Risk Of Small Vessel Stroke Research Articles

Hypertensive disorders of pregnancy and stroke: a univariate and multivariate Mendelian randomization study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of stroke later in life in multiparous women. However, causality of these associations remains unclear. This study employed 2-sample univariate and multivariate Mendelian randomization (MR) to assess the causal connection between HDP and stroke. Genetic variants for HDP and two subtypes were identified from recent large-scale genome-wide association studies and the FinnGen consortium. Stroke summary data were obtained from the MEGASTROKE consortium. The primary analytical approach for univariate MR was the inverse variance weighting method. Sensitivity analyses incorporated methods such as MR-Egger regression, weighted median, and maximum likelihood to ascertain the robustness of the results. Additionally, multivariable MR analyses were conducted to account for potential associative effects of hypertension and type 2 diabetes. Genetically predicted HDP was associated with a high risk of large artery atherosclerosis (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.17-1.91, P=1.13×10-3) and small vessel stroke (OR=1.29, 95% CI: 1.20-1.50, P=1.52×10-3). HDP may also correlate with ischemic stroke (OR=1.13, 95% CI: 1.04-1.23, P=4.99×10-3) and stroke (OR=1.11, 95% CI: 1.03-1.20, P=8.85×10-3). An elevated risk of small vessel stroke (OR=1.20, 95% CI: 1.01-1.43, P=3.74×10-2) and large artery atherosclerosis (OR=1.22, 95% CI: 1.01-1.47, P=4.07×10-2) may be related with genetically predicted susceptibility to gestational hypertension. Genetically predicted susceptibility to preeclampsia or eclampsia may be associated with an increased risk of stroke (OR = 1.10, 95% CI: 1.02-1.19, P = 1.16×10-2) and ischemic stroke (OR = 1.10, 95% CI: 1.02-1.20, P = 1.84×10-2). Type 2 diabetes mellitus and hypertension were identified as significant factors contributing to the association between HDP and stroke. This study provides genetic evidence supporting an association between HDP and increased stroke risk bolstering HDP as a cerebrovascular risk factor.

Biological aging mediates the association between periodontitis and cardiovascular disease: results from a national population study and Mendelian randomization analysis

BackgroundThe relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging.MethodsWe included 3269 participants from the National Health and Nutrition Examination Survey (2009–2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera–Doubal method’s calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging.ResultsPeriodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging.ConclusionsPeriodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk.

Causal Effect of Macronutrient and Micronutrient Intake on Stroke: A Two-Sample Mendelian Randomization Study.

(1) Background: Estimating the causal association between nutrient intake, as a modifiable risk factor, and stroke risk is beneficial for the prevention and management of stroke. However, observational studies are unavoidably influenced by confounding factors and reverse causation. (2) Methods: We performed a two-sample Mendelian randomization (MR) to estimate the effects of nutrient intake on stroke risk. Summary statistics for nutrients, including 4 macronutrients and 14 micronutrients, were derived from 15 genome-wide association studies (GWAS). Data on stroke and its subtypes were sourced from the MEGASTROKE consortium. (3) Results: Genetically predicted magnesium levels, as the protective factors, were significantly associated with a lower risk of cardioembolic stroke (OR: 0.011, 95% CI: 0-0.25, p-value: 0.005) in the IVW method. Additionally, vitamin C reduced the risk of cardioembolic stroke (OR: 0.759, 95% CI: 0.609-0.946, p-value: 0.014) and vitamin B9 reduced the risk of small vessel stroke (OR: 0.574, 95% CI: 0.393-0.839, p-value: 0.004) with the IVW method. However, the association of vitamin B6 with an increased risk of large-artery stroke (OR: 1.546, 95% CI: 1.009-2.37, p-value: 0.046) in the Wald ratio method should be interpreted cautiously due to the limited number of SNPs. There was also suggestive evidence that magnesium might decrease the risk of both any stroke and ischemic stroke. (4) Conclusions: Our MR analysis highlights the protective roles of magnesium, vitamin C, and vitamin B9 in stroke prevention, making them key targets for public health strategies. However, the findings related to vitamin B6 are less certain and require further validation.

