scholarly journals Blood pressure and risk of cancer: a Mendelian randomization study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Io Ieong Chan ◽  
Man Ki Kwok ◽  
C. Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Kidney Cancer ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Adult Health ◽  
Uk Biobank ◽  
Site Specific ◽  
Total Cancer ◽  
The Uk ◽  
Risk Of Cancer

Abstract Background 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 site-specific cancers. Methods We 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. Results Systolic 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. Conclusions In 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.

scholarly journals Interaction-based Mendelian randomization with measured and unmeasured gene-by-covariate interactions

2020 ◽  
Author(s):  
Wes Spiller ◽  
Fernando Pires Hartwig ◽  
Eleanor Sanderson ◽  
George Davey Smith ◽  
Jack Bowden
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
Gene Environment ◽  
Gxe Interactions ◽  
Using Data ◽  
The Uk ◽  
Positive Effect

Studies leveraging gene-environment (GxE) interactions within Mendelian randomization (MR) analyses have prompted the emergence of two methodologies: MR-GxE and MR-GENIUS. Such methods are attractive in allowing for pleiotropic bias to be corrected when using individual instruments. Specifically, MR-GxE requires an interaction to be explicitly identified, while MR-GENIUS does not. We critically examine the assumptions of MR-GxE and MR-GENIUS, and propose sensitivity analyses to evaluate their performance. Finally, we explore the association between body mass index (BMI) and systolic blood pressure (SBP) using data from the UK Biobank. We find both approaches share similar assumptions, though differences between the approaches lend themselves to differing research settings. Where interactions are identified, MR-GxE relies on weaker assumptions and allows for further sensitivity analyses. MR-GENIUS circumvents the need to identify interactions, but relies on the MR-GxE assumptions holding globally. Through applied analyses we find evidence of a positive effect of BMI upon SBP.

scholarly journals Blood Pressure and Risk of Cardiovascular Disease in UK Biobank

Hypertension ◽  
2021 ◽  
Author(s):  
Eric Yuk Fai Wan ◽  
Wing Tung Fung ◽  
C. Mary Schooling ◽  
Shiu Lun Au Yeung ◽  
Man Ki Kwok ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Randomization Test ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Causal Association ◽  
Uk Biobank ◽  
Cvd Risk ◽  
The Uk

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

scholarly journals Effects of blood lead on coronary artery disease and its risk factors: a Mendelian Randomization study

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
C. Mary Schooling ◽  
Glen D. Johnson ◽  
Jean Grassman
Keyword(s):  
Blood Pressure ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Blood Lead ◽  
Uk Biobank ◽  
1000 Genomes ◽  
A Genome ◽  
Artery Disease ◽  
The Uk

Abstract Lead is pervasive, although lead exposure has fallen in response to public health efforts. Observationally, lead is positively associated with cardiovascular disease and hypertension. We used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) based on 13 single nucleotide polymorphisms (SNP), from a genome wide association study, strongly (p-value < 5 × 10−6) and independently associated with blood lead. These SNPs were applied to a large extensively genotyped coronary artery disease (CAD) study (cases = <76014, controls = <264785) largely based on CARDIoGRAPMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to the UK Biobank (n = 361,194) for blood pressure and to the DIAGRAM 1000 genomes diabetes case (n = 26,676)-control (n = 132,532) study. SNP-specific Wald estimates were combined using inverse variance weighting, MR-Egger and MR-PRESSO. Genetically instrumented blood lead was not associated with CAD (odds ratio (OR) 1.01 per effect size of log transformed blood lead, 95% confidence interval (CI) 0.97, 1.05), blood pressure (systolic −0.18 mmHg, 95% CI −0.44 to 0.08 and diastolic −0.03 mmHg, 95% CI −0.09 to 0.15) or diabetes (OR 0.98, 95% CI 0.92 to 1.03) using MR-PRESSO estimates corrected for an outlier SNP (rs550057) from the highly pleiotropic gene ABO. Exogenous lead may have different effects from endogenous lead; nevertheless, this study raises questions about the role of blood lead in CAD.

