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Wei CC, Huang YQ, Yu CH. Relationship between longitudinal changes in lipid composition and ischemic stroke among hypertensive patients. World J Clin Cases 2025; 13:95803. [PMID: 39917573 PMCID: PMC11586792 DOI: 10.12998/wjcc.v13.i4.95803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/10/2024] [Accepted: 11/01/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Dyslipidemia was strongly linked to stroke, however the relationship between dyslipidemia and its components and ischemic stroke remained unexplained. AIM To investigate the link between longitudinal changes in lipid profiles and dyslipidemia and ischemic stroke in a hypertensive population. METHODS Between 2013 and 2014, 6094 hypertension individuals were included in this, and ischemic stroke cases were documented to the end of 2018. Longitudinal changes of lipid were stratified into four groups: (1) Normal was transformed into normal group; (2) Abnormal was transformed into normal group; (3) Normal was transformed into abnormal group; and (4) Abnormal was transformed into abnormal group. To examine the link between longitudinal changes in dyslipidemia along with its components and the risk of ischemic stroke, we utilized multivariate Cox proportional hazards models with hazard ratio (HR) and 95%CI. RESULTS The average age of the participants was 62.32 years ± 13.00 years, with 329 women making up 54.0% of the sample. Over the course of a mean follow-up of 4.8 years, 143 ischemic strokes happened. When normal was transformed into normal group was used as a reference, after full adjustments, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.089 (95%CI: 0.598-1.982; P = 0.779), 2.369 (95%CI: 1.424-3.941; P < 0.001) and 1.448 (95%CI: 1.002-2.298; P = 0.047) (P for trend was 0.233), respectively. CONCLUSION In individuals with hypertension, longitudinal shifts from normal to abnormal in dyslipidemia-particularly in total and low-density lipoprotein cholesterol-were significantly associated with the risk of ischemic stroke.
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Affiliation(s)
- Cheng-Cheng Wei
- Department of Cardiology, Tongxiang First People's Hospital, Tongxiang 314500, Zhejiang Province, China
| | - Yu-Qing Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangzhou 510080, Guangdong Province, China
| | - Cheng-Hong Yu
- Department of Cardiology, Tongxiang First People's Hospital, Tongxiang 314500, Zhejiang Province, China
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He Y, Li S, Jiang L, Wu K, Chen S, Su L, Liu C, Liu P, Luo W, Zhong S, Li Z. Palmitic Acid Accelerates Endothelial Cell Injury and Cardiovascular Dysfunction via Palmitoylation of PKM2. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412895. [PMID: 39665133 PMCID: PMC11791964 DOI: 10.1002/advs.202412895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/17/2024] [Indexed: 12/13/2024]
Abstract
High serum level of palmitic acid(PA) is implicated in pathogenesis of cardiovascular diseases. PA serves as the substrate for protein palmitoylation. However, it is still unknown whether palmitoylation is involved in PA-induced cardiovascular dysfunction. Here, in clinical cohort studies of 1040 patients with coronary heart disease, high level of PA is associated with risk of major adverse cardiovascular events (MACE) and death. In ApoE-/-mice, 10 mg/kg-1 PA treatment induces blood pressure elevation, cardiac contractile dysfunction, endothelial dysfunction and atherosclerotic plaqueformation. In endothelial cells, inhibition of palmitoylation bypalmitoyl-transferase inhibitor 2-BP eliminates PA-induced endothelial injury, whereas promotion of palmitoylation by depalmitoylase inhibitor ML349 exacerbates the harmful effect of PA. Palmitoyl-proteomics analysis identifies pyruvate kinase isozyme type M2 (PKM2) as the palmitoylated protein responsible for PA-induced endothelial injury, and Cys31 as the predominant palmitoylated site. PKM2-C31S mutants (cysteine replaced by serine) prevents PA-induced endothelial injury. Endothelial-specific AAV-C31S PKM2endo ameliorates cardiovascular dysfunction caused by PA in ApoE-/- mice. Mechanistically, PKM2-C31 palmitoylation impairs PKM2 tetramerization to inhibit its pyruvate kinase activity and endothelial glycolysis. Finally, zDHHC13 is identified as the palmitoyl acyltransferase of PKM2. In conclusion, these findings suggest that PKM2-C31 palmitoylation contributes to PA-induced endothelial injury and cardiovascular dysfunction.
