Identification and verification of genes associated with hypoxia microenvironment in Alzheimer's disease.

As the incidence of Alzheimer's disease (AD) increases year by year, more people begin to study this disease. In recent years, many studies on reactive oxygen species (ROS), neuroinflammation, autophagy, and other fields have confirmed that hypoxia is closely related to AD. However, no researchers have used bioinformatics methods to study the relationship between AD and hypoxia. Therefore, our study aimed to screen the role of hypoxia-related genes in AD and clarify their diagnostic significance. A total of 7681 differentially expressed genes (DEGs) were identified in GSE33000 by differential expression analysis and cluster analysis. Weighted gene co-expression network analysis (WGCNA) was used to detect 9 modules and 205 hub genes with high correlation coefficients. Next, machine learning algorithms were applied to 205 hub genes and four key genes were selected. Through the verification of external dataset and quantitative real-time PCR (qRT-PCR), the AD diagnostic model was established by ANTXR2, BDNF and NFKBIA. The bioinformatics analysis results suggest that hypoxia-related genes may increase the risk of AD. However, more in-depth studies are still needed to investigate their association, this article would guide the insights and directions for further research.

Machine learning models identify ferroptosis-related genes as potential diagnostic biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is a complex, and multifactorial neurodegenerative disease. Previous studies have revealed that oxidative stress, synaptic toxicity, autophagy, and neuroinflammation play crucial roles in the progress of AD, however, its pathogenesis is still unclear. Recent researches have indicated that ferroptosis, an iron-dependent programmed cell death, might be involved in the pathogenesis of AD. Therefore, we aim to screen correlative ferroptosis-related genes (FRGs) in the progress of AD to clarify insights into the diagnostic value. Interestingly, we identified eight FRGs were significantly differentially expressed in AD patients. 10,044 differentially expressed genes (DEGs) were finally identified by differential expression analysis. The following step was investigating the function of DEGs using gene set enrichment analysis (GSEA). Weight gene correlation analysis was performed to explore ten modules and 104 hub genes. Subsequently, based on machine learning algorithms, we constructed diagnostic classifiers to select characteristic genes. Through the multivariable logistic regression analysis, five features (RAF1, NFKBIA, MOV10L1, IQGAP1, FOXO1) were then validated, which composed a diagnostic model of AD. Thus, our findings not only developed genetic diagnostics strategy, but set a direction for further study of the disease pathogenesis and therapy targets.

Cilostazol for Aneurysmal Subarachnoid Hemorrhage: An Updated Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Cilostazol, a selective inhibitor of phosphodiesterase 3, was reported to reduce cerebral vasospasm and improve outcomes. We aimed to conduct an updated systematic review and meta-analysis of the efficacy and safety of cilostazol in aSAH. METHODS: We systematically searched PubMed, Embase, MEDLINE, and the Cochrane Library for articles published in English with the latest publishing time in August 2020. Articles reporting favorable outcome as the primary outcome and reporting severe angiographic vasospasm (aVS), symptomatic vasospasm (sVS), new cerebral infarction, or mortality as the secondary outcome were included in this review. Furthermore, we examined whether clinical outcomes were associated with the dosage of cilostazol (300 mg/day vs. 100-200 mg/day). RESULTS: Data from 405 patients in 4 randomized controlled trials (RCTs) and 461 patients in 4 observational studies (OSs) were included. In RCT studies, cilostazol was associated with significant favorable outcomes at discharge or 1 month (risk ratio [RR] 1.41, 95% confidence interval [CI] 1.01-1.97, p = 0.04) or 3 or 6 months (RR 1.16, 95% CI 1.05-1.28, p = 0.002). However, in OSs, no significant difference was indicated in favorable outcomes at discharge or 1 month (RR 1.22, 95% CI 0.94-1.60, p = 0.14) nor 3 or 6 months (RR 1.29, 95% CI 0.92-1.81, p = 0.14). The analyses found that cilostazol significantly reduced the incidences of severe aVS (RCT: RR 0.64, 95% CI 0.41-1.01, p = 0.05; OS: RR 0.61, 95% CI 0.43-0.88, p = 0.007), sVS (RCT: RR 0.46, 95% CI 0.31-0.70, p = 0.0002; OS: RR 0.38, 95% CI 0.21-0.68, p = 0.001), and new cerebral infarction (RCT: RR 0.40, 95% CI 0.24-0.67, p = 0.0005; OS: RR 0.38, 95% CI 0.23-0.64, p = 0.0002). However, no significant difference in mortality (RCT: RR 0.86, 95% CI 0.23-3.21, p = 0.82; OS: RR 0.16, 95% CI 0.02-1.24, p = 0.08) was found. In 3 OSs which reported different doses of cilostazol (300 mg/day vs. 100-200 mg/day) for aSAH, the 300-mg/day cilostazol groups showed decreased delayed cerebral infarction (RR 0.27, 95% CI 0.09-0.81, p = 0.02) but no significant difference in shunt-dependent hydrocephalus (RR 0.92, 95% CI 0.33-2.60, p = 0.88) or functional outcomes (RR 1.14, 95% CI 0.74-1.75, p = 0.56) compared with the 100-200 mg/day cilostazol groups. CONCLUSIONS: The meta-analyses suggest the credible efficacy and safety of cilostazol in treating aSAH. Furthermore, 300-mg/day cilostazol treatment appeared to be more effective than 100-200 mg/day treatment.

