Genetically Predicted Levels of Lipoprotein(a) and Risk of Cerebrovascular Disease.

Introduction: A prior systematic Mendelian randomization screen of 653 circulating proteins in a predominantly older ischemic stroke (IS) population identified a causal role for several established and novel biomarkers for IS and IS subtypes. We contrasted the magnitude of genetically determined levels of 6 of these biomarkers between early- and late-onset IS. Methods: We constructed genetic risk scores (GRS) for these 6 protein biomarkers from previously published GWAS analyses carried out in European populations. Using regression analysis, we evaluated associations of these GRS with IS and IS subtypes in 10,549 early onset (ages 18-59) and 9,272 late onset (ages 60 and older) IS cases and associated controls. The Wald test was used to test for heterogeneity in the odds ratios between the two groups. Results: Of the 6 biomarkers, only genetically determined protein levels of histo-blood group ABO system transferase were more strongly associated with early compared to late onset stroke (p < 0.002). Higher genetically determined levels of F11 and LPA and lower genetically determined levels of MMP12 were associated with both early and late onset IS with no evidence for differential effect sizes, while genetically determined levels of CD40 and SCARA5 showed no association with either early or late onset stroke. In subtype-specific analyses, increasing levels of genetically determined F11 were correlated with increased risk of all strokes in both groups. Higher genetically determined LPA levels were associated with large artery atherosclerotic (LAA) strokes in both groups, while lower genetically determined MMP12 levels were associated with LAA strokes in both groups. Conclusions: Genetically determined histo-blood group ABO system transferase levels are more strongly associated with all strokes in early than in late onset stroke. Genetically determined blood protein levels of F11, LPA, and MMP12 were associated with both early and late onset stroke. Lack of association for CD40 and SCARA5 may be due to a smaller sample size than the initial discovery study.

Diabetes mellitus exerts a detrimental effect on cerebral vasculature affecting both macrovasculature and microvasculature. However, although ischaemic stroke is typically included among macrovascular diabetic complications, it is frequently omitted from microvascular diabetic complications. We aimed to compare the proportion of large-artery atherosclerotic and small-vessel occlusion strokes among diabetic stroke patients, explore their differences and outcomes, and assess potential mechanisms which may determine why some diabetic patients suffer large-artery atherosclerotic stroke whereas others suffer small-vessel occlusion stroke. We pooled data of diabetic patients from four prospective ischaemic stroke registries (Acute Stroke Registry and Analysis of Lausanne (ASTRAL), Athens, Austrian, and Helsinki Stroke Thrombolysis Registries). Stroke severity and prognosis were assessed with National Institutes of Health Stroke Scale (NIHSS) and ASTRAL scores, respectively; functional outcome with three-month modified Rankin score (0-2 considered as favourable outcome). Logistic-regression analysis identified independent predictors of large-artery atherosclerotic stroke. Among 5412 patients, 1069 (19.8%) were diabetics; of them, 232 (21.7%) had large-artery atherosclerotic and 205 (19.2%) small-vessel occlusion strokes. Large-artery atherosclerotic stroke had higher severity than small-vessel occlusion stroke (median NIHSS: 6 vs. 3, p < 0.001), worse prognosis (median ASTRAL score: 23 vs. 19, p < 0.001), and worse three-month outcome (60.3% vs. 83.4% with favourable outcome, p < 0.001). In logistic-regression analysis, peripheral artery disease (odds ratio: 4.013, 95% confidence interval: 1.667-9.665, p < 0.01) and smoking (odds ratio: 1.706, 95% confidence interval: 1.087-2.675, p < 0.05) were independently associated with large-artery atherosclerotic strokes. In the diabetic stroke population, small-vessel occlusion and large-artery atherosclerotic strokes occur with similar frequency. Large-artery atherosclerotic strokes are more severe and have worse outcome than small-vessel occlusion strokes. The presence of peripheral artery disease and smoking independently predicted large-artery atherosclerotic stroke.

