearby drug-target genes TNFRSF1A and TNF (encoding TNFR1 and TNF) associated with circulating CRP levels. The other instruments were the expression quantitative trait loci (eQTLs) near the genes. Inverse variance-weighted MR (IVW-MR) and summary-based MR (SMR) methods were employed to estimate causal effects. RESULTS: In IVW-MR analysis, TNF-mediated circulating CRP levels were significantly associated with 4 out of 12 CVDs, including hypertension [odds ratio (OR) = 1.13; 95% CI, 1.09-1.18], coronary artery disease (OR = 3.18; 95% CI, 1.77-5.71), coronary atherosclerosis (OR = 1.05; 95% CI, 1.02-1.08) and type 2 diabetes (OR = 3.48; 95% CI, 1.98-6.10). These findings were also validated in the FinnGen study. Moreover, TNF inhibition was also associated with total cholesterol, triglycerides, apolipoprotein B, systolic blood pressure, serum cystatin C, height, weight, and body mass index. CONCLUSIONS: In this study, the decrease in several CVDs and cardiometabolic risk factors has been found to be causally associated with genetically proxied TNF inhibitors.
