Promising therapeutic targets for ischemic stroke identified from plasma and cerebrospinal fluid proteomes: a multicenter Mendelian randomization study.

BACKGROUND: Ischemic stroke (IS) is more common every year, the condition is serious, and have a poor prognosis. New, efficient, and safe therapeutic targets are desperately needed as early treatment especially prevention and reperfusion is the key to lowering the occurrence of poorer prognosis. Generally circulating proteins are attractive therapeutic targets, this study aims to identify potential pharmacological targets among plasma and cerebrospinal fluid (CSF) proteins for the prevention and treatment of IS using a multicenter Mendelian randomization (MR) approach. METHODS: First, the genetic instruments of 734 plasma and 151 CSF proteins were assessed for causative connections with IS from MEGASTROKE consortium by MR to identify prospective therapeutic targets. Then, for additional validation, plasma proteins from the deCODE consortium and the Fenland consortium, as well as IS GWAS data from the FinnGen cohort, the ISGC consortium and UK biobank, were employed. A thorough evaluation of the aforementioned possible pharmacological targets was carried out using meta-analysis. The robustness of MR results was then confirmed through sensitivity analysis using several techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Finally, methods like Protein-Protein Interaction (PPI) Networking were utilized to investigate the relationship between putative drug targets and therapeutic agents. RESULTS: The authors discovered three proteins that may function as promising therapeutic targets for IS and meet the Bonferroni correction ( P <0.05/885=5.65×10 -5 ). Prekallikrein (OR=0.41, 95% CI: 0.27-0.63, P =3.61×10 -5 ), a protein found in CSF, has a 10-fold protective impact in IS, while the plasma proteins SWAP70 (OR=0.85, 95% CI: 0.80-0.91, P =1.64×10 -6 ) and MMP-12 (OR=0.92, 95% CI: 0.89-0.95, P =4.49×10 -6 ) of each SD play a protective role in IS. Prekallikrein, MMP-12, SWAP70 was replicated in the FinnGen cohort and ISGC database. MMP-12 (OR=0.93, 95% CI: 0.91-0.94, P <0.001), SWAP70 (OR=0.92, 95% CI: 0.90-0.94, P <0.001), and prekallikrein (OR=0.53, 95% CI: 0.33-0.72, P <0.001) may all be viable targets for IS, according to the combined meta-analysis results. Additionally, no evidence of reverse causality was identified, and Bayesian colocalization revealed MMP-12 (PPH 4 =0.995), SWAP70 (PPH 4 =0.987), and prekallikrein (PPH 4 =0.894) shared the same variant with IS, supporting the robustness of the aforementioned causation. Prekallikrein and MMP-12 were associated with the target protein of the current treatment of IS. Among them, Lanadelumab, a new drug whose target protein is a prekallikrein, may be a promising new drug for the treatment of IS. CONCLUSION: The prekallikrein, MMP-12, and SWAP70 are causally associated with the risk of IS. Moreover, MMP-12 and prekallikrein may be treated as promising therapeutic targets for medical intervention of IS.

Inflammatory bowel disease and the risk of intracerebral hemorrhage: A Mendelian randomization study and meta-analysis.

BACKGROUND: The link between inflammatory bowel disease (IBD) and intracerebral hemorrhage (ICH) is still unclear. AIMS: We conducted a Mendelian randomization research and meta-analysis to explore the impact of IBD and its subtypes (Crohn's disease [CD], ulcerative colitis [UC]) on the risk of ICH. METHODS: Two large genome-wide association analysis studies of International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and International Stroke Genetics Consortium as exposure (IBD, UC, and CD) and outcome (ICH) in the initial stage. IBD, CD, UC GWAS data from the FinnGen consortium were adopted for the replication phase, and ultimately, the results of the initial stage and replication phase data were combined in a meta-analysis to evaluate the causal association between IBD and its subtypes and the risk of ICH. RESULTS: In the initial stage, we found that in the IVW (odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.71-0.96, p = .01), MR-PRESSO (OR = 0.85, 95% CI: 0.75-0.97, p = .02) and MR.RAPS (OR = 0.86, 95% CI: 0.76-0.98, p = .02) method showed that UC is associated with the risk of ICH. The causal relationship between IBD, CD, and the risk of ICH cannot be found by the IVW method. IBD and its subtypes UC, CD, and risk of ICH cannot find the presence of heterogeneity and pleiotropy. In replication stage, IBD (OR = 0.74, 95% CI: 0.59-0.94, p = .0135) related to ICH, while the IVW approach did not establish a causal link in UC and CD. The meta-analysis still indicated that UC (OR = 0.83, 95% CI: 0.72-0.93, p < .05) would lessen the risk of ICH while the causality between IBD, CD, and ICH was unable to be established. CONCLUSION: UC was causally related to ICH, but IBD and CD are not associated with ICH. The precise pathophysiological mechanism needs to be thoroughly investigated in more detail.