Genetic predisposition to Parkinson's disease and risk of cardio and cerebrovascular disease: a Mendelian randomization study

Lipoprotein(a) in Alzheimer, Atherosclerotic, Cerebrovascular, Thrombotic, and Valvular Disease Mendelian Randomization Investigation

Objective To investigate the relationship between the total burden of cerebral small vessel disease (CSVD) and the outcomes in patients with large artery atherosclerotic (LAA) stroke. Methods From June 2016 to January 2018, patients with LAA stroke treated at the Department of Neurology, the Affiliated Hospital of Qingdao University were enrolled retrospectively. The overall burden of CSVD was evaluated according to MRI findings. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the severity of stroke. The modified Rankin scale (mRS) was used to evaluate the outcomes at day 90 after the onset. The mRS score 0-2 was defined as good outcome, and >2 was defined as poor outcome. Results A total of 148 patients with LAA stroke were enrolled, including good outcome in 72 (48.65%) and poor outcome in 76 (51.35%). There were significant differences in the proportions of hypertension (69.44% vs. 85.52%; χ2=5.519, P=0.019), taking antihypertensive drugs before the onset (48.61% vs. 69.74%; χ2=6.845, P=0.009), white matter hyperintensity (18.06% vs. 39.47%; χ2=8.228, P=0.004), enlarged perivascular space (33.33% vs. 60.53%; χ2=10.968, P=0.001), as well as the baseline NIHSS scores (3.00 [2.00-4.00] vs. 7.0 [5.0-10.0]; Z=-8.159, P=0.001), baseline systolic blood pressure (149.40±15.80 mmHg vs. 157.21±14.05 mmHg; t=3.180, P=0.002; 1 mmHg=0.133 kPa), fasting glucose (5.91±2.06 mmol/L vs. 6.92±2.65 mmol/L; t=2.595, P=0.010), and the proportions of total CSVD scores 0, 1, 2, 3, and 4 (Z=-4.927, P=0.001)between the 2 groups. After adjustment for the confounding factors, such as hypertension and fasting glucose, multivariate regression analysis showed that the total CSVD score (odds ratio 4.457, 95% confidence interval 1.768-11.236; P=0.002) and baseline NIHSS score (odds ratio 2.070, 95% confidence interval 1.580-2.710; P<0.001) were the independent risk factors for the poor outcomes in patients with LAA stroke. Conclusions The total CSVD burden was closely associated with the outcomes in patients with LAA stroke. Higher CSVD total score and baseline NIHSS scores were independently associated with the poor outcome at 90 d in patients with LAA stroke. Key words: Stroke; Brain Ischemia; Cerebral Small Vessel Diseases; Magnetic Resonance Imaging; Atherosclerosis; Treatment Outcome; Risk Factors

Elevated serum lipoprotein(a) as a potential predictor for combined intracranial and extracranial artery stenosis in patients with ischemic stroke

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.

Background and purposeBesides cerebral collaterals, few studies have examined other additional factors affecting the prognosis of patients with large artery atherosclerotic (LAA) stroke. Our study aims to explore the effect of the cerebral small vessel disease (SVD) and the effects of its interaction with cerebral collaterals on the prognosis of patients with acute LAA stroke.MethodPatients aged 18 years or older with LAA stroke within 24 h after stroke onset were consecutively enrolled. The functional outcome was determined using the modified Rankin Scale (mRS) at 3 months after stroke onset. Logistic multivariate analyses were used to identify the risk factors for stroke prognosis. Receiver operating characteristic (ROC) curves were constructed to compare the effects of cerebral collaterals and SVD on predicting the prognosis.ResultsOf the 274 enrolled patients, 174 (63.50%) were identified as having a favorable prognosis, and 100 (36.50%) were identified as having an unfavorable prognosis. After adjusting for covariates, the logistic regression analysis identified that unfavorable prognosis was related to the total SVD score (Model 1, adjusted odds ratio = 1.73, 95% CI: 1.15–2.61, P < 0.01; Model 2, adjusted odds ratio = 1.85, 95% CI: 1.23–2.79, P < 0.01) and Tan score (Model 1, adjusted odds ratio = 0.38, 95% CI: 0.23–0.64, P < 0.01; Model 2, adjusted odds ratio = 0.52, 95% CI: 0.33–0.82, P < 0.01). Compared with cerebral collaterals (AUC = 0.59; 95% CI: 0.52–0.67; P < 0.01) or SVD (AUC = 0.62; 95% CI: 0.56–0.69; P < 0.01) alone, the combination of collaterals and SVD (AUC = 0.66; 95% CI: 0.59–0.73; P < 0.01) had higher diagnostic value for an unfavorable prognosis, and the optimal sensitivity and specificity were 77.01 and 53.00%, respectively.ConclusionsThe total SVD burden was related to the prognosis of patients with LAA stroke. Compared with cerebral collaterals or SVD alone, cerebral collaterals combined with total SVD burden are better at predicting the prognosis of patients with acute LAA stroke.

