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BACKGROUND: Coronary heart disease (CHD) and stroke have become the leading cause of premature mortality and morbidity worldwide. Therefore, sensitive and accurate biomarkers for early detection of CHD and stroke are urgently needed for effective prevention and treatment. We aim to investigate the association between blood-based HYAL2 methylation and the risk of CHD and stroke in Chinese population. METHODS: In a prospective nested case-control study comprising 171 CHD cases, 139 stroke cases, who developed the diseases after recruitment and 356 controls who remained healthy during the 2.5 years of follow-up time, the methylation level of HYAL2 in the peripheral blood was quantified using mass spectrometry, and the association was calculated by logistic regression adjusted for covariant. RESULTS: Significant association between HYAL2 methylation in the peripheral blood and increased risk of preclinical CHD and stroke were identified [odds ratios (ORs) per - 10% methylation: 1.35-1.64, p ≤ 0.045 for HYAL2_CpG_1, HYAL2_CpG_2 and HYAL2_CpG_3 in CHD; ORs per - 10% methylation: 0.76-1.64, p ≤ 0.033 for HYAL2_CpG_2 and HYAL2_CpG_4 in stroke]. The association in CHD was further enhanced by female gender, younger age (< 70 years old), without the history of hypertension and cancer. The combination of four HYAL2 methylation sites showed an effective discrimination of CHD and stroke cases without hypertension from controls [area under curve (AUC) = 0.78 and 0.75, respectively]. CONCLUSIONS: This study presents a strong association of altered HYAL2 methylation in peripheral blood with preclinical CHD and stroke, providing a novel biomarker for risk assessment and early detection of cardiovascular diseases.

Asunto(s)

Biomarcadores , Enfermedad Coronaria , Metilación de ADN , Hialuronoglucosaminidasa , Accidente Cerebrovascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Metilación de ADN/genética , Estudios de Casos y Controles , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/sangre , Estudios Prospectivos , Enfermedad Coronaria/genética , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Anciano , Biomarcadores/sangre , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/sangre , China , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/sangre , Diagnóstico Precoz , Moléculas de Adhesión Celular

RESUMEN

BACKGROUND: The lipid-lowering effects of Omega-3 fatty acids have been widely reported, yet their impact on ischemic stroke remains controversial. Reports on the protective effects of unsaturated fatty acids, such as Omega-6 and Omega-7, as well as saturated fatty acids in cardiovascular diseases, including hypertension and ischemic stroke, are less frequent. OBJECTIVES: This study aims to identify fatty acids associated with blood pressure and ischemic stroke through Mendelian randomization. Besides, it seeks to determine whether specific fatty acids can prevent ischemic stroke by managing blood pressure and revealing the specific mechanisms of this action. METHODS: This research involved downloading relevant data from websites and extracting SNPs that met the standard criteria as instrumental variables. Simultaneously, the 'MR-PRESSO' package and 'Mendelian Randomization' package were used to eliminate confounding SNPs that could bias the study results. Then, inverse variance weighting and the weighted median were employed as primary analysis methods, accompanied by sensitivity analysis to assess the validity of the causal relationships. Initially, multivariable Mendelian randomization was used to identify fatty acids linked to blood pressure and the incidence of ischemic stroke. The causal link between certain fatty acids and the initiation of ischemic stroke was then investigated using bidirectional and mediator Mendelian randomization techniques. Stepwise Regression and the Product of Coefficients Method in mediator Mendelian randomization were utilized to ascertain whether specific fatty acids reduce ischemic stroke risk by lowering blood pressure. RESULTS: Multivariable Mendelian randomization analysis indicated a potential inverse correlation between Omega-3 intake and both blood pressure and ischemic stroke. Consequently, Omega-3 was selected as the exposure, with blood pressure and ischemic stroke-related data as outcomes, for further bidirectional and mediation Mendelian Randomization analyses. Bidirectional Mendelian Randomization revealed that Omega-3 significantly influences DBP (P = 1.01e-04) and IS (P = 0.016). It also showed that DBP and SBP significantly affect LAS, SVS, CES, IS, and LS. Mediator Mendelian Randomization identified five established mediating pathways: Omega-3-Diastolic blood pressure-Small vessel stroke, Omega-3-Diastolic blood pressure-Cardioembolic stroke, Omega-3-Diastolic blood pressure-Lacunar stroke, Omega-3-Diastolic blood pressure-Large artery atherosclerosis stroke, and Omega-3-Diastolic blood pressure-Ischemic stroke. Of these, four pathways are complete mediation, and one pathway is partial mediation. CONCLUSIONS: The findings suggest that Omega-3 may indirectly reduce the incidence of ischemic stroke by lowering blood pressure. Thus, blood pressure modulation might be one of the mechanisms through which Omega-3 prevents ischemic stroke. In summary, incorporating an increased intake of Omega-3 in the diet can serve as one of the dietary intervention strategies for patients with hypertension. Additionally, it can act as an adjunctive therapy for the prevention of ischemic strokes and their complications.