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Affiliation(s)
- Yu He
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Senlin Li
- Department of PharmacyGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080P. R. China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease PreventionGuangdong Cardiovascular InstituteGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhou510080P. R. China
- School of MedicineSouth China University of TechnologyGuangzhou510006P. R. China
| | - Lujing Jiang
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Kejue Wu
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Shanshan Chen
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Linjie Su
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Cui Liu
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Peiqing Liu
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
| | - Wenwei Luo
- Department of PharmacyGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080P. R. China
| | - Shilong Zhong
- Department of PharmacyGuangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080P. R. China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease PreventionGuangdong Cardiovascular InstituteGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhou510080P. R. China
- School of MedicineSouth China University of TechnologyGuangzhou510006P. R. China
| | - Zhuoming Li
- Department of Pharmacology and ToxicologySchool of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat‐sen UniversityGuangzhou510006P. R. China
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Moore A, Ritchie MD. Is the Relationship Between Cardiovascular Disease and Alzheimer's Disease Genetic? A Scoping Review. Genes (Basel) 2024; 15:1509. [PMID: 39766777 PMCID: PMC11675426 DOI: 10.3390/genes15121509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Cardiovascular disease (CVD) and Alzheimer's disease (AD) are two diseases highly prevalent in the aging population and often co-occur. The exact relationship between the two diseases is uncertain, though epidemiological studies have demonstrated that CVDs appear to increase the risk of AD and vice versa. This scoping review aims to examine the current identified overlapping genetics between CVDs and AD at the individual gene level and at the shared pathway level. METHODS Following PRISMA-ScR guidelines for a scoping review, we searched the PubMed and Scopus databases from 1990 to October 2024 for articles that involved (1) CVDs, (2) AD, and (3) used statistical methods to parse genetic relationships. RESULTS Our search yielded 2918 articles, of which 274 articles passed screening and were organized into two main sections: (1) evidence of shared genetic risk; and (2) shared mechanisms. The genes APOE, PSEN1, and PSEN2 reportedly have wide effects across the AD and CVD spectrum, affecting both cardiac and brain tissues. Mechanistically, changes in three main pathways (lipid metabolism, blood pressure regulation, and the breakdown of the blood-brain barrier (BBB)) contribute to subclinical and etiological changes that promote both AD and CVD progression. However, genetic studies continue to be limited by the availability of longitudinal data and lack of cohorts that are representative of diverse populations. CONCLUSIONS Highly penetrant familial genes simultaneously increase the risk of CVDs and AD. However, in most cases, sets of dysregulated genes within larger-scale mechanisms, like changes in lipid metabolism, blood pressure regulation, and BBB breakdown, increase the risk of both AD and CVDs and contribute to disease progression.
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Affiliation(s)
- Anni Moore
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Marylyn D. Ritchie
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- Division of Informatics, Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Penn Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Clocchiatti-Tuozzo S, Szejko N, Rivier C, Renedo DB, Huo S, Sheth KN, Gill TM, Falcone GJ. APOE epsilon variants and composite risk of dementia, disability, and death in the health and retirement study. J Am Geriatr Soc 2024; 72:2989-2999. [PMID: 38946154 PMCID: PMC11461103 DOI: 10.1111/jgs.19043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Clinical trials in older adults are increasingly focused on functional outcomes, and the composite outcome of dementia, disability, and death is gaining pivotal importance. Genetic variation, particularly the APOE epsilon(ε) variants, may modify responses to new treatments. Although APOE ε4 is known to influence these outcomes separately, the magnitude of its effect on this composite outcome remains unknown. We tested the hypothesis that APOE ε4 increases, whereas APOE ε2 decreases, the risk of a composite outcome of dementia, disability, and death. METHODS We evaluated clinical and genomic data from the Health and Retirement Study collected from 1992 to 2020. We used variants rs429358 and rs7412 to determine APOE genotypes, modeled dominantly (carriers/noncarriers). We conducted survival analysis, using multivariable Cox proportional hazards models with a composite endpoint of dementia, disability, and death. Our primary analysis evaluated participants with genetic data and no previous dementia or disability. In secondary analyses, we focused on persons aged > = 75 years without heart disease or stroke, a subpopulation increasingly important in clinical trials of older adults. RESULTS We included 14,527 participants in the primary analysis. Over a median of 18 (Interquartile Range [IQR] 12-24) years, 6711 (46%) participants developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.15, 95%CI:1.09-1.22) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.92, 95%CI:0.86-0.99). In the secondary analysis, we included 3174 participants. Over a median of 7 (IQR 4-11) years, 1326 participants (42%) developed the composite outcome. In Cox analyses, APOE ε4 associated with higher risk (HR:1.25, 95%CI:1.10-1.41) of the composite outcome, whereas APOE ε2 associated with lower risk (HR:0.84, 95%CI:0.71-0.98). CONCLUSIONS APOE ε variants are linked to the risk of dementia, disability, and death in older adults. By examining these variants in clinical trials, we can better elucidate how they might alter the effectiveness of tested interventions. Importantly, this genetic information could help identify participants who may have greater absolute benefit from such interventions.
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Affiliation(s)
- Santiago Clocchiatti-Tuozzo
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, United States
- Division of Geriatric Medicine, Yale School of Medicine, New Haven, CT, Unites States
| | - Natalia Szejko
- Department of Bioethics, Medical University of Warsaw, Warsaw, Poland
- Department of Neurosciences, University of Calgary, Canada
| | - Cyprien Rivier
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, United States
| | - Daniela B. Renedo
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
| | - Shufan Huo
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, United States
| | - Kevin N. Sheth
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, United States
| | - Thomas M. Gill
- Division of Geriatric Medicine, Yale School of Medicine, New Haven, CT, Unites States
| | - Guido J. Falcone
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Yale Center for Brain and Mind Health, Yale School of Medicine, New Haven, CT, United States
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Onos KD, Lin PB, Pandey RS, Persohn SA, Burton CP, Miner EW, Eldridge K, Kanyinda JN, Foley KE, Carter GW, Howell GR, Territo PR. Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction. Alzheimers Dement 2024; 20:4951-4969. [PMID: 38713704 PMCID: PMC11247674 DOI: 10.1002/alz.13842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 05/09/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. HIGHLIGHTS We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.
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Affiliation(s)
| | - Peter B. Lin
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
- Department of NeurologyWashington University in St. LouisSt. LouisMissouriUSA
| | - