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Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom. Biomarkers and Susceptibility Unit, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain. Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada. Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada. Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada. Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada. Department of Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada. Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America. Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, United States of America. Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Australia. Division of General Surgery, University Health Network, University of Toronto, Toronto, Canada. Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America. Division of Epidemiology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, United States of America. Department of Medicine, Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, Texas, United States of America. University Hospitals Bristol, NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, United Kingdom. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.

PLoS medicine. 2022;(2):e1003897
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Abstract

BACKGROUND Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.