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Abstract
BackgroundTumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer.MethodsSingle-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia.FindingsGenetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94).InterpretationThis study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.
Highlights
Research in contextEvidence before this studyTumour necrosis factor (TNF) is a pro-inflammatory cytokine secreted primarily by immune cells
In the present Mendelian randomization (MR) study, we provided the first causal evidence of positive associations of TNF levels with atherothrombotic disease and venous thromboembolism
The associations of TNF levels instrumented by three single-nucleotide polymorphisms (SNPs) with the cardiovascular disease (CVD) and cancer outcomes are displayed in Fig. 1 and Fig. 2
Summary
Tumour necrosis factor (TNF) is a pro-inflammatory cytokine secreted primarily by immune cells. It is involved in a broad range of both homoeostatic and pathophysiological processes, such as immunity, inflammation, cell proliferation, apoptosis and lipid metabolism. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer. Methods: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Interpretation: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers
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