Exploring the Causality of Type 1 Diabetes and Stroke Risk: A Mendelian Randomization Study and Meta-analysis.

Type II diabetes was causally related to stroke, which is a risk factor for stroke. However, the causal relationship between type I diabetes(T1D) and stroke, especially its subtypes, remains unclear. To determine whether T1D has a genetic causal link to stroke and its subtypes, we undertook this mendelian randomization (MR) study. The genome-wide association studies (GWAS) of T1D was the source of exposure. The outcomes were strokes and their subtypes, including ischemic stroke (IS), small vessel stroke (SVS), cardioembolic stroke (CES), large artery atherosclerosis stroke (LAS), intracerebral hemorrhage (ICH), lobar intracerebral hemorrhage (LICH), and non-lobar intracerebral hemorrhage (NLICH). We used outcome GWAS conducted by ISGC consortium for the initial phase and GWAS from MEGASTROKE consortium as the data for the replication phase to confirm the causal association. Besides, we conducted a meta-analysis of the causal association from ISGC and MEGASTROKE databases to confirm robust causality. Inverse-variance weighting (IVW) was utilized as the primary method to estimate the causality between T1D and stroke. The Cochran's Q test and the MR-PRESSO global test were used to examine the sensitivity. We discovered the causal relationship between T1D and SVS (OR = 1.17, 95% CI: 1.07-1.28, p = 6.0 × 10- 4), CES (OR = 1.11, 95%CI: 1.03-1.21, p = 0.0080) in initial stage. The replication phase validated T1D has a causal relationship with SVS (OR = 1.12, 95% CI: 1.06-1.18, p = 4.0 × 10- 5), but not with stroke and other subtypes. The meta-analysis of initial and replication stage again supported the causal link between T1D and SVS (OR = 1.13, 95% CI: 1.08-1.18, p < 0.05). However, no causal relationship was found between T1D and other stroke subtypes. The sensitivity analysis also supported the robust of these results. In conclusion, T1D was causally associated with SVS, but not with other subtypes of stroke. More investigation is needed to understand the underlying biology mechanism.

Potential preventive markers in the intracerebral hemorrhage process are revealed by serum untargeted metabolomics in mice using hypertensive cerebral microbleeds.