Low-density lipoprotein cholesterol (LDL) is the primary lipid target for vascular risk reduction in stroke patients, but emerging data suggest that other lipid indices may better predict vascular hazard. We evaluated the relationship between several measures of the classically obtained serum lipid panel and the occurrence of large artery atherosclerotic stroke. Data prospectively collected over a 4-year period on subjects admitted with ischemic stroke or TIA to a university medical center were analyzed. Independent associations of fasting serum lipid indices with large artery atherosclerotic (LAA) stroke mechanism were evaluated. Of 1,049 patients, 247 (23.5%) were classified with LAA, 224 (21.4%) were classified with small vessel disease (SVD), and 578 (55%) were non-LAA, non-SVD subtype. Lipid levels were similar between LAA and SVD patients. Total cholesterol, triglycerides, LDL, non-high-density lipoprotein cholesterol (HDL), and triglyceride:HDL ratio were significantly higher in LAA vs non-LAA, non-SVD patients. After adjustment for age, hypertension, diabetes, smoking, body mass index, and premorbid statin use, significant odds ratios (ORs) for LAA compared with all other ischemic stroke subtypes for patients in the uppermost lipid quartiles (vs lowest) were triglycerides (OR 2.69, 95% CI 1.44 to 5.02) and non-HDL (OR 2.39, 95% CI 1.40 to 4.11). LDL was not associated with LAA. Compared with all other ischemic stroke subtypes, elevated levels of serum triglycerides and non-high-density lipoprotein, but not low-density lipoprotein (LDL), are associated with large artery atherosclerotic stroke. These non-LDL lipid measures may have utility in delineating atherosclerotic stroke risk.

ObjectivesTo explore the association of plasma trimethylamine N-oxide (TMAO) concentration with large artery atherosclerotic (LAA) ischemic stroke and its role in predicting neurological outcome and major vascular event recurrence.Materials and MethodsWe performed a case-control study that included patients with first-ever LAA stroke as cases (n = 291) and asymptomatic patients as controls (n = 235). Clinical data and venous blood samples were collected within 72 hours after stroke. All subjects were followed for 3 months. TMAO level was detected by liquid chromatography mass spectrometry (LC-MS). Logistic and Cox proportional hazard regression were performed to evaluate plasma TMAO concentration as a predictor of LAA stroke and major vascular event recurrence, respectively. Kaplan–Meier survival analysis was performed to compare major vascular event recurrence between patients with high and low TMAO concentration.ResultsAfter adjusting for traditional stroke risk factors, the plasma TMAO level was significantly higher in the LAA stroke group than the control group (OR = 1.031, 95% CI 1.024-1.037, P < .001). At a cutoff level of 106.9 pg/ml, TMAO had a sensitivity of 63.23% and specificity of 80.00% in discriminating the LAA stroke subjects from the controls in Receiver operator characteristic (ROC) analysis. Kaplan–Meier survival analysis demonstrated TMAO plasma concentration was significantly relevant with recurrent vascular events (Log Rank, P = .006). Moreover, this association was still existed after adjusting for traditional risks (adjusted HR, 3.128; 95% CI, 1.018-9.610) in Cox regression model. But TMAO plasma levels were not relevant with functional disability after 3 months of the LAA stroke.ConclusionElevated plasma TMAO concentration was independently associated with LAA ischemic stroke. The risk of major vascular event recurrence increased by 2.128 times in the LAA stroke subjects with plasma TMAO level higher than 126.83 pg/mL. Plasma TMAO concentration might be a potential biomarker of major vascular event recurrence.

Background: Current ischemic stroke (IS) subtyping systems are very labor-intensive and costly to implement in large samples. There is a need to develop phenotyping approaches for genetic and other studies that can be implemented using generally available items captured in electronic medical records. Objective: In this report, we seek to validate a simplified approach using results from a genetic association study. Specifically, the strength of association for known genetic signals in the NINDS Stroke Genetics Network study (SiGN) is compared between the established IS subtyping systems (TOAST and Causative Classification System (CCS) subtypes) and phenotyping based on a single item within the CCS. Methods: Non-mutually exclusive “Simple” IS subtypes were defined from single CCS items as follows: 1) Small vessel stroke- lacunar infarct on imaging (with no other imaging or other requirements); 2) large artery stroke - vascular imaging showing &gt; 50% stenosis or &lt;50% stenosis with plaque rupture or thrombosis judged to be due to atherosclerosis in clinically relevant artery; and 3) cardioembolic stroke - persistent or paroxysmal atrial fibrillation. We compared the GWAS signals using these definitions to the published SiGN GWAS results for TOAST and CCS, among those of European ancestry only. Results: The Table shows that, for loci significant in SiGN GWAS study, the “Simple” IS subtypes had similar strengths of association and p-values compared to results from TOAST and the causative and phenotypic CCS subtypes. Conclusions: “Simple” IS subtypes perform as well in GWAS analyses as more complex phenotyping systems and could potentially be derived through automated or semi-automated methods applied to electronic medical record systems. Since the ‘Simple” phenotypes were based on high quality CCS data, the current findings reflect optimal performance. Additional validation studies will be required for implementation in other settings.