BIOM-08. CDKN2A --AN INDEPENDENT CYCLIN-DEPENDENT KINASE INHIBITOR VARIANT ASSOCIATED WITH MALIGNANCY AND WITH SMALL VESSEL STROKE, AS A POTENTIAL MARKER FOR RISK OF LARGE-VESSEL STROKE COMPLICATING BENIGN TERATOMA

Abstract BACKGROUND Cyclin-dependent kinase inhibitor variants, particularly those of CDKN2A are known to be associated with autosomal dominant Familial Atypical Multiple Mole/Melanoma Syndrome and pancreatic cancer predisposition. These variants are associated with risk of small vessel stroke in African/ African-American populations, and are risk factors for stroke in Nordic populations with hypertension, independent of cardiovascular risk factors. METHODS We performed a case review of a female presenting in late infancy with a central nervous system teratoma, that later was complicated by a right hemispheric middle cerebral artery (MCA)stroke, associated with a CDKN2A germline mutation. RESULTS This 14month old female presented with transient alterations of consciousness and apparent abdominal migraine events with pernicious vomiting. Neuroimaging revealed a right heterogeneous para- suprasellar mass and bilateral complex arachnoid adjacent cysts. She was observed closely for any progression, as the lesion was immediately adjacent to the optic chiasm. One year after presentation, she developed an acute ischemic right middle cerebral artery (MCA) stroke and had radiographic evidence of severe stenosis and decreased flow primarily within the right supra-clinoid internal carotid artery, the M1 segment and portion of the right A1 segment of cerebral vessels, with decreased enhancement and number of vessels in the distal right MCA territory. The vessels did not appear to be compressed by any mass effect. The radiologic appearance was consistent with vasospasm. The patient upon stoke recovery, underwent near- complete resection of the mass with no evidence of disruption of the capsule surrounding it and no vascular infiltration. Pathology revealed the expected teratoma with prominence of pancreatic acinar structures, and molecular evidence of a variant of CDKN2A, which was present in the patient and mother in the germline. CONCLUSION We propose that the imaging evidence of a vasculopathy was related to the genotype at the cyclin- dependent kinase site.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

BackgroundSodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.MethodsGenetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.ResultsA lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.ConclusionsSGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Causal associations of male infertility with stroke: a two-sample Mendelian randomization study.

Stroke is a devastating global health issue, with high mortality and disability rates. The increasing prevalence of male infertility among reproductive-aged men has become a growing concern worldwide. However, the relationship between male infertility and stroke incidence remains uncertain. This study aimed to address this knowledge gap by employing a Mendelian randomization (MR) approach. Utilizing genetic instrumental variables derived from a genome-wide association study (GWAS) on male infertility and stroke, a two-sample MR design was implemented. Five different analysis methods, with inverse-variance weighted as the primary approach, were used to examine the genetic causal associations between male infertility and various stroke subtypes. Heterogeneity analysis, pleiotropy tests, and leave-one-out validation were conducted to assess heterogeneity, evaluate pleiotropy, and ensure the robustness of the findings. The results indicate a potential lower risk of small vessel stroke associated with male infertility (odds ratio, 95% confidence interval: 0.82, 0.68 to 0.99, p=0.044), although no significant impact on other stroke subtypes was observed. The study exhibited low heterogeneity and no apparent pleiotropy; however, the stability of the results was not optimal. Male infertility might potentially confer a protective effect against small vessel stroke risk. Caution is warranted due to potential confounding factors. Additional studies are necessary to confirm these findings and provide further validation.

Impact of Immune Cells on Stroke Limited to Specific Subtypes: Evidence from Mendelian Randomization Study.

