Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects

Gill, Dipender; Georgakis, Marios K.; Koskeridis, Fotios; Jiang, Lan; Feng, QiPing; Wei, Wei‐Qi; Τheodoratou, Evropi; Elliott, Paul; Denny, Joshua C.; Malik, Rainer; Εvangelou, Εvangelos; Dehghan, Abbas; Dichgans, Martin; Tzoulaki, Ioanna

doi:10.1161/circulationaha.118.038814

Cited by 116 publications

(150 citation statements)

References 25 publications

(42 reference statements)

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“…27,28 MR further allows for prediction of the effects of pharmacological interventions by using variants located close to genes encoding candidate drug targets. 29,30 Hence, MR has become a powerful strategy to prioritize interventions for exploration in clinical trials. 28 Here, leveraging data from large genome-wide association studies (GWASs) [31][32][33] and applying MR analyses, we aimed to: (i) identify genetic proxies for downregulated IL-6 signaling on the basis of their effects on CRP levels, a well-established IL-6 signaling downstream effector, 13,20,34 (ii) validate their utility by comparing the consistency of their effects on upstream regulators and downstream effectors of the IL-6 signaling pathway with the effects of pharmacological IL-6R inhibition, as derived from clinical trials, (iii) explore associations of genetic predisposition to downregulated IL-6 signaling with the risk of ischemic stroke and coronary artery disease, (iv) examine associations with major etiological subtypes of ischemic stroke (large artery, cardioembolic, and small vessel stroke), and (v) examine associations with a broad range of other cardiovascular phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

Georgakis¹,

Malik²,

Franceschini³

et al. 2019

Preprint

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Background: Studies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown. Methods: In a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R. Results: We identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque. Conclusions: We provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.

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Section: Introductionmentioning

confidence: 99%

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

Georgakis¹,

Malik²,

Franceschini³

et al. 2019

Preprint

Self Cite

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“…Second, we only assumed a single causal signal in each LD block and neglected genetic interactions among multiple variants/loci, such as the complex CVD locus 9p21.3, which contains multiple independent causal variants that may interact in either a synergetic or an antagonistic manner to predispose cardiovascular phenotypes (67), which further limits the identification of genetic evidence. Recent Mendelian randomization analysis leverages genetic proxies for the effect of antihypertensive drug classes to inform drug efficacy and side effects, which represents a complementary angle of combined genetic effects (68). Third, although we considered directions of noncoding risk alleles affecting gene expression in cardiovascular tissues, we did not assess effects in other human tissues or effects that were controlled by other types of variant, including splicing and protein translation-altering variants.…”

Section: Discussionmentioning

confidence: 99%

The support of genetic evidence for cardiovascular risk induced by antineoplastic drugs

et al. 2020

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Cardiovascular dysfunction is one of the most common complications of long-term cancer treatment. Growing evidence has shown that antineoplastic drugs can increase cardiovascular risk during cancer therapy, seriously affecting patient survival. However, little is known about the genetic factors associated with the cardiovascular risk of antineoplastic drugs. We established a compendium of genetic evidence that supports cardiovascular risk induced by antineoplastic drugs. Most of this genetic evidence is attributed to causal alleles altering the expression of cardiovascular disease genes. We found that antineoplastic drugs predicted to induce cardiovascular risk are significantly enriched in drugs associated with cardiovascular adverse reactions, including many first-line cancer treatments. Functional experiments validated that retinoid X receptor agonists can reduce triglyceride lipolysis, thus modulating cardiovascular risk. Our results establish a link between the causal allele of cardiovascular disease genes and the direction of pharmacological modulation, which could facilitate cancer drug discovery and clinical trial design.

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“…10,11 Published genetic variants corresponding to the effects of a range of antihypertensives exist. [12][13][14] Here, to be comprehensive we used these genetic variants to assess the effects of a comprehensive range of antihypertensives on key markers of immune function and inflammation related to COVID-19, ie, lymphocyte percentage, neutrophil percentage and tumour necrosis factor alpha (TNF-α). Severe COVID-19 is associated with a major immune inflammatory response with abundant lymphocytes, neutrophils and excess inflammation.…”

Section: Introductionmentioning

confidence: 99%

Using genetics to understand the role of antihypertensive drugs modulating angiotensin‐converting enzyme in immune function and inflammation

Zhao

Schooling

Leung

2020

Brit J Clinical Pharma

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Angiotensin-converting enzyme 2 (ACE 2) is the binding domain for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARSCoV-2. Some antihypertensive drugs affect ACE2 expression or activity (ACE inhibitors and angiotensin II receptor blockers [ARBs]), suggesting use of other hypertensives might be preferable, such as calcium channel blockers (CCBs). Given the limited evidence, the International Society of Hypertension does not support such a policy. Methods: We used a Mendelian randomization study to obtain unconfounded associations of antihypertensives, instrumented by published genetic variants in genes regulating target proteins of these drugs, with immune (lymphocyte and neutrophil percentage) and inflammatory (tumour necrosis factor alpha [TNF-α]) markers in the largest available genome-wide association studies. Results: Genetically predicted effects of ACE inhibitors increased lymphocyte percentage (0.78, 95% confidence interval [CI] 0.35, 1.22), decreased neutrophil percentage (−0.64, 95% CI −1.09, −0.20) and possibly lowered TNF-α (−4.92, 95% CI −8.50, −1.33). CCBs showed a similar pattern for immune function (lymphocyte percentage 0.21, 95% CI 0.05 to 0.36; neutrophil percentage −0.23, 95% CI −0.39 to −0.08) but had no effect on TNF-α, as did potassium-sparing diuretics and aldosterone antagonists, and vasodilator antihypertensives. ARBs and other classes of hypertensives had no effect on immune function or TNF-α. Conclusion: Varying effects of different classes of antihypertensives on immune and inflammatory markers do not suggest antihypertensive use based on their role in ACE2 expression, but instead suggest investigation of the role of antihypertensives in immune function and inflammation might reveal important information that could optimize their use in SARSCoV-2.

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Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects

Abstract: Supplemental Digital Content is available in the text.

Cited by 116 publications

References 25 publications

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

The support of genetic evidence for cardiovascular risk induced by antineoplastic drugs

Using genetics to understand the role of antihypertensive drugs modulating angiotensin‐converting enzyme in immune function and inflammation

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