Previous studies have shown that increased body fat is associated with stroke risk, with evidence suggesting that body fat distribution, rather than total body fat, exerts a more prominent role in cerebrovascular risk prediction. In this study, we explore causal associations between body mass index (BMI)-independent adipose tissue distribution profiles and cerebrovascular disease (CVD) risk, aiming to refine the association between body fat distribution and stroke. We selected variants associated with BMI-independent visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT) volumes in UK Biobank, and performed univariable and multivariable Mendelian randomization (MR) analyses with ischemic stroke (IS) and subtypes (large artery stroke [LAS], cardioembolic stroke [CES], and small vessel stroke [SVS]). We used coronary artery disease (CAD), carotid intima media thickness (cIMT), and MRI-confirmed lacunar stroke as positive controls. We explored the mediatory role of common cardiovascular (systolic blood pressure, diabetes, and low-density lipoprotein), insulin resistance, inflammatory (C-reactive protein), and adipose tissue-specific (adiponectin, leptin) factors by performing 2-step mediation MR analyses. Estimates were expressed per standard deviation increase in adjusted adipose tissue volume. Genetic predisposition to higher GFAT volume was associated with lower risk of IS (odds ratio [OR] 0.92, 95% CI 0.86-0.98), LAS (OR 0.80, 95% CI 0.66-0.96), and SVS (OR 0.77, 95% CI 0.67-0.88), but not CES, consistent in multivariable analyses. Genetic predisposition to higher GFAT volume was also associated with lower risk of CAD (OR 0.82, 95% CI 0.76-0.88), lacunar stroke (OR 0.78, 95% CI 0.67-0.92), and mean cIMT (β = -0.073, 95% CI -0.114 to -0.031). Associations were largely consistent in sensitivity analyses. No association was observed between genetic predisposition to ASAT or VAT and IS risk. Although common vascular risk factors were the predominant mediators in the GFAT-CVD axis, adiponectin and leptin mediated a proportion of IS and CAD risk (∼15% (1.8%-57%) and ∼4.6% (0.8%-13.5%) mediated by adiponectin, respectively). This study supports a protective role of gluteofemorally distributed fat volume in CVD risk. Although this role is predominantly mediated by common vascular risk factor modification, adipose tissue-specific factors may exert a mediatory effect, suggesting a possible novel target for attenuating adiposity-related CVD risk.

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.

Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

An increasing number of epidemiological studies have identified a close relationship between dyslipidemia and atherosclerotic stroke. Indeed, lipid metabolism is significantly different among the different ischemic stroke subtypes. There are few studies available regarding risk factors for specific subtypes of ischemic stroke, and in particular, there is little evidence about the role of dyslipidemia. The aim of this study is to determine the relationship between acute ischemic stroke subtype and serum lipid level. The levels of serum lipid including TC, TG, LDL-C, HDL-C, apoA, apoB, apoE, and LP (a) were tested in 362 ischemic stroke patients and 181 healthy controls. Lipid levels were analyzed in stroke subtypes according to the TOAST classification. Levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP (a) were significantly higher and HDL-C levels were significantly lower in the patient group relative to control. The TC/HDL-C ratio, TG/HDL-C ratio, and LDL-C/HDL-C ratio were remarkably higher in the patient group. The levels of TC, TG, LDL-C, apoA, apoB, apoE, and LP(a) were markedly higher and HDL-C was markedly lower in the large-artery atherosclerosis stroke subtype relative to the cardioembolism subtype. Compared with the small-vessel occlusion group, the level of LP(a), TC, and TC/HDL-C were strikingly higher in the cardioembolism group. The TC/HDL-C ratio was different among subgroups, with the large-artery atherosclerosis group exhibiting the highest value. For TC, TG, LDL-C, apoA, apoB, apoE, LP(a), TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C levels a statistically significant difference was found between the large-artery atherosclerosis group and the small-vessel occlusion group. We found that LDL-C and TC levels may be independent predictors for the occurrence of large-artery atherosclerotic stroke.