Abstract
BackgroundPrevious large observational cohort studies showed higher blood pressure (BP) positively associated with cancer. We used Mendelian randomization (MR) to obtain less confounded estimates of BP on total and site-specific cancers.MethodsWe applied replicated genetic instruments for systolic and diastolic BP to summary genetic associations with total cancer (37387 cases, 367856 non-cases) from the UK Biobank, and 17 site-specific cancers (663–17881 cases) from a meta-analysis of the UK Biobank and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging. We used inverse-variance weighting with multiplicative random effects as the main analysis, and sensitivity analyses including the weighted median, MR-Egger and multivariable MR adjusted for body mass index and for smoking. For validation, we included breast (Breast Cancer Association Consortium: 133384 cases, 113789 non-cases), prostate (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium: 79194 cases, 61112 non-cases) and lung (International Lung and Cancer Consortium: 10246 cases, 38295 non-cases) cancer from large consortia. We used asthma as a negative control outcome.ResultsSystolic and diastolic BP were unrelated to total cancer (OR 0.98 per standard deviation higher [95% confidence interval (CI) 0.89, 1.07] and OR 1.00 [95% CI 0.92, 1.08]) and to site-specific cancers after accounting for multiple testing, with consistent findings from consortia. BP was nominally associated with melanoma and possibly kidney cancer, and as expected, not associated with asthma. Sensitivity analyses using other MR methods gave similar results.ConclusionsIn contrast to previous observational evidence, BP does not appear to be a risk factor for cancer, although an effect on melanoma and kidney cancer cannot be excluded. Other targets for cancer prevention might be more relevant.
Highlights
Previous large observational cohort studies showed higher blood pressure (BP) positively associated with cancer
*Correspondence: cms1@hku.hk 1 School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong, SAR, China Full list of author information is available at the end of the article (CVD) [4], hypertension has been linked with higher risk of cancer observationally [5,6,7], but the evidence is inconsistent with the possible exception of kidney cancer [8]
The UK Biobank analysis used a linear mixed model [24], adjusted for age, age2, sex and body mass index (BMI), with genomic control applied at the study level to correct for inflation due to population stratification and cryptic relatedness [25], followed by fixed-effect meta-analysis with the International Consortium for Blood Pressure (ICBP) summary statistics which adjusted for the same covariates
Summary
Previous large observational cohort studies showed higher blood pressure (BP) positively associated with cancer. We used Mendelian randomization (MR) to obtain less confounded estimates of BP on total and sitespecific cancers. Mendelian randomization (MR), by using genetic variants randomly allocated at conception as instrumental variables, is less susceptible to confounding than conventional observational studies [15]. In this MR study using two-sample methods, we assessed the effects of systolic and diastolic BP on total cancer as well as on 17 common site-specific cancers, by applying replicated genetic instruments for BP to large population-based cohorts. We used multivariable MR [16, 17] to mitigate potential pleiotropic effects via obesity and smoking
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