Hypertensive cerebral microbleeds (HCMB) may be the early stage of hypertensive intracerebral hemorrhage (HICH), which is a serious threat to health due to its high mortality and disability rates. The early clinical symptoms of HCMB may not be significant. Moreover, it is difficult to achieve early diagnosis and intervention for targeted prevention of HICH. Although hypertension (HTN) is a predisposition for HCMB, it remains unclear whether there is any difference between hypertensive patients with or without HCMB. Therefore, we carried out liquid chromatography-mass spectrometry (LC-MS) to analyze early biomarkers for HCMB in mice with hypertension and to lay the foundation for early prevention of HICH in hypertensive patients. In total, 18 C57 male mice were randomly divided into the HCMB (n = 6), HTN (n = 6), and control groups (CON, n = 6). Hematoxylin-eosin and diaminobenzidine staining were used to assess the reliability of the model. The metabolite expression level and sample category stability were tested using the displacement test of orthogonal partial least squares discriminant analysis (OPLS-DA). Significant differences in metabolites were screened out using variable importance in the projection (VIP > 1), which were determined using the OPLS-DA model and the P-value of the t-test (P < 0.05) combined with the nonparametric rank-sum test. With an area under the curve (AUC) > 0.85 and a P-value of 0.05, the receiver operating characteristic curve (ROC) was used to further screen the distinct metabolites of HCMB. Compared with the HTN and CON groups, the HCMB group had significantly higher blood pressure and lower average body weight (P < 0.05). Through untargeted LC-MS analysis, 93 distinct metabolites were identified in the HCMB (P < 0.05, VIP > 1) group. Among these potential biomarkers, six significantly decreased and eight significantly increased differential metabolites were found. Meanwhile, we found that the HCMB group had statistically distinct arginine and purine metabolism pathways (P < 0.05), and citrulline may be the most significant possible biomarker of HCMB (AUC > 0.85, P < 0.05). All of these potential biomarkers may serve as early biomarkers for HICH in hypertension.

Mendelian randomization study and meta-analysis exploring the causality of age at menarche and the risk of intracerebral hemorrhage and ischemic stroke.

BACKGROUND: The relationship between the age at menarche (AAM) and the risk of intracerebral hemorrhage (ICH) and ischemic stroke (IS) is still up for debate. The purpose of this study was to investigate potential causal connections between them. METHODS: Genome-wide association analysis (GWAS) of AAM conducted by the MRC-IEU consortium was utilized for association analyses of ICH and IS by two-sample Mendelian randomization (MR) study. AAM data of the within-family GWAS consortium were used as replication phase data to verify the causal relationship between each other. Inverse variance weighting (IVW) method was the primary method used in this MR study. For additional proof, the weighted median estimation, MR-Egger regression, MR-PRESSO test, and MR-Robust Adjusted Profile Score evaluation were performed. The Cochran's Q test and the MR-PRESSO global test were used, respectively, to examine the sensitivity and pleiotropy. Random effects meta-analysis was utilized to analyze the causal data from the two consortiums to further explore the causality between AAM and ICH, IS. RESULTS: We found that the AAM was causally linked with the risk of ICH (OR = 0.48, 95% CI: 0.28-0.80, p = 0.006). On the contrary, the causal effect from AAM to IS (OR = 0.98, 95% CI: 0.91-1.06, p = 0.64) has not been confirmed. For all subtypes of ICH, we found that nonlobar intracerebral hemorrhage (NLICH, OR = 0.41, 95% CI: 0.23-0.75, p = 0.004) but not lobar intracerebral hemorrhage (LICH, OR = 0.65, 95% CI: 0.34-1.24, p = 0.19) was associated with AAM without surprise. Similarly, we used the within-family GWAS consortium data to explore causality and found that AAM may reduce the risk of ICH (OR = 0.78, 95% CI: 0.72-0.86, p = 9.5 × 10-8 ) and NLICH (OR = 0.68, 95% CI: 0.61-0.75, p = 3.4 × 10-13 ) by IVW methods, but is not related to IS (OR = 0.97, 95% CI: 0.93-1.02, p = 0.26). These findings are further supported by the meta-analysis. Both Cochran's Q test and the MR-PRESSO global test failed to detect the presence of sensitivity. CONCLUSION: AAM and ICH, particularly NLICH, are causally related, but not LICH, IS, or its subtypes in European population.

Illuminating the potential causality of serum level of matrix metalloproteinases and the occurrence of cardiovascular and cerebrovascular diseases: a Mendelian randomization study.