Stroke is one of the common diseases that pose a severe threat to human health, with immune cells playing a crucial role in its onset and recovery. However, the specific mechanisms and causal relationships of different immune cell groups in various clinical stroke subtypes are unclear. This study explored the causal relationship between immune cells and stroke and its subtypes using Mendelian randomization (MR) analysis. Data from genome-wide association studies were analyzed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods for MR analysis, along with heterogeneity tests, sensitivity analysis, and pleiotropy analysis. CD45RA+CD28-CD8+ Tcell %Tcell (OR 1.002, 95%CI 1.001-1.003; PFDR = 0.02), CD27 on CD24+CD27+ Bcell (OR 1.127, 95%CI 1.061-1.198; PFDR = 0.04), CD27 on IgD-CD38dim Bcell (OR 1.138, 95%CI 1.076-1.203; PFDR = 0.005), and CD27 on switched memory Bcell (OR 1.144, 95%CI 1.076-1.216; PFDR = 0.01) were found to increase the risk of large artery stroke. Switched memory Bcell %lymphocyte (OR 1.206, 95%CI 1.103-1.318; PFDR = 0.02) increased the risk of small vessel stroke. Reverse MR analysis did not reveal any reverse causal associations. Furthermore, by substituting the outcome data, a secondary MR analysis was conducted to validate the primary findings. Our study reveals several causal links between immune phenotypes and stroke and its different subtypes, highlighting the complex interactions between the immune system and stroke. These findings provide new directions for further uncovering the biological basis of stroke and assist in advancing research on early interventions and treatment strategies.

Causal relationship between inflammatory factors and cerebral small vessel disease: Univariate, multivariate, and summary-data-based mendelian randomization analysis.

To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary-data-based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation. Using public databases such as UKB and IEU, and original genome-wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR-Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR-Egger intercept test, MR-Presso, and leave-one-out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers. ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF-related apoptosis-inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08-1.39) and interleukin-1 receptor-like 2, (IL-1RL2, OR, 1.29, 95% CI, 1.04-1.61). IL-18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00-1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E-selectin (OR, .98, 95% CI, .97-1.00), IL-1RL2 (OR, .97, 95% CI, .95-1.00), IL-3 receptor subunit alpha (IL-3Ra, OR, .98, 95% CI, .97-1.00), and IL-5 receptor subunit alpha (IL-5Ra, OR, .98, 95% CI, .97-1.00). Mediation and multivariate MR analysis indicated that E-selectin and IL-3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL-related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen-1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (βsmr=.10, Psmr=.003, FDR=.04). Instruments (rs507666 and rs2519093) related to E-selectin and IL-3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (βsmr=.01-.02, Psmr=.001, FDR=.01-.03). According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E-selectin and IL-3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue.

Causal Association between Tea Intake and Acute Cerebrovascular Events: A Multivariate Mendelian Randomized Study in European Populations

BackgroundNumerous research works have investigated the association between tea consumption and the risk of acute cerebrovascular events; however, the results are inconsistent. ObjectivesWe used Mendelian randomization (MR) to evaluate the causal association between tea intake and several acute cerebrovascular events, including any ischemic stroke, large atherosclerotic stroke (LAS), cardiogenic embolic stroke (CES), small vessel stroke (SVS), intracranial hemorrhage (ICH), and subarachnoid hemorrhage (SAH). MethodsWe obtained summary genome-wide association study (GWAS) data on tea intake and acute cerebrovascular events in populations of European ancestry. The GWAS on tea intake is derived from the UK Biobank, where we have chosen single-nucleotide polymorphisms (SNPs) closely associated with it as instrumental variables. We also obtained summary data on ischemic stroke from a GWAS meta-analysis, as well as summary data on ICH and SAH from the FinnGen study. We first explored the causal association between tea intake and several acute cerebrovascular events using univariate Mendelian randomization (UVMR), and then further assessed the causal association between tea intake and SVS using multivariate Mendelian randomization (MVMR) corrected for multiple confounders. ResultsIn UVMR, genetically predicted increases in tea intake were linked to a lower risk of SVS (OR: 0.58; 95% CI: 0.39, 0.86). There was no causal association between tea intake and the risk of other acute cerebrovascular events. In the MVMR, our results show that there was still a significant causal association between drinking tea and SVS, after adjusting body mass index, total cholesterol, low-density lipoprotein cholesterol, diabetes, hypertension, smoking, and alcohol consumption. ConclusionThis MR study provides new genetic evidence that increased tea intake reduces the risk of SVS in the European population. However, possibly because of limited statistical power, the study did not find that tea consumption reduced the risk of several other acute cerebrovascular events.

