Effects of Genetic Variants on Stroke Risk.

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

ObjectiveWe employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.MethodsWe selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).ResultsGenetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.ConclusionsThis study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.

Clinical Relevance of Cerebral Small Vessel Diseases.

November 2020 Stroke Highlights.

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. CLINICAL PERSPECTIVE What is new We identified genetic proxies for downregulated IL-6 signaling that had effects on upstream and downstream regulators of the IL-6 signaling pathway consistent with those of pharmacological IL-6R blockade Genetically downregulated IL-6 signaling was associated with a lower risk of ischemic stroke, and in particular large artery and small vessel stroke Similar associations were obtained for a broad range of other cardiovascular outcomes What are the clinical implications Inhibition of IL-6 signaling is a promising therapeutic target for lowering risk of stroke and other cardiovascular outcomes and should be further investigated in clinical trials

Cardiovascular diseases (CVDs) are a major source of morbidity and mortality worldwide. Despite a decline of ≈30% over the past decade, heart disease remains the leading killer of Americans.1 For rare and familial forms of CVD, we are increasingly recognizing single-gene mutations that impart relatively large effects on individual phenotype. Examples include inherited forms of cardiomyopathy, arrhythmias, and aortic diseases. However, the prevalence of monogenic disorders typically accounts for a small proportion of the total CVD observed in the population. CVDs in the general population are complex diseases, with several contributing genetic and environmental factors. Although recent progress in monogenic disorders has occurred, we have seen a period of intense investigation to identify the genetic architecture of more common forms of CVD and related traits. Genomics serves several roles in cardiovascular health and disease, including disease prediction, discovery of genetic loci influencing CVD, functional evaluation of these genetic loci to understand mechanisms, and identification of therapeutic targets. For single-gene CVDs, progress has led to several clinically useful diagnostic tests, extending our ability to inform the management of afflicted patients and their family members. However, there has been little progress in developing genetic testing for complex CVD because individual common variants have only a modest impact on risk. The study of the genomics of complex CVDs is further challenged by the influence of environmental variables, phenotypic heterogeneity, and pathogenic complexity. Characterization of the clinical phenotype requires consideration of the clinical details of the diseases and traits under study. This update expands the prior scientific statement on the relevance of genetics and genomics for the prevention and treatment of CVDs.2 In the earlier report, we focused on the current status of the field, which consisted of predominantly family-based linkage studies and single-gene or mendelian mutations of relatively large phenotypic effect …

Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. We evaluated whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischemic stroke and its subtypes and hemorrhagic stroke. We performed 2-sample and multivariable Mendelian randomization to assess the causal effect of 12 lifestyle factors on risk of stroke and whether these effects are independent. Genetically predicted years of education was inversely associated with ischemic, large artery, and small vessel stroke, and intracerebral hemorrhage. Genetically predicted smoking, body mass index, and waist-hip ratio were associated with ischemic and large artery stroke. The effects of education, body mass index, and smoking on ischemic stroke were independent. Our findings support the hypothesis that reduced education and increased smoking and obesity increase risk of ischemic, large artery, and small vessel stroke, suggesting that lifestyle modifications addressing these risk factors will reduce stroke risk.

ObjectiveWe employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.MethodsWe selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).ResultsGenetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.Classification of EvidenceThis study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.

Abstracts of Literature

Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes. We used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization. A PRS for lower eGFR was associated with higher large artery stroke (LAS) risk (p = 1 × 10-4). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38-3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12-4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH. Impaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.

Advances in Neurocardiology: Focus on Atrial Fibrillation.