BACKGROUND: It is still not clear that whether the expression levels of matrix metalloproteinases (MMPs) family are associated with cardiovascular and cerebrovascular diseases (CCDs) in genetic level. We explored the causal role of 12 members of MMPs in CCDs with mendelian randomization (MR) method to facilitate further exploring the underlying mechanisms. METHODS: The relationship between MMPs and CCDs including intracerebral hemorrhage (ICH), hypertension, coronary heart disease (CHD), atrial fibrillation (AF), and outstanding risk factors of type II diabetes were determined with the inverse variance-weighted (IVW) method. The sensitivity analyses including MR-Egger regression, weighted median estimation, and MR pleiotropy residual sum and outlier were utilized to test the robustness of the results generated from the MR method. RESULTS: We found that a higher serum level of MMP-12 was related to a lower risk of ICH (OR = 0.8287, 95% CI: 0.7526-0.9125, p = 0.00013), but not hypertension, CHD, type II diabetes or AF. And our study also revealed that a higher serum level of MMP-8 could result in a lower risk of hypertension (OR = 0.9976, 95% CI: 0.9964-0.9988, p = 0.00012) and AF (OR = 0.9851, 95% CI: 0.9741-0.9963, p = 0.0092), but not ICH, CHD or type II diabetes. All other members of MMPs other than MMP-8 and MMP-12 showed no statistical association with CCDs according to this study. Sensitivity analyses confirmed the reliability of our results. CONCLUSIONS: We provided statistical evidences for a potential causal relationship between MMP-12 and ICH, as well as MMP-8 and hypertension, while other MMPs showed weaker association with CCDs. The underlying mechanisms need to be established in the future.

Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies.

The high morbidity, mortality, and disability rates associated with cerebrovascular disease (CeVD) pose a severe danger to human health. Gut bacteria significantly affect the onset, progression, and prognosis of CeVD. Gut microbes play a critical role in gut-brain interactions, and the gut-brain axis is essential for communication in CeVD. The reflection of changes in the gut and brain caused by gut bacteria makes it possible to investigate early warning biomarkers and potential treatment targets. We primarily discussed the following three levels of brain-gut interactions in a systematic review of the connections between gut microbiota and several cerebrovascular conditions, including ischemic stroke, intracerebral hemorrhage, intracranial aneurysm, cerebral small vessel disease, and cerebral cavernous hemangioma. First, we studied the gut microbes in conjunction with CeVD and examined alterations in the core microbiota. This enabled us to identify the focus of gut microbes and determine the focus for CeVD prevention and treatment. Second, we discussed the pathological mechanisms underlying the involvement of gut microbes in CeVD occurrence and development, including immune-mediated inflammatory responses, variations in intestinal barrier function, and reciprocal effects of microbial metabolites. Finally, based on the aforementioned proven mechanisms, we assessed the effectiveness and potential applications of the current therapies, such as dietary intervention, fecal bacterial transplantation, traditional Chinese medicine, and antibiotic therapy.

Epidemiology of intracerebral hemorrhage: A systematic review and meta-analysis.

Background: Intracerebral hemorrhage (ICH) is associated with high mortality and disability rates. This study aimed to investigate the relationship between sex, age, study year, risk factors, bleeding site, median year of study, and the incidence of ICH. Method: Literature on the incidence of ICH published on 1 January 1980 and 1 January 2020, was systematically retrieved from PubMed and Embase databases. The random-effects model and subgroup analysis were used to explore the relationship between the incidence of ICH and different ages, sex, bleeding sites, and risk factors. Results: We summarized the epidemiological changes in ICH in the past 40 years according to 52 studies and found that the total incidence of ICH is 29.9 per 100,000 person-years (95% CI: 26.5-33.3), which has not decreased worldwide. The incidence of ICH in the Asian population is much higher than in other continents. In addition, the incidence of ICH increases with age and differs at the 85-year-old boundary. Men are more likely to develop ICH than women, and the basal ganglia region is the most common area for ICH. Of the 10 risk factors examined in this study, those with hypertension had the highest incidence of ICH, followed by those with excessive alcohol consumption and heart disease. Conclusion: The prevention and treatment of ICH still need to be improved continuously according to age, sex, risk factors, and other factors, and targeted and normative strategies should be gradually developed in the future.

A systematic review and meta-analysis expounding the relationship between methylene tetrahydrofolate reductase gene polymorphism and the risk of intracerebral hemorrhage among populations.