[Investigation of anxiety and depression in patients from the emergency department during COVID-19 epidemic].

OBJECTIVE: To investigate the status of anxiety and depression in patients requiring emergency treatment during the epidemic of COVID-19 to identify the patients with acute psychological stress disorder. METHODS: During the COVID-19 epidemic, the medical staff divided the patients visiting the emergency department into suspected group, fever group and control group through interview of the patients at triage. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were distributed to each patient, and a trained medical staff was responsible for assisting the patient to complete the scales. RESULTS: A total of 557 sets of scales were distributed, including 211 in suspected COVID-19 case group, 167 in fever group and 179 in the control group. A total of 516 scales were retrieved, including 197 in suspected case group, 151 in fever group and 168 in control group. In the 3 groups, the incidence rates of anxiety and depression were 57.87% and 58.88%, 48.34% and 43.71%, and 18.31% and 18.99%, respectively, and the rates were significantly higher in suspected group and fever group than in the control group (P < 0.01), and significantly higher in suspected group than in fever group (P < 0.05). The standardized anxiety and depression scale scores in suspected case group, fever group and control group were 57.38±16.25 and 42.58±14.27, 51.23±15.29 and 38.32±15.39, and 32.58±17.8 and 12.25±12.94, respectively. Compared with the control group, both suspected case group and fever group had significantly higher standard scores for anxiety and depression (P < 0.01), and suspected case group had significantly higher standardized scores than fever group (P < 0.01). CONCLUSIONS: Among the patients visiting the emergency treatment, the patients with suspected COVID-19 and common fever are more likely to develop anxiety and depressive symptoms.

Novel and Recurring NOTCH3 Mutations in Two Chinese Patients with CADASIL.

BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant, inherited, systemic, vascular disorder primarily involving the small arteries. It is characterized by migraine, recurrent ischemic strokes, cognitive decline, and dementia. Mutations in the Notch receptor 3 gene (NOTCH3) and the HtrA serine peptidase 1 gene (HTRA1) are 2 genetic causes for CADASIL. The NOTCH3 gene, located on chromosome 19p13.12, is the most common disease-causing gene in CADASIL. OBJECTIVE: To investigate genetic causes in 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL. METHODS: Exome sequencing was performed on both patients and potential pathogenic mutations were validated by Sanger sequencing. RESULTS: This study reports on 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL, identifying that NOTCH3 mutations were the genetic cause. A common mutation, c.268C>T (p.Arg90Cys), and a novel mutation, c.331G>T (p.Gly111Cys) in the NOTCH3 gene, were detected and confirmed in the patients, respectively, and were predicted to be deleterious based on bioinformation analyses. CONCLUSIONS: We identified 2 NOTCH3 mutations as likely genetic causes for CADASIL in these 2 patients. Our findings broaden the mutational spectrum of the NOTCH3 gene accountable for CADASIL. Clinical manifestations supplemented with molecular genetic analyses are critical for accurate diagnosis, the provision of genetic counseling, and the development of therapies for CADASIL.