Stroke places a large burden on healthcare and social services resources in the older adult population. Because the incidence of stroke increases with advancing age, and the population is aging, the number of patients affected by stroke is increasing. See p 900 The burden of stroke goes well beyond those cases that are clinically recognized. Imaging techniques of the brain have revealed a remarkably high prevalence of white matter lesions (WML) and silent brain lacunar infarcts (SBLI). In the National Heart, Lung, and Blood Institute–sponsored Cardiovascular Health Study, SBLI ≥3 mm were found in 31% of all subjects.1 Fewer than 15% of patients with such lesions had a clinical history of stroke. The prevalence of SBLI increased with advancing age; 22% of subjects 65 to 69 years old had SBLI, as compared with 43% in subjects ≥80 years old. WML involving in particular the centrum ovale are a subject of great interest. Partly this is because modern neuroimaging methods detect subcortical WM changes with increasing frequency in people >60 years old and also because these abnormalities may be associated with specific neurobehavioral deficits, including dementing syndromes.2 The descriptive term leukoaraiosis (LA), frequently applied to these neuroimaging abnormalities of the WM, refers to bilateral and either patchy or diffuse areas of hypodensity on CT or hyperintensity on T2-weighted MRI.3 In this issue of Circulation , van Dijk and colleagues4 explore the relationship of C-reactive protein (CRP), a well-known systemic marker of inflammation, with the severity and progression of cerebral WML/LA on MRI scans. The investigators examined the prevalence and incidence of brain WML/LA and SBLI in the prospective cohort of 1033 older adult participants of the population-based Rotterdam Scan study. They confirmed a relationship between inflammation and the severity and progression of cerebral WML/LA and SBLI independent …

Stroke is a complex disease, with both genetic and environmental factors having a role in its pathogenesis. A review of past studies shows some evidence of genetic influences in the development of stroke. This is supported by studies of cardiovascular disease, which indicate major genetic influences at several levels including the development of risk factors. New approaches to phenotypic classifications, patient ascertainment, and genetic analysis will stimulate research into the role of genetics in cerebrovascular disease.

Decoding cryptogenic cardioembolism

Background The relative impact of low density lipoprotein cholesterol (LDL-C) lowering on risk of ischaemic stroke [IS] and coronary heart disease [CHD] has been debated. The relevance of aetiologically distinct IS subtypes may contribute to this complex relationship, but the causal relationship and relative importance of LDL-C for risk of large artery, cardioembolic and small vessel stroke and CHD remains unclear. Purpose To disentangle the relative impact and quantify the causal effects of life-long differences in LDL-C on risk of cardioembolic, small vessel, and large artery stroke, and CHD. Methods We undertook a multi-ethnic Mendelian randomization (MR) study of 1,008,662 individuals including 66,218 IS cases (with TOAST subtyping available in 3 times more cases than previously available), and 103,536 CHD cases. IS results were based on a meta-analysis of summary and individual participant data from the MEGASTROKE Consortium and UK Biobank respectively, and CHD results on data from the CARDIoGRAMplusC4D Consortium and UK Biobank. We created a weighted genetic risk score based on 175 independent variants identified in previous genome-wide studies of LDL-C that included individuals of multiple ethnicities. This genetic instrument was used to estimate the causal effects of life-long differences in LDL-C for risk of IS, IS subtypes and CHD. In addition, the associations between functionally informed genomic regions representing LDL-lowering drug targets including HMGCR (for statins), NPC1L1 (for ezetimibe), and PCSK9 (for PCSK9-inhibitors) and the disease outcomes were examined. Results Life-long lower genetically determined LDL-C was associated with a 25% lower risk of CHD per standard deviation of the genetic score (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.73–0.77; p=2×10–91), but had a significantly weaker effect on IS (OR 0.92, 95% CI 0.88–0.95, p=8x10–6, p for heterogeneity=7.3x10–18). Underlying the relationship with IS was a strong association with large artery stroke (OR 0.75, 95% CI 0.68–0.83; p=2×10–8), comparable to that for CHD, but no significant effects on cardioembolic (OR 1.02, 95% CI 0.95–1.10; p=0.60) or small vessel strokes (OR 0.95, 95% CI 0.88–1.03; p=0.23). Results from multivariable MR analyses that accounted for potential pleiotropy with HDL-C and triglycerides showed no material difference. Additional analyses to examine sensitivity of these findings to the genetic risk score, ethnicity, and wider sources of pleiotropy were performed, and effects of genetic proxies for individual LDL-lowering drug targets assessed. Conclusion This study, the largest of its type to date, demonstrates that life-long lower genetically determined LDL-C levels have a materially weaker effect on IS than on CHD, and differences in the relative importance of life-long lower LDL-C for aetiologically distinct IS subtypes contribute to the differences observed. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation