Genetically-proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers

AbstractBackgroundEpidemiological 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.MethodsSingle-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 x 10-8) with systolic blood pressure 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). 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 colocalisation analyses were employed to examine robustness of findings to violations of Mendelian randomization assumptions.ResultsGenetically-proxied ACE inhibition equivalent to a 1 mmHg reduction in systolic blood pressure was associated with increased odds of colorectal cancer (OR 1.13, 95% CI 1.06-1.22; P = 3.6 x 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02-1.92; P = 0.035). There was little evidence of association of genetically-proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94-1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92-1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99-1.13; P = 0.08). Genetically-proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers.ConclusionGenetically-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 randomised controlled trials for these medications.

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Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian Randomization study

10.1101/486878 ◽

2018 ◽

Author(s):

Venexia M Walker ◽

Patrick G Kehoe ◽

Richard M Martin ◽

Neil M Davies

Keyword(s):

Alzheimer’S Disease ◽

Blood Pressure ◽

Alzheimer's Disease ◽

Systolic Blood Pressure ◽

Antihypertensive Drug ◽

Drug Targets ◽

Mendelian Randomization ◽

Disease Risk ◽

Drug Classes ◽

Do So

ABSTRACTBackgroundEvidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure (SBP), via different antihypertensive drug classes, on Alzheimer’s disease.MethodsWe used summary statistics from genome wide association studies of SBP (from UK Biobank) and Alzheimer’s disease (from the International Genomics of Alzheimer’s Project) in a two-sample Mendelian randomization analysis. We identified single nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive targets and estimated the effect of lowering SBP, via antihypertensive drug classes, on Alzheimer’s disease. We also report the effect of lowering SBP on Alzheimer’s disease by combining all drug targets and without consideration of the associated drugs.ResultsThere was limited evidence that lowering SBP, via antihypertensive drug classes, affected Alzheimer’s disease risk. For example, calcium channel blockers had an odds ratio (OR) per 10mmHg lower SBP of 1.53 (95% confidence interval (CI): 0.94 to 2.49; p=0.09; SNPs=17). We also found limited evidence for an effect of lowering SBP on Alzheimer’s disease when combining all drug targets (OR per 10mmHg lower SBP: 1.14; 95%CI: 0.83 to 1.56; p=0.41; SNPs=59) and without consideration of the associated drug targets (OR per 10mmHg lower SBP: 1.04; 95%CI: 0.95 to 1.13; p=0.45; SNPs=153).ConclusionsLowering SBP itself is unlikely to affect risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect risk of Alzheimer’s disease, they are unlikely to do so via SBP.KEY MESSAGESThis is the first study to use Mendelian randomization to estimate the effects of the twelve most common antihypertensive drug classes on Alzheimer’s disease.Lowering systolic blood pressure itself is unlikely to affect risk of developing Alzheimer’s disease.If specific antihypertensive drug classes do affect Alzheimer’s disease risk, they are unlikely to do so via systolic blood pressure.

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Mendelian randomization study of spermine oxidase and cancer risk

10.1101/2020.10.22.20217935 ◽

2020 ◽

Author(s):