Asunto(s)

Presión Sanguínea , Ácidos Grasos Omega-3 , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular , Ácidos Grasos Omega-3/uso terapéutico , Humanos , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/genética , Hipertensión/genética , Factores de Riesgo

RESUMEN

The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p = 3.87 × 10-9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10-10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p = 3.0 × 10-6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

Asunto(s)

Pueblo Asiatico , Predisposición Genética a la Enfermedad , Receptor Notch3 , Accidente Cerebrovascular , Humanos , Receptor Notch3/genética , Pueblo Asiatico/genética , Masculino , Accidente Cerebrovascular/genética , Femenino , Pakistán , Reino Unido/epidemiología , Persona de Mediana Edad , Frecuencia de los Genes , Secuenciación del Exoma , Anciano , Imagen por Resonancia Magnética , Polimorfismo de Nucleótido Simple , Mutación Missense , Personas del Sur de Asia

RESUMEN

This case report concerns a 48-year-old man with a history of ischemic stroke at the age of 41 who reported cardiac hypertrophy, registered in his twenties when explained by increased physical activity. Family history was positive for a mother with permanent atrial fibrillation from her mid-thirties. At the age of 44, he had a first episode of persistent atrial fibrillation, accompanied by left atrial thrombosis while on a direct oral anticoagulant. He presented at our clinic at the age of 45 with another episode of persistent atrial fibrillation and decompensated heart failure. Echocardiography revealed a dilated left atrium, reduced left ventricular ejection fraction, and an asymmetric left ventricular hypertrophy. Cardiac magnetic resonance was positive for a cardiomyopathy with diffuse fibrosis, while slow-flow phenomenon was present on coronary angiography. Genetic testing by whole-exome sequencing revealed three variants in the patient, c.309C > A, p.His103Gln in the ACTC1 gene, c.116T > G, p.Leu39Ter in the PLN gene, and c.5827C > T, p.His1943Tyr in the SCN5A gene, the first two associated with hypertrophic cardiomyopathy and the latter possibly with familial atrial fibrillation. This case illustrates the need for advanced diagnostics in unexplained left ventricular hypertrophy, as hypertrophic cardiomyopathy is often overlooked, leading to potentially debilitating health consequences.

Asunto(s)

Fibrilación Atrial , Cardiomiopatía Hipertrófica , Hipertrofia Ventricular Izquierda , Humanos , Fibrilación Atrial/genética , Fibrilación Atrial/diagnóstico , Masculino , Persona de Mediana Edad , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/complicaciones , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/diagnóstico , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/diagnóstico , Ecocardiografía , Canal de Sodio Activado por Voltaje NAV1.5/genética