The role of neurovascular unit damage in the occurrence and development of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with progressive cognitive impairment. It is the most common type of senile dementia, accounting for 65%-70% of senile dementia [Alzheimer's Association (2016). 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 12, 459-509]. At present, the pathogenesis of AD is still unclear. It is considered that ß-amyloid deposition, abnormal phosphorylation of tau protein, and neurofibrillary tangles are the basic pathological changes of AD. However, the role of neurovascular unit damage in the pathogenesis of AD has been attracting more and more attention in recent years. The composition of neurovascular unit and the role of neurovascular unit damage in the occurrence and development of AD were reviewed in this paper.

Comparative Epidemiological Investigation of Alzheimer's Disease and Colorectal Cancer: The Possible Role of Gastrointestinal Conditions in the Pathogenesis of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects approximately 35 million people worldwide, and diet has been reported to influence the prevalence/incidence of AD. Colorectal cancer is among the most common cancers in Western populations, and the correlation between constipation and the occurrence of colorectal cancer has been identified in a number of studies, which show that a Westernized diet is a mutual risk factor. Constipation is a growing health problem, particularly in middle-aged and older adults. As the most common gastrointestinal disorder in adults, constipation affects 2-20% of the world population, and it is associated with several diseases, such as diabetes, Parkinson's disease, and others. Comparing the epidemiological data on colorectal cancer and AD, we find that colorectal cancer and AD have similar epidemiologic feature, which is both disease correlate with high prevalence of constipation. Therefore, we hypothesized that constipation may influence Alzheimer's disease in a similar way that it contributes to colorectal cancer. This review aimed to systemically elucidate the evidence that constipation contributes to Alzheimer's disease progression.

[Verification of a sporadic Alzheimer disease model in SORL1 gene knockout mice].

OBJECTIVE: To compare the behavioral and pathological features of SORL1 gene knockout mice with those of normal mice and APP/PSE1 mice to verify the feasibility of using SORL1 knockout mice as a model of sporadic Alzheimer disease. METHODS: SORL1 gene of fertilized mouse eggs were edited using Crispr/Case9 technique. SORL1-/- mice were screened and identified by detecting the DNA sequence, and Western blotting was used to detect the expression of SORL1. SORL1-/- mice, control mice and APP/PSE1 mice all underwent Morris water maze test to assess their learning and memory abilities with positioning navigation and space exploration experiments. The expression of APP and Aß in the brain of the mice was detected using immunohistochemistry and Western blotting, respectively. RESULTS: DNA sequencing showed CAAT deletion in SORL1 gene in two chromosomes of SORL1-/- mice, and the control mice had intact SORL1 gene without the deletion; Western blotting did not detect the expression of the SORL1 in the brain of SORL1-/- mice. Morris water maze test showed that in positioning navigation experiment, the average avoidance latency was similar between SORL1-/- mice and APP/PSE1 mice (P>0.05) but increased significantly in both mice as compared with the control group (P<0.05); similar results were obtained in the space exploration experiment. Immunohistochemistry and Western blotting revealed significantly increased APP and Aß expression in the brain tissue of both SORL1-/- mice and APP/PSE1 mice compared with the control mice without significant differences between the two transgenic mice. CONCLUSION: SORL1-/- mice exhibit similar behavioral and pathological changes with APP/PSE1 mice and can be used as a model of sporadic Alzheimer's disease.

Eight-and-a-Half Syndrome: A Combination of Intracranial Capillary Telangiectasia and Hematencephalon.