Background: The relationship between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphism with the risk of intracerebral hemorrhage (ICH) has remained to be controversial in recent years. This meta-analysis is aimed to confirm the association of these. Methods: Systematically searching the related studies from the PubMed, Embase, Cochrane Library, China national knowledge internet database from 1 January 1990 to 1 June 2022. The odd ratio (ORs) and 95% confidence interval (CIs) of gene-disease correlation in various gene models were calculated by fixed or random effect model of meta-analysis. We included 20 case-control studies in this meta-analysis with a total of 1,989 ICH patients and 4,032 health controls originated from Asian, Caucasian, and African populations. Results: The statistical analysis demonstrated the association of MTHFR C677T gene polymorphism with ICH in allele model [ORT VS. C = 1.20 (95%CI: 1.06-1.36)]; homozygote model [OR TT VS. CC = 1.50 (95%CI: 1.20-1.88)]; dominant model [OR CT+ TT VS. CC = 1.23 (95%CI: 1.03-1.48)] and recessive model [ORTT VS. CT+CC = 1.37 (95%CI: 1.17-1.60)]. Besides, we also found the relationship of MTHFR C677T gene polymorphism with Asian in four comparison model (ORT VS. C = 1.19.95%CI:1.09-1.37, ORTT VS. CC = 1.46.95%CI: 1.15-1.85, OR CT+ TT VS. CC = 1.25.95%CI: 1.01-1.54, ORTT VS. CT+CC = 1.34.95%CI: 1.54-1.17) and Caucasian in four comparison model (ORT VS. C = 1.90.95%CI: 1.22-2.97, ORTT VS. CC = 2.67.95%CI: 1.42-5.00, OR CT+ TT VS. CC = 1.56.95%CI: 1.05-2.32, ORTT VS. CT+CC = 2.25.95%CI: 1.46-4.00). But no statistically significant correlation between A1298C polymorphism and the occurrence of ICH was detected in four studies. Conclusion: MTHFR C677T gene polymorphism increases the risk of ICH in Asian and Caucasian populations but has no impact on the incidence in African communities. More importantly, the risk of ICH increases in TT genotype individuals in comparison to CT and CC genotype individuals in Asian and Caucasian populations.

Evaluating the Causal Effects of TIMP-3 on Ischaemic Stroke and Intracerebral Haemorrhage: A Mendelian Randomization Study.

Aim: Since tissue inhibitors of matrix metalloproteinase 3 (TIMP-3) was reported to be a potential risk factor of atherosclerosis, aneurysm, hypertension, and post-ischaemic neuronal injury, it may also be a candidate risk factor of stress. Therefore, this study was designed to explore the causal role of TIMP-3 in the risk of ischaemic stroke (IS) and intracerebral haemorrhage (ICH), which are the two main causes of stress via this Mendelian Randomisation (MR) study. Methods: The summarised data of TIMP-3 level in circulation was acquired from the Cooperative Health Research in the Region of Augsburg public database and the outcome of IS and ICH was obtained from genome-wide association studies conducted by MEGASTROKE and the International Stroke Genetics Consortium, respectively. Five statistical methods including inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test, and MR-Robust Adjusted Profile Score were applied to evaluate the causal role of TIMP-3 in the occurrence of IS and ICH. Inverse-variance weighting was applied for assessing causality. Furthermore, heterogeneity and pleiotropic tests were utilised to confirm the reliability of this study. Results: We found that TIMP-3 could be a positively causal relationship with the incidence of IS (OR = 1.026, 95% CI: 1.007-1.046, p = 0.0067), especially for the occurrence of small vessel stroke (SVS; OR = 1.045, 95% CI: 1.016-1.076, p = 0.0024). However, the causal effects of TIMP-3 on another IS subtype cardioembolic stroke (CES; OR = 1.049, 95% CI: 1.006-1.094, p = 0.024), large artery stroke (LAS; OR = 1.0027, 95% CI: 0.9755-1.0306, p = 0.849) and ICH (OR = 0.9900, 95% CI: 0.9403-1.0423, p = 0.701), as well as ICH subtypes were not observed after Bonferroni corrections (p = 0.00714). Conclusion: Our results revealed that high levels of circulating TIMP-3 causally increased the risk of developing IS and SVS, but not CES, LAS, ICH, and all ICH subtypes. Further investigation is required to elucidate the underlying mechanism.

