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Effects of tumour necrosis factor on cardiovascular disease and cancer: A two-sample Mendelian randomization study.

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Yuan, Shuai 
Bruzelius, Maria 
Vithayathil, Mathew 
Kar, Siddhartha 


BACKGROUND: Tumour 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. 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. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia. FINDINGS: Genetically-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). 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.



Cancer, Cardiovascular disease, Tumour necrosis factor, Cardiovascular Diseases, Disease Susceptibility, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mendelian Randomization Analysis, Meta-Analysis as Topic, Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Tumor Necrosis Factors

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Elsevier BV
Wellcome Trust (204623/Z/16/Z)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
Medical Research Council (MC_UU_00002/7)