scholarly journals Birth weight, BMI in adulthood and latent autoimmune diabetes in adults: A Mendelian randomization study

2021 ◽  
Author(s):  
Yuxia Wei ◽  
Yiqiang Zhan ◽  
Josefin E. Lofvenborg ◽  
Tiinamaija Tuomi ◽  
Sofia Carlsson
Keyword(s):  
Type 2 Diabetes ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Mendelian Randomization ◽  
Autoimmune Diabetes ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
Latent Autoimmune Diabetes ◽  
The Uk

Aims: Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birth weight and adult overweight/obesity. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomization (MR) design. In addition, we wanted to compare results for LADA and type 2 diabetes. Methods: We identified 129 SNPs as instrumental variables (IVs) for birth weight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2,634 cases and 5,947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results: Genetically determined birth weight was inversely associated with LADA (OR per SD [~500 g] decrease in birth weight: 2.02, 95% CI: 1.37-2.97). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m2] increase in BMI: 1.40, 95% CI: 1.14-1.71). Results persisted in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birth weight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation: This study provides genetic support for a causal link between low birth weight, adult overweight/obesity, and LADA.

scholarly journals High Blood Pressure and Risk of Dementia: a Two-Sample Mendelian Randomization study in the UK Biobank

2020 ◽  
Author(s):  
William Sproviero ◽  
Laura Winchester ◽  
Danielle Newby ◽  
Marco Fernandes ◽  
Liu Shi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
High Blood Pressure ◽  
Mendelian Randomization ◽  
Uk Biobank ◽  
The Uk

scholarly journals Effect of n-3 polyunsaturated fatty acids on ischemic heart disease and cardiometabolic risk factors: a two-sample Mendelian randomization study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bayi Xu ◽  
Zhixia Xu ◽  
Duanmin Xu ◽  
Xuerui Tan
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Blood Pressure ◽  
Fatty Acids ◽  
Cardiometabolic Risk ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Cardiometabolic Risk Factors ◽  
Uk Biobank ◽  
The Uk

Abstract Background The cardioprotective ability of n-3 polyunsaturated fatty acids (PUFAs) is controversial. Most studies suggest a specific role for PUFAs in cardioprotection from ischemic heart disease (IHD). However, few studies have used genetic biomarkers of n-3 PUFAs to examine their potential relationships with IHD. This study aimed to use Mendelian randomization to evaluate whether genetically-predicted n-3 PUFAs affect IHD and cardiometabolic risk factors (CRFs). Methods Genetic variants strongly (p < 5 × 10–8) and independently (r2 > 0.1) associated with n-3 PUFAs were derived from the CHARGE Consortium (including 8,866 subjects of European ancestry) and were used as instrumental variables (IVs) for evaluating the effect of n-3 PUFAs, including α-linolenic acid (ALA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Data on the associations between the IVs and IHD, myocardial infarction, and CRFs (including diabetes, lipids, blood pressure, body mass index, and waist-to-hip ratio (WHR)) were obtained from the UK Biobank SOFT CAD GWAS with the CARDIoGRAMplusC4D 1000 Genomes-based GWAS (113,937 IHD cases and 339,115 controls), the Myocardial Infarction Genetics and CARDIoGRAM Exome consortia (42,335 MI cases and 78,240 controls), the DIAbetes Genetics Replication And Meta-analysis consortium (26,676 diabetes mellitus cases and 132,532 controls), the Global Lipids Genetics Consortium (n = 196,475), the International Consortium for Blood Pressure (n = 69,395), and the meta-analysis of GWAS for body fat distribution in the UK Biobank and Genetic Investigation of Anthropometric Traits (n = 694,649). Results Genetically-predicted higher ALA was associated with lower risk of IHD, type 2 diabetes (T2D), and lower serum lipids. The effect size per 0.05-unit increase (about 1 standard deviation) in plasma ALA level) was − 1.173 (95% confidence interval − 2.214 to − 0.133) for IHD. DPA and EPA had no association with IHD but were associated with a higher risk of T2D, higher levels of lipids or WHR. DHA had no association with IHD or CRFs. Conclusions Our study suggests a benefit of ALA for IHD and its main risk factors. DHA, DPA, and EPA had no association with IHD but were partly associated with increasing cardiometabolic risk factors.