RESUMEN

INTRODUCTION: This study investigates the causal relationship between plasma metabolites and stroke. METHOD: The primary analytical approach employed was the inverse variance weighted (IVW) method, complemented by the weighted median (WM) and MR Egger methods for Additionally, validation of the identified plasma metabolites was performed using the Steiger test and LD linkage disequilibrium score. Furthermore, the main results were confirmed through data from the UK Biobank. RESULT: The IVW analysis revealed the most notable negative association found in X-17335 levels (OR [95 % CI]: 0.82 [0.72, 0.94]). On the other hand, the strongest positive effect was seen in the 5'-homophase (AMP) to phase ratio (OR [95 % CI]: 1.17 [1.03, 1.32]). Moving on to the validation dataset, the most significant positive effect was observed in the 13 HODE+9-HODE levels (OR [95 % CI]: 0.996 [0.993, 0.999]), whereas the most significant negative effect was seen in the Dihydroxide levels (OR [95 % CI]: 1.004 [1.00, 1.007]). Notably, Alpha ketoglutarate levels exhibited strong causal effects in both datasets (OR 0.908 [0.841, 0.981], p = 0.0144). Enrichment analysis highlighted the association of Alpha ketoglutarate levels with five plasma metabolites in metabolic pathways relevant to stroke, specifically Arginine biosynthesis, Butanoate metabolism, Citrate cycle (TCA cycle), Alanine, aspartate, and glutamate metabolism, and Lipid acid metabolism, all linked to oxoglutaric acid. CONCLUSION: The discovery dataset showed the most significant positive effect of the 5'-homophase (AMP) to phase ratio, while the validation dataset revealed the most significant positive effect of the 13 HODE+9-HODE levels. Additionally, alpha ketoglutarate may offer a potential protective effect on stroke by influencing five metabolic pathways that intersect with Oxoglutaric acid during the progression of the condition.

Asunto(s)

Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/genética , Polimorfismo de Nucleótido Simple

RESUMEN

BACKGROUND: Serum corin has been associated with stroke in observational studies, but the underlying causality is uncertain. This study examined the causal association between corin and stroke through Mendelian randomization study. METHODS AND RESULTS: In the Gusu cohort, serum corin was assayed at baseline, and stroke incidents were prospectively obtained during 10 years of follow-up. Single-nucleotide polymorphisms (SNPs) in CORIN were genotyped by MassArray for 2310 participants (mean age, 53 years; 39% men). Seventeen SNPs passed the Hardy-Weinberg test and were considered the potential instruments. Only 1 SNP (rs2271037) determined variability of serum corin was significantly associated with stroke even after adjusting for conventional risk factors (hazard ratio [HR], 1.36 [95% CI, 1.00-1.85]). The weighted genetic risk score generated from the SNP-corin associations was significantly associated with stroke (HR, 2.01 [95% CI, 1.15-3.51]). Using this genetic risk score as the instrument, 1-sample Mendelian randomization analysis found a significant HR of stroke per-SD higher log2-transformed corin (HR, 1.37 [95% CI, 1.07-1.76]). The inverse variance-weighted analysis based on the SNP-corin and SNP-stroke associations found that the HR of stroke pre-SD higher log2-transformed corin was 5.92 (95% CI, 2.23-15.72). The effect estimates stayed consistent regardless of an individual SNP being removed from the instruments. An almost identical effect estimate was also confirmed by multiple other 2-sample Mendelian randomization methods. CONCLUSIONS: Genetically determined variations of serum corin concentration were significantly associated with the risk of stroke in Chinese adults. Elevated serum corin may be a risk factor for stroke.

Asunto(s)

Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Serina Endopeptidasas , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/epidemiología , Femenino , Persona de Mediana Edad , Masculino , China/epidemiología , Serina Endopeptidasas/genética , Serina Endopeptidasas/sangre , Factores de Riesgo , Estudios Prospectivos , Predisposición Genética a la Enfermedad , Pueblo Asiatico/genética , Adulto , Medición de Riesgo , Biomarcadores/sangre , Anciano , Incidencia , Pueblos del Este de Asia

RESUMEN

Burden of stroke differs by region, which could be attributed to differences in comorbid conditions and ethnicity. Genomewide variation acts as a proxy marker for ethnicity, and comorbid conditions. We present an integrated approach to understand this variation by considering prevalence and mortality rates of stroke and its comorbid risk for 204 countries from 2009 to 2019, and Genome-wide association studies (GWAS) risk variant for all these conditions. Global and regional trend analysis of rates using linear regression, correlation, and proportion analysis, signifies ethnogeographic differences. Interestingly, the comorbid conditions that act as risk drivers for stroke differed by regions, with more of metabolic risk in America and Europe, in contrast to high systolic blood pressure in Asian and African regions. GWAS risk loci of stroke and its comorbid conditions indicate distinct population stratification for each of these conditions, signifying for population-specific risk. Unique and shared genetic risk variants for stroke, and its comorbid and followed up with ethnic-specific variation can help in determining regional risk drivers for stroke. Unique ethnic-specific risk variants and their distinct patterns of linkage disequilibrium further uncover the drivers for phenotypic variation. Therefore, identifying population- and comorbidity-specific risk variants might help in defining the threshold for risk, and aid in developing population-specific prevention strategies for stroke.