João Fadista ◽

Victor Yakimov ◽

Urmo Võsa ◽

Christine S. Hansen ◽

Silva Kasela ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Cancer Risk ◽

Genetic Variants ◽

Mendelian Randomization ◽

Summary Statistics ◽

Spermine Oxidase ◽

Mendelian Randomization Analysis ◽

Risk Of Cancer ◽

Randomization Analysis

ABSTRACTImportanceSpermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of induced reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention.ObjectiveTo test the causality of SMOX levels with cancer risk using a Mendelian randomization analysis.Design, Setting, and ParticipantsWe performed a GWAS of spermidine/spermine ratio, from blood of 534 infants, to identify genetic variants associated with regulation of SMOX activity. In two additional data sets of 262 newborns and 508 adults, we quantified SMOX gene expression using RNA-sequencing and performed expression and methylation QTL lookups. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and various cancer types using GWAS summary statistics.Main Outcomes and MeasuresNeuroblastoma, gastric, lung, breast, prostate, and colorectal cancers.ResultsThe GWAS of spermidine/spermine ratio identified a genome-wide significant locus (P=1.34×10−49) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P=8.48×10−28) and adults (P=2.748×10−8) explaining 37% and 6% of the variance, respectively. rs1741315 was not associated with neuroblastoma (OR=0.95; 95% CI:0.88, 1.03; P=0.18), gastric (OR=0.99; 95% CI:0.95, 1.03; P=0.54), lung (OR=0.97; 95% CI:0.94, 1.00; P=0.08), breast (OR=0.99; 95% CI:0.96, 1.02; P=0.47), prostate (OR=0.98; 95% CI:0.96, 1.00; P=0.05) nor colorectal cancer (OR=1.03; 95% CI:0.99, 1.07; P=0.10). A PheWAS of rs1741315 did not reveal any associations with risk factors of the cancers tested.Conclusions and RelevanceGenetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. Further studies are needed to understand the effect of SMOX inhibition in relation to cancer risk.ARTICLE SUMMARYQuestionIs SMOX causally associated with risk of cancer?FindingsIn this Mendelian randomization study, genetically lower levels of SMOX were not associated with decreased risk of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer.MeaningThese findings do not support a causal association between SMOX activity and risk of cancer, suggesting that ongoing efforts to identify SMOX inhibitors for chemoprevention may not be successful.STRENGHTS AND LIMITATIONS-Previous studies which examined SMOX activity and cancer risk were susceptible to recall bias, confounding and reverse causation, none of which are concerns of this Mendelian randomization study.-Our genetic instrument explained a sizeable proportion of the variance of SMOX activity-We used summary statistics from the largest meta-analyses of primary cancer GWAS to date.-Elevated SMOX levels in cancer could also be due to environmental factors not captured by genetics.-Our genetic instrument was developed based on normal range SMOX activity data, thus additional genetic variants might play a role in aberrant expression of this enzyme.

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Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian randomization study

International Journal of Epidemiology ◽

10.1093/ije/dyz155 ◽

2019 ◽

Vol 49 (4) ◽

pp. 1132-1140 ◽

Cited By ~ 8

Author(s):

Venexia M Walker ◽

Patrick G Kehoe ◽

Richard M Martin ◽

Neil M Davies

Keyword(s):

Alzheimer’S Disease ◽

Blood Pressure ◽

Alzheimer's Disease ◽

Systolic Blood Pressure ◽

Antihypertensive Drug ◽

Mendelian Randomization ◽

Antihypertensive Drugs ◽

Lower Systolic Blood Pressure ◽

Protein Targets ◽

Drug Classes

Abstract Background Evidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease. Methods We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets. Results There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153). Conclusions Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.

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Faculty Opinions recommendation of Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717964810.793469147 ◽

2013 ◽

Author(s):

Yiqian Nancy You ◽

Brian Keith Bednarski

Keyword(s):

Colorectal Cancer ◽

Randomised Controlled Trial ◽

Cancer Risk ◽

Resistant Starch ◽

Controlled Trial ◽

Hereditary Colorectal Cancer ◽

Term Effect ◽

Long Term Effect ◽

Randomised Controlled

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Long-term time-related predictivity of coronary events as a function of a single measurement of serum cholesterol and systolic blood pressure

Acta Cardiologica ◽

10.2143/ac.55.2.2005726 ◽

2000 ◽

Vol 55 (2) ◽

pp. 87-93 ◽

Cited By ~ 9

Author(s):

Alessandro MENOTTI ◽

Mariapaola LANTI ◽

Paolo Emilio PUDDU

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Serum Cholesterol ◽

Single Measurement ◽

Coronary Events

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Intradialytic systolic blood pressure variation can predict long-term mortality in patients on maintenance hemodialysis

International Urology and Nephrology ◽

10.1007/s11255-020-02701-w ◽

2021 ◽

Author(s):

Jinbo Yu ◽

Xiaohong Chen ◽

Yaqiong Wang ◽

Zhonghua Liu ◽

Bo Shen ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Pressure Variation ◽