scholarly journals Elevated Blood Pressure Increases Pneumonia Risk: Epidemiological Association and Mendelian Randomization in the UK Biobank

Med ◽  
2020 ◽  
Author(s):  
Seyedeh M. Zekavat ◽  
Michael Honigberg ◽  
James P. Pirruccello ◽  
Puja Kohli ◽  
Elizabeth W. Karlson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Elevated Blood Pressure ◽  
Elevated Blood ◽  
Uk Biobank ◽  
The Uk ◽  
Epidemiological Association

scholarly journals Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank

2020 ◽  
Vol 9 (14) ◽  
Author(s):  
Shan Luo ◽  
Shiu Lun Au Yeung ◽  
Verena Zuber ◽  
Stephen Burgess ◽  
Catherine Mary Schooling
Keyword(s):  
Venous Thromboembolism ◽  
General Population ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Uk Biobank ◽  
Increased Risk ◽  
The Uk

Background Red blood cell (RBC) transfusion and erythropoiesis‐stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome‐wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best‐fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance–weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05–1.41) with VTE. Sensitivity analyses (mendelian randomization–Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

scholarly journals Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255801
Author(s):  
Joanna Lankester ◽  
Daniela Zanetti ◽  
Erik Ingelsson ◽  
Themistocles L. Assimes
Keyword(s):  
Blood Pressure ◽  
Alcohol Consumption ◽  
Alcohol Use ◽  
Mendelian Randomization ◽  
Multivariable Analysis ◽  
Positive Association ◽  
Cardiometabolic Health ◽  
Uk Biobank ◽  
The Uk ◽  
Cardiometabolic Traits

Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

scholarly journals Blood pressure and bladder cancer risk in men by use of survival analysis and in interaction with NAT2 genotype, and by Mendelian randomization analysis

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241711
Author(s):  
Stanley Teleka ◽  
George Hindy ◽  
Isabel Drake ◽  
Alaitz Poveda ◽  
Olle Melander ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Bladder Cancer ◽  
Survival Analysis ◽  
Mendelian Randomization ◽  
Cox Regression ◽  
Least Square ◽  
Weighted Estimate ◽  
Uk Biobank ◽  
Muscle Invasive ◽  
The Uk

The association between blood pressure (BP) and bladder cancer (BC) risk remains unclear with confounding by smoking being of particular concern. We investigated the association between BP and BC risk among men using conventional survival-analysis, and by Mendelian Randomization (MR) analysis in an attempt to disconnect the association from smoking. We additionally investigated the interaction between BP and N-acetyltransferase-2 (NAT2) rs1495741, an established BC genetic risk variant, in the association. Populations consisting of 188,167 men with 502 incident BC’s in the UK-biobank and 27,107 men with 928 incident BC’s in two Swedish cohorts were used for the analysis. We found a positive association between systolic BP and BC risk in Cox-regression survival analysis in the Swedish cohorts, (hazard ratio [HR] per standard deviation [SD]: 1.14 [95% confidence interval 1.05–1.22]) and MR analysis (odds ratio per SD: 2-stage least-square regression, 7.70 [1.92–30.9]; inverse-variance weighted estimate, 3.43 [1.12–10.5]), and no associations in the UK-biobank (HR systolic BP: 0.93 [0.85–1.02]; MR OR: 1.24 [0.35–4.40] and 1.37 [0.43–4.37], respectively). BP levels were positively associated with muscle-invasive BC (MIBC) (HRs: systolic BP, 1.32 [1.09–1.59]; diastolic BP, 1.27 [1.04–1.55]), but not with non-muscle invasive BC, which could be analyzed in the Swedish cohorts only. There was no interaction between BP and NAT2 in relation to BC on the additive or multiplicative scale. These results suggest that BP might be related to BC, more particularly MIBC. There was no evidence to support interaction between BP and NAT2 in relation to BC in our study.

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