Asunto(s)

Comorbilidad , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Factores de Riesgo , Fenotipo , Etnicidad/genética , Prevalencia , Variación Genética

RESUMEN

(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.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Micronutrientes , Nutrientes , Accidente Cerebrovascular , Humanos , Micronutrientes/administración & dosificación , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/epidemiología , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Magnesio/administración & dosificación , Dieta

RESUMEN

Stroke causes death of brain tissue leading to long-term deficits. Behavioral evidence from neurorehabilitative therapies suggest learning-induced neuroplasticity can lead to beneficial outcomes. However, molecular and cellular mechanisms that link learning and stroke recovery are unknown. We show that in a mouse model of stroke, which exhibits enhanced recovery of function due to genetic perturbations of learning and memory genes, animals display activity-dependent transcriptional programs that are normally active during formation or storage of new memories. The expression of neuronal activity-dependent genes are predictive of recovery and occupy a molecular latent space unique to motor recovery. With motor recovery, networks of activity-dependent genes are co-expressed with their transcription factor targets forming gene regulatory networks that support activity-dependent transcription, that are normally diminished after stroke. Neuronal activity-dependent changes at the circuit level are influenced by interactions with microglia. At the molecular level, we show that enrichment of activity-dependent programs in neurons lead to transcriptional changes in microglia where they differentially interact to support intercellular signaling pathways for axon guidance, growth and synaptogenesis. Together, these studies identify activity-dependent transcriptional programs as a fundamental mechanism for neural repair post-stroke.

Asunto(s)

Memoria , Recuperación de la Función , Accidente Cerebrovascular , Animales , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/metabolismo , Ratones , Plasticidad Neuronal , Masculino , Modelos Animales de Enfermedad , Microglía/metabolismo , Neuronas/metabolismo , Ratones Endogámicos C57BL , Redes Reguladoras de Genes , Transcripción Genética , Actividad Motora

Asunto(s)

Afibrinogenemia , Mutación Missense , Accidente Cerebrovascular , Humanos , Afibrinogenemia/genética , Afibrinogenemia/sangre , Fibrinógeno/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/sangre , Preescolar

RESUMEN

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.

Asunto(s)

Ferroptosis , Oligodendroglía , Transcriptoma , Animales , Ferroptosis/genética , Oligodendroglía/metabolismo , Ratas , Masculino , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Ratas Sprague-Dawley , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Hemorragia Cerebral/genética , Apoptosis/genética , Análisis de la Célula Individual

RESUMEN

BACKGROUND: Clinical observational study demonstrated that hypertension is an independent risk factor for stroke. Furthermore, both hypertension and stroke exhibit genetic predispositions. However, the genetic relationship between hypertension and stroke in first-degree relatives remains unclear. METHOD: The Genetic effects were validated using an across-Mendelian randomization (MR) approach. The Genome-Wide Association Study summary data used in this study were obtained from a publicly available platform. The primary MR effect employed was inverse-variance weighted (IVW), and the other analysis methods included MR-Egger, weighted median, simple mode, and weighted mode. Prior to MR analysis, tests for MR_PRESSO, pleiotropy, and heterogeneity were conducted. RESULT: The presence of family history of hypertension significantly contributed to the genetic predisposition to various types of stroke, including ischemic stroke, subarachnoid hemorrhage, lacunar stroke, cardioembolic ischemic stroke, small vessel ischemic stroke, and large artery atherosclerosis-related ischemic stroke. CONCLUSION: Briefly, hypertension in first-degree relatives has a genetic impact on the risk of stroke development. Shared genetic factors may exist between hypertension and stroke.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Herencia , Hipertensión , Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular , Humanos , Hipertensión/genética , Hipertensión/epidemiología , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Factores de Riesgo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Medición de Riesgo , Fenotipo , Linaje , Polimorfismo de Nucleótido Simple , Presión Sanguínea/genética , Bases de Datos Genéticas