Eight-and-a-half syndrome, a combination of one-and-a-half syndrome and ipsilateral facial palsy, was first described by Eggenberger in 1998. Intracranial capillary telangiectasia (ICT) is a rare type of latent cerebral vascular malformation characterized by a number of small, dilated, and thin-walled blood capillaries with normal brain tissues between them. Susceptibility weighted imaging is the recommended diagnostic method to detect ICT. Oommen once reported 1 case about pontine hemorrhage causing Fisher one-and-a-half syndrome with facial paralysis. Here, we report a case with regard to pontine tegmentum ICT and hematencephalon presenting as eight-and-a-half syndrome.

Role of miR-181a in the process of apoptosis of multiple malignant tumors: A literature review.

It has been recognized that miR-181a expression is dysregulated and intimately associated with clinical prognosis in a variety of human cancers. However, the direct role of miR-181a in tumor progression has been elusive. Moreover, mounting evidence has demonstrated that cellular apoptosis, a physiological process of programmed cell death, is disrupted in various categories of human malignancies. Multiple apoptosisrelated genes have been proven to act as the target genes of miR-181a. In this study, we hypothesize that miR-181a probably plays a potential role in modulating the procession and apoptosis of cancer cells. We performed a literature review and elucidated how miR-181a modulated cellular apoptosis, especially the malignant neoplasm cells. We also unraveled the potential role of miR-181a in the diagnosis, treatment and clinical prognosis of multiple human malignancies - miR-181a plays a pivotal role in the development, treatment and prognosis of patients suffering from malignant tumors. It also participates in the development of cancer partially by modulating cellular apoptosis.

[Establishment of a new cell model mimicking Alzheimer's disease by knocking down SORL1 expression].

OBJECTIVE: To establish a cell model mimicking Alzheimer's disease (AD) by knocking down SORL1 gene and compare the viability, apoptosis, and expressions of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in this model with a traditional Alzheimer's disease cell model. METHODS: A traditional cell model of AD was established by inducing N2a cells with Aß25-35, and the optimal Aß25-35 concentration was determined by assessing the cell viability changes. Another cell model of AD was established by transfecting N2a cells with SORL1-shRNA lentiviral vector, and SORL1 expression in the transfected cells were detected using Western blotting and qRT-PCR. With wild-type N2a cells without any treatment and cells transfected with a scramble shRNA as the control groups, the two cell models were examined for cell viability with MTT assay, cell apoptosis with flow cytometry, and TNF-α and IL -1ß levels in the culture supernatant with ELISA. RESULTS: The two cell models of AD showed obviously decreased viability and increased cell apoptosis compared with the untreated control cells or cells transfected with a scramble shRNA (P < 0.05); no significant difference was found in the cell viability and apoptosis rate between the two AD cell models or between the two control groups (P>0.05). Significantly increased expressions of TNF-α and IL-1ß were observed in both of the two cell models compared with their respective control groups (P < 0.05) without significant differences between the two cell models or between the two control groups (P>0.05). CONCLUSIONS: A new AD cell model similar to Aß25-35-induced AD model can be established by SORL1 knockdown in N2a cells.

Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population.

BACKGROUND/AIMS: To investigate the roles of the oxidative stress related-genes ALOX5, ALOX5AP and MPO in ischemic stroke susceptibility in the Han Chinese population. METHODS: A total of 351 ischemic stroke patients and 417 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 gene polymorphisms were genotyped. RESULTS: We identified that rs2107545 of MPO gene was significantly associated with ischemic stroke susceptibility after adjusting for covariates. Furthermore, we also considered the likely complexity of oxidative stress and inflammatory process in stroke by assessing the combined effects of multiple genes. Generalized multifactor dimensionality reduction (GMDR) analysis revealed that the combination of ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 was significantly associated with increased risk of ischemic stroke (P=0.0040, OR (95% CI) =1.991 (1.241 to 3.195)). Additionally, the MPO rs2107545 genotype was significantly associated with clinical outcomes at 6 months after discharge from the hospital. CONCLUSION: Our study revealed that epistatic interaction among the ALOX5, ALOX5AP and MPO genes played a significant role in vulnerability to ischemic stroke. Furthermore, these results also suggest that the rs2107545 of MPO gene can be used as a biomarker for the susceptibility and prognosis of ischemic stroke patients.