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study

BackgroundStroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain.MethodsWe performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used.ResultsForward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10−12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW β = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10−7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR.ConclusionsWe identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.

Associations of lipids and lipid-lowering drugs with risk of stroke: a Mendelian randomization study.

Stroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes. We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes. The inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04). We cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.

Causal Associations between Functional/Structural Connectivity and Stroke: A Bidirectional Mendelian Randomization Study

Disruption of brain resting-state networks (RSNs) is known to be related to stroke exposure, but determining causality can be difficult in epidemiological studies. We used data on genetic variants associated with the levels of functional (FC) and structural connectivity (SC) within 7 RSNs identified from a genome-wide association study (GWAS) meta-analysis among 24,336 European ancestries. The data for stroke and its subtypes were obtained from the MEGASTROKE consortium, including up to 520,000 participants. We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causality relationship between FC and SC within 7 RSNs and stroke and its subtypes. The results showed that lower global mean FC and limbic network FC were associated with a higher risk of any ischemic stroke and small vessel stroke separately. Moreover, ventral attention network FC and default mode network SC have a positive causal relationship with the risk of small vessel stroke and large artery stroke, respectively. In the inverse MR analysis, any stroke and large artery stroke were causally related to dorsal attention network FC and somatomotor FC, respectively. The present study provides genetic support that levels of FC or SC within different RSNs have contrasting causal effects on stroke and its subtypes. Moreover, there is a combination of injury and compensatory physiological processes in brain RSNs following a stroke. Further studies are necessary to validate our results and explain the physiological mechanisms.

Differentiating Associations of Glycemic Traits With Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation.

We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2 h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher levels of genetically predicted glycemic traits were consistently associated with increased risk of coronary atherosclerosis-related diseases and symptoms. Genetically predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically predicted FG and 2hGlu were positively associated with risk of large artery stroke. Genetically predicted 2hGlu levels showed positive associations with risk of small vessel stroke. Higher levels of genetically predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically predicted levels of 2hGlu and FI remained after adjustment for other glycemic traits. Increase in glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis but not thrombosis.

Genetically Predicted Coffee Consumption and Risk of Alzheimer's Disease and Stroke.

Observational studies have reported that coffee consumption was associated with Alzheimer's disease (AD) and stroke risk. However, the results are inconclusive. We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Summary-level data for AD (n = 54,162), ischemic stroke (n = 440,328), and intracerebral hemorrhage (ICH, n = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Genetically predicted coffee consumption (cups/day) was associated with an increased risk of AD (OR = 1.26, 95%CI = 1.05-1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08-4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51-0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p < 0.05), while the association with AD attenuated when adjusting for alcohol use. Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study.

Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study.

Several observational studies have shown that cannabis use has negative effects on the cardiovascular system, but the causality of this relationship has not been confirmed. The aim of the current study was to estimate the effects of genetically determined cannabis use on risk of cardiovascular diseases. Ten single-nucleotide polymorphisms related to cannabis use were employed as instruments to estimate the association between genetically determined cannabis use and risk of cardiovascular diseases using a two-sample Mendelian randomization (MR) method. Summary statistics data on exposure and outcomes were obtained from different genome-wide association meta-analysis studies. The results of this MR analysis showed no causal effects of cannabis use on the risk of several common cardiovascular diseases, including coronary artery disease, myocardial infarction, stroke and ischemic stroke subtypes, atrial fibrillation (AF), and heart failure. Various sensitivity analyses yielded similar results, and no heterogeneity and directional pleiotropy were observed. After adjusting for tobacco use and body mass index, multivariable MR analysis suggested a causal effect of cannabis use on small vessel stroke (SVS) [odds ratio (OR) 1.17; 95% CI 1.02–1.35; p = 0.03] and AF (OR 1.06; 95% CI 1.01–1.10; p = 0.01), respectively. This two-sample MR study did not demonstrate a causal effect of genetic predisposition to cannabis use on several common cardiovascular outcomes. After adjusting for tobacco use and body mass index, the multivariable MR analysis suggested a detrimental effect of cannabis use on the risk of SVS and AF, respectively.