Multi-omics reveals specific host metabolism-microbiome associations in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, but effective prevention and treatment strategies are lacking. Recently, gut microbiome and its metabolitesis are considered to be an influencing factor of stroke. However, little is known about the effects of the gut microbiome on ICH and host metabolic activity. Therefore, we used 16S sequencing, macrogenomics sequencing and untargeted metabolomics to explore the differences in gut microbial-metabolome interactions between patients with intracerebral hemorrhage and healthy control populations. We found a significant decrease in the phylum of Firmicutes and a significant increase of Bacteroidetes in ICH patients. At the genus level, Streptococcus, Bifidobacterium, Akkermansia, and Lactobacillus were more abundant in ICH patients. Macrogenomic analysis revealed active glycosaminoglycan degradation, heme synthesis, galactose degradation, lipopolysaccharide core region synthesis, and beta-Lactam resistance in ICH patients. Serum untargeted metabolomic analysis combined with ROC curves showed that octanoylcarnitine, decanoylcarnitine, dodecanoylcarnitine, glyceric acid, pyruvic acid, aspartic acid, methylcysteine, pyroglutamic acid, 9E-tetradecenoic acid, N-Acetylneuraminic acid, and aconitic acid were the best markers for the diagnosis of ICH. Correlation analysis showed that microbiome enriched in the gut of ICH patients were significantly correlated with serum metabolites, revealing a close correlation between the gut microbiome of ICH patients and the host metabolome, and significant differences from the healthy population. microbiota-host co-metabolites including pyruvic acid and 9E-tetradecenoic acid is associated with the the National Institutes of Health Stroke Scale (NIHSS) scores. In conclusion, microbiome-related metabolites in ICH patients was associated with the severity of ICH, the microbiota-host co-metabolites may be a potential may be potential therapeutic targets.

Deciphering the Irregular Risk of Stroke Increased by Obesity Classes: A Stratified Mendelian Randomization Study.

Background: To investigate the relationship between different classes of obesity and stroke, we conducted a stratified Mendelian randomization (MR) study. Methods: The body mass index (BMI) data of 263,407 Europeans with three classes of obesity (obesity class I, 30 kg/m2 ≤ BMI < 35 kg/m2; obesity class II, 35 kg/m2 ≤ BMI < 40 kg/m2; obesity class III, 40 kg/m2 ≤ BMI) were extracted from the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary-level data of stroke and its subtypes [ischemic stroke (IS) and intracerebral hemorrhage (ICH)] were obtained from the genome-wide association study (GWAS) meta-analysis, which was performed by the MEGASTROKE consortium. MR methods were used to identify the causal relationships. Results: The MR analysis revealed that both obesity class I [odds ratio (OR) = 1.08, 95% CI: 1.05-1.12, p = 1.0 × 10-5] and obesity class II (OR = 1.06, 95% CI: 1.03-1.09, p = 1 × 10-4) were significantly positively related to IS, while obesity class III was not (OR = 1.01, 95% CI: 0.96-1.06, p = 0.65). In contrast to IS, there was no class of obesity associated with ICH risk. Further examination of the relationship between obesity classification and IS subtypes revealed that certain degrees of obesity were related to large artery stroke (LAS) (OR = 1.14, 95% CI: 1.04-1.24, p = 2.8 × 10-3 for class I; OR = 1.08, 95% CI: 1.01-1.16, p = 0.002 for class II) and cardioembolic stroke (CES) (OR = 1.11, 95% CI: 1.02-1.20, p = 0.02 for class I; OR = 1.08, 95% CI: 1.02-1.15, p = 0.007 for class II). Conclusions: A higher risk of IS, but not ICH, could be linked to obesity classes I and II. A strong association between LAS and CES and obesity was observed among all IS subtypes in the obese population.