[Protective effect of butylphthalide in a cell model of Alzheimer's disease induced by Aß25-35 in Neuro 2a cells].

OBJECTIVE: To study the protective effect of butylphthalide in a cell model of Alzheimer's disease(AD) induced by Aß25-35 in Neuro 2a (N2a) cells. METHODS: N2a cells were divided into AD group, butylphthalide (NBP) group and control group. AD cell model was established by adding 20 µmol/L Aß25-35 to cultured N2a cells. The cells in NBP group were treated with 0.1, 1, 10, or 100 µmol/L NBP 4 h prior to treatment with 20 µmol/L Aß25-35. The cell viability were determined by MTT assay, the cell apoptotic rate were detected by AnnexinV-FITC flow cytometry, and the cell morphological changes were observed under inverted phase contrast microscope. The expression of TNF-α and IL-1ß mRNA were determined by qRT-PCR. RESULTS: Compared with those in the control group, the number of adherent cells was significantly decreased, neurite structures were reduced, and the cell viability was decreased, while the apoptotic rate and expressions of TNF-α and IL-1ß mRNA were increased in AD group (P<0.05). Compared with that in AD group, the number of adherent cells was increased in NBP group and the cell morphology was similar to the normal control cells. The cell viability of N2a cells was increased in NBP group with decreased apoptotic rate and expression of TNF-αand IL-1ß mRNA (P<0.05). CONCLUSION: Butylphthalide can protect against AD in the cell model induced by Aß25-35 possibly by inhibiting the expression of inflammatory cytokines.

Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer's disease: a Phase II multicenter randomised controlled trial.

Background: inhibition of acetylcholinesterase (AChE) has been a effective treatment for Alzheimer's disease (AD). Octohydroaminoacridine, a new AChE inhibitor, is a potential treatment for AD. Method: we conducted a multicenter, randomised, double blind, placebo-controlled, parallel-group Phase II clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate AD. Patients were randomised to receive placebo thrice daily, octohydroaminoacridine 1 mg/thrice daily (TID) (low-dose group), 2 mg/TID (middle-dose group) or 4 mg/TID (high-dose group). Doses in the middle-dose and high-dose group were titrated over 2-4 weeks. Changes from baseline to Week 16 were assessed with the AD Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician's Interview-Based Impression of Change Plus (CIBIC+), activities of daily living (ADL) and the neuropsychiatric inventory (NPI). ADAS-cog was the primary end point of the study. A two-way analysis of covariance and least squares mean t-test were used. Results: at Week 16, the changes from baseline in ADAS-cog were 1.4, -2.1, -2.2 and -4.2 for placebo, low-, middle- and high-dose groups, respectively. Patients in the high-dose group had better performance in CIBIC+ and ADL scores at the end of the study. There was no significant difference in the change in NPI score among the groups. The effects of octohydroaminoacridine were dose dependent, and were effective within 16 weeks of treatment. No evidence was found for more adverse events that occurred in different drug groups than placebo group. Conclusions: octohydroaminoacridine significantly improved cognitive function and behaviour in patients with mild-to-moderate AD and this effect was dose dependent.

