Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current ...observational research methods are subject to several biases. These include confounding by indication, reverse causality and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR addresses some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either before or after approval of the drug, and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized, and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.
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.
Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative ...contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.
Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.
ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86;
=0.003) and CAD (marginal inclusion probability, 0.92;
=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB 95% CI, 0.84-0.91;
=9×10
) and CAD (odds ratio,0.66 95% CI, 0.63-0.69;
=4×10
), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 95% CI, 2.29-4.60;
<1×10
). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91;
=2.3×10
), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95;
=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 95% CI, 1.03-1.04;
=1.0×10
).
ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors that influence on disease susceptibility. Studies of ...disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomisation (MR) analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and MR studies using both individual- and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-Hunter and Dudbridge et al.'s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, while our second example investigates genetic associations with breast cancer mortality.
Therapeutic targets for halting the progression of Alzheimer's disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the Cyclophilin-A matrix ...metalloproteinase-9 (CypA-MMP9) pathway, leading to an accelerated breakdown of the blood-brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA-MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence to suggest that CypA or MMP9 affects the risk of Alzheimer's disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in human APOE4 carriers.
Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive ...benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink.
We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over.
We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that β-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, β-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives.
We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis.
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