RESUMEN

BACKGROUND AND PURPOSE: Prior observational studies have suggested a strong correlation between sarcopenia and stroke, but the causal link between them remains uncertain. This study aims to investigate the associations between genetically predicted sarcopenia-related traits and stroke using a two-step Mendelian randomization (MR) approach. METHODS: Genome-wide association study (GWAS) summary data for sarcopenia-related traits were acquired from the UK Biobank. Genetic associations for ischemic stroke (IS) and its subtypes were selected from the MEGASTROKE consortium comprising European ancestry participants. GWAS summary data for cerebral hemorrhage were obtained from the FinnGen consortium, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). MR estimates were calculated using the inverse-variance weighted (IVW) method. The robustness of results was assessed for heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs). RESULTS: Higher appendicular lean mass (ALM) exhibited a potential causal association with a reduced incidence of large artery atherosclerosis (LAA) (odds ratio [OR] = 0.81, 95% confidence interval [CI]:0.71-0.93; P = 0.003) and small vessel disease (SVD) (OR = 0.83, 95% CI:0.74-0.94; P = 0.002). The associations of ALM with IS and ICH were compromised after adjusting for body fat and physical activity with multivariable MR. Two-step MR mediation analysis explored 33 candidate mediators, among which hypertension and SBP accounted for more than 10% of the mediation proportion in the relationship between ALM and stroke and its subtypes. CONCLUSION: Our research findings indicate that lower ALM is associated with a increased risk of stroke . It is necessary to explore the specific protective mechanisms of higher ALM for preventing stroke occurrence.

Asunto(s)

Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular Isquémico , Análisis de la Aleatorización Mendeliana , Fenotipo , Polimorfismo de Nucleótido Simple , Sarcopenia , Humanos , Factores de Riesgo , Medición de Riesgo , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/epidemiología , Sarcopenia/genética , Sarcopenia/epidemiología , Sarcopenia/diagnóstico , Masculino , Femenino , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Incidencia , Anciano , Persona de Mediana Edad , Factores Protectores , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Músculo Esquelético , Accidente Cerebrovascular Hemorrágico/genética , Accidente Cerebrovascular Hemorrágico/epidemiología , Accidente Cerebrovascular Hemorrágico/diagnóstico

RESUMEN

OBJECTIVE: Stroke is a highly prevalent and disabling disease whose disease mechanisms are not fully understood. The discovery of disease-associated proteins with genetic evidence of pathogenicity provides an opportunity to identify new therapeutic targets. METHOD: We examined the observed and causal associations of thousands of plasma and inflammatory proteins that were measured using affinity-based proteomic assays. First, we pooled >3000 relevant proteins using a fixed-effects meta-analysis of 2 population-based studies involving 48,383 participants, then investigated the causal effects of stroke and its subtype-associated proteins by forward Mendelian randomization using cis-protein quantitative locus genetic tools identified from genome-wide association studies of these >48,000 individuals. To improve the accuracy of causal estimation, we implemented a systematic Mendelian randomization model that accounts for cascading imbalances between instruments and tested the robustness of causal estimation through multi-method analyses. To further validate the hypothesis that ginsenoside Rg1 monomer acts on the five protein targets screened for drug-targeted regulation, we conducted a comparative analysis of the mRNA (gene) expression levels of a limited number of genes in the brain tissues of different groups of SD rats. The druggability of the candidate proteins was investigated and the mechanism of action and potential targeting side effects were explored by Phenome-wide MR. RESULTS: Six circulating proteins were identified to have a significant genetic association with stroke (PFDR < 0.05). For example, in patients with cardioembolic stroke, higher genetically predicted APRT was associated with a lower risk of cardioembolic stroke (ORivw [95 % CI] = 0.641 [0.517, 0.795]; P = 5.25 × 10-5, ORSMR [95 % CI] = 0.572, [0.397, 0.825], PSMR = 0.003). Mediation analyses suggested that atrial fibrillation, angina pectoris, and heart failure may mediate the association of CD40L, LIFR, and UPA with stroke. Molecular docking revealed promising interactions between the identified proteins and glycosides. Transcriptomic sequencing in animal models indicated that ginsenoside Rg1 may act through APRT, IL15RA, and VSIR pathways, with APRT showing significant variability in mRNA sequencing expression. Phenome-wide MR of the six target proteins showed an overwhelming predominance of PFDR > 0.05, indicating less toxicity. CONCLUSIONS: The present study provides genetic evidence to support the potential efficacy of targeting the three druggable protein targets for the treatment of stroke. This is achieved by triangulating population genomic and proteomic data. Furthermore, the study validates the pathway mechanisms by which APRT, IL15RA, and VSIR dock ginsenoside Rg1 in animal models. This will help to prioritize stroke drug development.