Krüppel-like factor 4 regulates amyloid-ß (Aß)-induced neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, is characterized by extracellular deposition of amyloid-ß (Aß) peptide, and neuro-inflammatory processes mediated by microglial activation are known to play a pivotal role in AD. However, the expression pattern and function of Krüppel-like factor (KLF) 4 in AD remain unknown. In this study, KLF4 was found to be increased at both the gene and protein levels in response to incubation with oligomeric Aß42 in a dose-dependent manner in BV2 microglial cells. An in vivo study also displayed that expression of KLF4 in the brains of J20 transgenic AD model mice was increased due to accumulation of Aß. Mechanistically, activation of p53 resulting from an increase in phosphorylation at ser15 was verified as the mediator of the oligomeric Aß42-induced expression of KLF4. Subsequent experiments have demonstrated that KLF4 silencing in BV2 cells attenuates oligomeric Aß42-induced neuroinflammation by ameliorating the release of proinflammatory cytokines, such as tumor necrosis factor-a (TNF-α), interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In addition, overexpression of KLF4 promoted oligomeric Aß42-induced neuroinflammation by exacerbating the release of pro-inflammatory factors. These results suggest a KLF4 plays a potential role in oligomeric Aß42-induced neurotoxicity and the pathogenesis of AD.

Mutant presenilin2 promotes apoptosis through the p53/miR-34a axis in neuronal cells.

Neurodegenerative disorders have attracted attention in last decades due to their high incidence in the world. The p53/miR-34a axis triggers apoptosis and suppresses viability in multiple types of cells, but little is known about its role in neurodegenerative diseases. In this study, we showed that presenilin (PS)-2, a major gene associated with familial Alzheimer's disease (AD) could trigger the apoptosis through the p53/miR-34a axis in PC12 cells. First we found that PC12 cell viability was downregulated by PS-2 and mutant PS-2 overexpression, especially by mutant PS-2 overexpression. Then, we established a mutant PS-2-overexpressing PC12 cell line and confirmed that mutant PS-2 induced not only p53 but also miR-34a expression. The transfection of miR-34a inhibitor reversed PS-2-induced effects on cellular viability and apoptosis. Mutant PS-2 overexpression promoted caspase-3 expression, reduced Sirt1 and Bcl-2 expression, all of which were miR-34a downstream genes related with cell apoptosis. Moreover, mutant PS-2 also activated the p53/miR-34a axis and induced apoptosis in AD transgenic mice brain. These results implied that mutant PS-2 might promote the apoptosis of neuronal cells through triggering the p53/miR-34a axis. Altogether our results provide a novel insight into neurodegenerative disease and deepen our understandings of AD pathogenic processes.

Role of ABC transporters in the pathology of Alzheimer's disease.

The ATP-binding cassette (ABC) transporter superfamily is a large family of proteins that transport specific molecules across membranes. These proteins are associated with both cholesterol metabolism and Alzheimer's disease (AD). Cholesterol homeostasis has a key role in AD, and ABC transporters are important mediators of lipid transportation. Emerging evidence suggests that decreased expression and hypofunction of ABC transporters are crucial to the occurrence and development of AD. In the present article, we review the current knowledge regarding ABC transporters and speculate on their role in the pathogenesis of AD.

Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population.

BACKGROUND: Obesity is a well-established risk factor for large artery atherosclerotic (LAA) stroke. The aim of the study was to explore whether obesity genes, such as MC4R and FTO, contribute to LAA stroke risk in the Chinese Han population. METHODS: 322 LAA stroke patients and 473 controls were recruited. Gene polymorphism of MC4R (rs17782313) and FTO (rs8050136 and rs9939609) were genotyped. RESULTS: No differences were observed in genotype frequencies of variants of FTO (rs8050136 and rs9939609) or MC4R (rs17782313) between LAA stroke patients and control subjects. However, rs17782313 of the MC4R gene was associated with LAA stroke susceptibility in smokers (rs17782313: p = 0.020, OR (95% CI) = 1.55 (1.07-2.23)) in the stratified analysis. Furthermore, multifactor dimensionality reduction analysis revealed that the combination of MC4R variant (rs17782313), hypertension and smoking habit was significantly associated with increased risk of LAA stroke (p < 0.0001, OR (95% CI) = 6.57 (4.79-9.01)). CONCLUSION: Our study indicated that the synergistic effects of MC4R variants, hypertension, and smoking habit contribute significantly to the risk of LAA stroke in the Chinese Han population. The finding revealed that obesity gene MC4R contribute to the risk of LAA stroke via a synergistic mechanism, which will provide new insight into the genetic architecture of LAA stroke.