Effects of tumour necrosis factor on cardiovascular disease and cancer: A two-sample Mendelian randomization study
Shuai Yuan,
Paul Carter,
Maria Bruzelius,
Mathew Vithayathil,
Siddhartha Kar,
Amy M. Mason,
Ang Lin,
Stephen Burgess,
Susanna C. Larsson
Affiliations
Shuai Yuan
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Paul Carter
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Maria Bruzelius
Coagulation Unit, Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Mathew Vithayathil
MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom
Siddhartha Kar
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom
Amy M. Mason
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom
Ang Lin
Department of Medicine Solna, Division of Immunology and Allergy, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Stephen Burgess
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
Susanna C. Larsson
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Corresponding author.
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.