Asunto(s)

Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular , Transcriptoma , Accidente Cerebrovascular/genética , Humanos , Animales , Ratas , Proteómica , Ratas Sprague-Dawley , Masculino , Multiómica

RESUMEN

Inflammasome activation by circulating DNA leads to recurrent stroke associated with atherosclerosis.

Asunto(s)

ADN , Inflamasomas , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Inflamasomas/metabolismo , ADN/genética , ADN/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Animales

RESUMEN

BACKGROUND: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke. METHODS AND RESULTS: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population. CONCLUSIONS: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

Asunto(s)

Estudio de Asociación del Genoma Completo , Hiperaldosteronismo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/epidemiología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/epidemiología , Predisposición Genética a la Enfermedad , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Pueblo Asiatico/genética , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etnología , Población Blanca/genética , Medición de Riesgo , Factores de Riesgo

RESUMEN

BACKGROUND AND PURPOSE: Genetic factors play an important role in the pathogenesis of stroke(S). This study aimed to screen the loci associated with S risk in northwestern Chinese population by genome-wide association analysis (GWAS). METHODS: A total of 1394 subjects, including 682 S patients and 692 controls, were enrolled in this study. SPSS 25.0 software was used for statistical analysis, and the independent sample t-test as well as Chi-square test were used to analyze the differences in age and gender between the case and control groups. The Precision Medicine Diversity Array (PMDA) genotyping chip was used in this study. The genotyping platform was the Gene Titan multi-channel instrument, and the Axiom Analysis Suite 6.0 software was used for the data analyzing. Besides, the LASSO analysis, SNP-SNP and GO/KEGG analysis were conducted to analyze the association between significant loci and S risk. RESULTS: A total of 30 SNPs were found to be associated with the S risk based on additive model (p < 5 × 10-8). After the LASSO screening, 22 SNPs showed the diagnostic value in S. The SNPs interaction analysis further screened the SNP-SNP interaction groups associated with the S risk(p < 0.05). Finally, the GO/KEGG analysis discovered the suggestive significance loci could be involved in the S development mainly by immune-related functions and pathways. CONCLUSION: This study discovered 30 S related SNPs and analyzed the potential pathways associated with genes located on the 30 SNPs, which were beneficial for enriching the genetic mechanism analysis of S in northwestern Chinese population.

Asunto(s)

Pueblo Asiatico , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular , Humanos , Estudio de Asociación del Genoma Completo/métodos , Masculino , Femenino , Persona de Mediana Edad , Accidente Cerebrovascular/genética , China , Pueblo Asiatico/genética , Anciano , Estudios de Casos y Controles , Sitios Genéticos , Genotipo , Factores de Riesgo , Pueblos del Este de Asia

RESUMEN

Despite decreases in overall stroke incidence and mortality in the United States, racial and ethnic disparities continue unabated. Of note, the long-standing disproportionate burden of stroke on African Americans compared to other racial and ethnic groups persists, and national projections indicate this toll will likely worsen over the next decade. Why have we not been able to bend the stroke disparities curve for African Americans? Well, this is mainly because traditional stroke risk factors, such as hypertension, diabetes, etc., account for just half of the Black vs. non-Hispanic White stroke disparity. As such, there is increasing interest in evaluating understudied factors like upstream social determinants of health, including geography, psychosocial stress, and environmental pollution; identifying potential mediators; and testing multilevel interventions to address them. This paper highlights emerging avenues that may help decode the excess stroke risk in African Americans, focusing on zip codes, color codes, and epigenetic codes.