Childhood Obesity and Risk of Stroke: A Mendelian Randomisation Analysis.

Background: The causal relationship between childhood obesity and stroke remains unclear. Our objective was to elucidate the causal relationship between childhood obesity and the risk of stroke and its subtypes by performing Mendelian randomisation (MR) analyses. Methods: Genetic instruments for childhood obesity were obtained from a genome-wide association study (GWAS) of 13,848 European participants. Summary level data for stroke, intracerebral haemorrhage, ischaemic stroke (IS), and its subtypes were evaluated using the MEGASTROKE GWAS dataset, which included 446,696 European adults. Inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and MR-Robust Adjusted Profile Score were applied in this MR analysis. The leave-one-out sensitivity test, MR-PRESSO Global test, and Cochran's Q test were conducted to confirm the accuracy and robustness of our results. Results: Genetic evaluations revealed that childhood obesity was associated with a higher risk of stroke (OR = 1.04, 95%CI: 1.01-1.07, p = 0.005) and IS (OR = 1.05, 95%CI: 1.02-1.08, p = 0.003), but not with intracerebral haemorrhage (ICH, OR = 0.93, 95%CI: 0.80-1.09, p = 0.39). In the subtype analysis, childhood obesity was also associated with large artery stroke (LAS, OR = 1.12, 95%CI: 1.02-1.22, p = 0.016) but not with cardioembolic stroke (OR = 1.06, 95%CI: 0.96-1.18, p = 0.21) and small vessel stroke (OR = 1.06, 95%CI: 0.98-1.15, p = 0.17). These results were stable in the sensitivity analysis and remained significant after Bonferroni correction. Conclusion: Our study provides evidence that childhood obesity is associated with a higher risk of stroke, IS, and LAS. The prevention of stroke, especially IS and LAS, should be promoted in populations with childhood obesity.

Influential factors for large volume of spontaneous supratentorial intracerebral hemorrhage. / è‡ªå‘æ€§å¹•ä¸Šå¤§å®¹ç§¯è„‘å‡ºè¡€çš„å½±å“å› ç´ .

OBJECTIVES: To explore the relevant protective and risk factors that affect spontaneous supratentorial large volume intracerebral hemorrhage. METHODS: Clinical data of hospitalized patients with spontaneous supratentorial intracerebral hemorrhage in Xiangya Hospital of Central South University from January 2014 to December 2018 were retrospectively analyzed. According to the amount of intracerebral hemorrhage (≥30 mL), the patients were divided into a large volume intracerebral hemorrhage group (255 cases) and a non-large volume intracerebral hemorrhage group (397 cases). Univariate and multivariate logistic regression analysis for the clinical data from the two groups of patients were performed. RESULTS: Systolic blood pressure, diastolic blood pressure, white blood cell count, neutrophil count, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, calcium ion concentration, and international standard ratio between the large volume intracerebral hemorrhage group and the non-large volume intracerebral hemorrhage group were significantly different (all P<0.05). Multivariate logistic regression analysis showed the increased LDL cholesterol (OR=0.709, 95% CI 0.564 to 0.892, P=0.003) and the increased calcium concentration (OR=0.084, 95% CI 0.023 to 0.309, P<0.001) were the protective factors for large volume intracerebral hemorrhage on the screen; while the increased white blood cell count (OR=1.268, 95% CI 1.194 to 1.347, P<0.001), the increased high-density lipoprotein cholesterol (OR=1.884, 95% CI 1.199 to 2.961, P=0.006), the increased systolic blood pressure at admission (OR=1.022, 95% CI 1.014 to 1.030, P<0.001), and the increased international standard ratio (OR=26.209, 95% CI 4.712 to 145.764, P<0.001) were the risk factors. CONCLUSIONS: The occurrence of spontaneous supratentorial large volume intracerebral hemorrhage is the result of combination of multiple factors. The increased white blood cell count, the increased systolic blood pressure, the increased high-density lipoprotein cholesterol, and the increased international standard ratio may increase its risk, while the increased LDL cholesterol and calcium concentration may reduce its risk.