Causal associations of serum matrix metalloproteinase-8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis. No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p<0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p=0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.

Height and risk of ischaemic stroke subtypes: a Mendelian randomisation study

Abstract Background Taller adult height is associated with lower risks of ischaemic heart disease in both conventional and Mendelian randomisation studies, providing support for a causal association, but the associations of height with ischaemic stroke and ischaemic stroke subtypes are uncertain. Purpose To examine the causal relevance of height for ischaemic stroke and ischaemic stroke subtypes. Methods Two-sample Mendelian randomisation analyses were used to examine the associations of height with: (i) ischaemic stroke and ischaemic stroke subtypes in MEGASTROKE (using summary data from 34 217 ischaemic stroke cases), and with (ii) established cardiovascular and other risk factors using individual data from 336 433 participants in UK Biobank and 57 785 in the China Kadoorie Biobank. Instruments for Mendelian randomisation were constructed from up to 3280 height-associated genetic variants, previously identified as having genome-wide significant effects on height. Results Genetically-determined taller height was inversely associated with ischaemic stroke (3% [95% CI: 1–6] lower risk per 1 standard deviation taller height) in MEGASTROKE but this masked much stronger opposing associations on risks of different ischaemic stroke subtypes: 15% (95% CI: 9–21) higher risk of cardioembolic stroke, 10% (4–15) lower risk of large-artery atherosclerotic stroke, and 15% (10–20) lower risk of small-vessel stroke (Figure). Genetically-determined taller height was strongly associated with atrial fibrillation and higher lean body mass and lung function but more weakly associated with lower levels of LDL cholesterol and blood pressure. Conclusions The findings support a causal association between taller adult height and risk of atrial fibrillation and cardioembolic stroke. The opposing associations of height with other ischaemic stroke subtypes provide further support for considering ischaemic stroke subtypes as distinct diseases in both research and clinical practice. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Medical Research Council, British Heart Foundation

Higher tea consumption is associated with decreased risk of small vessel stroke

Observational studies have reported that tea consumption is associated with risk of stroke. However, this observed association is inconsistent, and whether this observed association is due to confounding factors or reverse causation remains unclear. Thus, we applied a two-sample mendelian randomization (MR) approach to determine whether genetically predicted tea consumption is causally associated with risk of stroke, ischemic stroke (IS), and IS subtypes. UK Biobank available data (349,376 samples of European ancestry) was used to identify single nucleotide polymorphisms associated with tea consumption (cups/day). The summary statistics for stroke, IS, and IS subtypes were obtained from the MEGASTROKE consortium with 40,585 stroke cases and 406,111 controls. We found that genetically predicted an extra daily cup of tea consumption was casually associated with a reduced risk of small vessel stroke (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.69-0.91; P=0.001), but not with cardioembolic stroke (OR, 0.97; 95% CI, 0.86-1.09; P=0.582), large artery stroke (OR, 0.95; 95% CI, 0.82-1.10; P=0.506), stroke (OR, 1.00; 95% CI, 0.95-1.06; P=0.889) or IS (OR, 0.95; 95% CI, 0.89-1.01; P=0.083). Our study provided evidence that genetically predicted an extra daily cup of tea consumption is causally associated with a reduced risk of small vessel stroke.

Effects of Genetic Variants on Stroke Risk.

Effects of Genetic Variants on Stroke Risk.

Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.