Maintenance Hemodialysis ◽

Blood Pressure Variation ◽

Long Term Mortality

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Long-term effects (>24 months) of multiple lifestyle intervention on major cardiovascular risk factors among high risk subjects: a meta-analysis

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.253 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

H Bergum ◽

I Sandven ◽

TO Klemsdal

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Risk ◽

Systolic Blood Pressure ◽

Total Cholesterol ◽

Cardiovascular Risk Factors ◽

Lifestyle Intervention ◽

Small Study ◽

Long Term Effects

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Norwegian health department Background The evidence of the long-term effects of multiple lifestyle intervention on cardiovascular risk is uncertain. We aimed to summarize the evidence from randomized clinical trials examining the efficacy of lifestyle intervention on major cardiovascular risk factors in subjects at high cardiovascular risk. Methods Eligible trials investigated the impact of lifestyle intervention versus usual care with minimum 24 months follow-up, reporting more than one major cardiovascular risk factor. A literature search updated April 15, 2020 identified 12 eligible studies. The results from individual trials were combined using fixed and random effect models, using the standardized mean difference (SMD) to estimate effect sizes. Small-study effect was evaluated, and heterogeneity between studies examined by subgroup and meta-regression analyses considering patient- and study-level variables. Results Small-study effect was not identified. Lifestyle intervention reduced systolic blood pressure modestly with an estimated SMD of -0.13, 95% confidence interval (CI): -0.21 to -0.04, with moderate heterogeneity (I² = 59%), corresponding to a mean difference of approximately 2 mmHg (MD = -1.86, 95% CI: -3.14 to -0.57, p = 0.0046). This effect disappeared in the subgroup of trials judged at low risk of bias (SMD = 0.02, 95% CI: -0.08 to 0.11). For the outcome total cholesterol SMD was -0.06, 95% CI: -0.13 to 0.00, with no heterogeneity (I² = 0%), indicating no effect of the intervention. Conclusion Lifestyle intervention resulted in only a modest effect on systolic blood pressure and no effect on total cholesterol after 24 months. Further lifestyle trials should consider the challenge of maintaining larger long-term benefits to ensure impact on cardiovascular outcomes.

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Long term habitual vigorous physical activity is associated with lower visit-to-visit systolic blood pressure variability

American Journal of Hypertension ◽

10.1093/ajh/hpaa198 ◽

2020 ◽

Author(s):

Xiaoyong Xu ◽

Xianghong Meng ◽

Shin-ichi Oka

Keyword(s):

Physical Activity ◽

Blood Pressure ◽

Standard Deviation ◽

Systolic Blood Pressure ◽

Blood Pressure Variability ◽

Vigorous Physical Activity ◽

Systolic Blood Pressure Variability ◽

Average Real Variability ◽

Post Hoc

Abstract Objective Our work aimed to investigate the association between vigorous physical activity and visit-to-visit systolic blood pressure variability (BPV). Methods We conducted a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a well-characterized cohort of participants randomized to intensive (<120 mmHg) or standard (<140 mmHg) SBP targets. We assessed whether patients with hypertension who habitually engage in vigorous physical activity would have lower visit-to-visit systolic BPV compared with those who do not engage in vigorous physical activity. Visit-to-visit systolic BPV was calculated by standard deviation (SD), average real variability (ARV), and standard deviation independent of the mean (SDIM) using measurements taken during the 1-, 2-, 3-, 6-, 9- and 12-month study visits. A medical history questionnaire assessed vigorous physical activity, which was divided into three categories according to the frequency of vigorous physical activity. Results A total of 7571 participants were eligible for analysis (34.8% female, mean age 67.9±9.3 years). During a follow-up of 1-year, vigorous physical activity could significantly reduce SD, ARV, and SDIM across increasing frequency of vigorous physical activity. There were negative linear trends between frequency of vigorous physical activity and visit-to-visit systolic BPV. Conclusions Long-term engagement in vigorous physical activity was associated with lower visit-to-visit systolic BPV.

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