Asunto(s)

Negro o Afroamericano , Disparidades en el Estado de Salud , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etnología , Negro o Afroamericano/genética , Factores de Riesgo , Estados Unidos/epidemiología , Determinantes Sociales de la Salud/etnología , Epigénesis Genética

RESUMEN

We previously showed that stroke alters circular RNA (circRNA) expression profiles. Many circRNAs undergo epitranscriptomic modifications, particularly methylation of adenosine to form N6-methyladenosine (m6A). This modification significantly influences the circRNA metabolism and functionality. Hence, we currently evaluated if transient focal ischemia in adult C57BL/6J mice alters the m6A methylation of circRNAs. Changes in m6A were profiled in the peri-infarct cortex following immunoprecipitation coupled with microarrays. Correlation and gene ontology analyses were performed to understand the association of m6A changes with circRNA regulation and functional implications after stroke. Many circRNAs showed differential regulation (up or down) after stroke, and this change was highest at 24h of reperfusion. Notably, most circRNAs differentially regulated after stroke also exhibited temporal changes in m6A modification patterns. The majority of circRNAs that showed post-stroke differential m6A modifications were derived from protein-coding genes. Hyper-than hypomethylation of circRNAs was most prevalent after stroke. Gene ontology analysis of the host genes suggested that m6A-modified circRNAs might regulate functions such as synapse-related processes, indicating that m6A epitranscriptomic modification in circRNAs could potentially influence post-stroke synaptic pathophysiology.

Asunto(s)

Adenosina , Ratones Endogámicos C57BL , ARN Circular , Accidente Cerebrovascular , Animales , ARN Circular/genética , ARN Circular/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Masculino , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Ratones , ARN/genética , ARN/biosíntesis , Metilación

RESUMEN

BACKGROUND: Active rheumatoid arthritis (RA) may damage vascular endothelial cells, thereby increasing the likelihood of adverse cardiovascular events. However, it is not yet clearly established whether RA also increases the risk of adverse cerebrovascular events, particularly stroke. OBJECTIVE: This study was designed to evaluate the likelihood of a causal association between RA and stroke. METHOD: A two-sample Mendelian randomization (MR) analysis was performed using the inverse variance-weighted (IVW) average, weighted median, and MR-Egger regression methods. The analysis utilized publicly available summary statistics datasets from Genome-wide association studies (GWAS) meta-analyses for RA in individuals of European descent (total n = 484,598; case = 5427, control = 479,171) as the exposure cohort, and from GWAS meta-analyses for "vascular/heart problems diagnosed by doctor: stroke" in individuals included in the UK Biobank (total n = 461,880; case = 7055, control = 454,825, MRC-IEU consortium) as the outcome cohort. RESULTS: Eight single-nucleotide polymorphisms with genome-wide significance were selected from the GWASs on RA as the instrumental variables. The results of the MR-Egger and weighted median analyses showed no causal association between RA and stroke (OR = 1.081, 95 % CI [0.943-1.240], P = 0.304) vs. OR = 1.079, 95 % CI [0.988-1.179], P = 0.091), respectively. However, the inverse variance-weighted (IVW) analysis results revealed a causal association between RA and stroke (OR = 1.115, 95 % CI [1.040-1.194], P = 0.002). Cochran's Q test and MR-Egger regression revealed no evidence of heterogeneity and horizontal pleiotropy. CONCLUSION: The MR analysis results indicated that rheumatoid arthritis (RA) may be causally associated with an increased risk of stroke.

Asunto(s)

Artritis Reumatoide , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular , Humanos , Artritis Reumatoide/genética , Artritis Reumatoide/complicaciones , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Predisposición Genética a la Enfermedad/genética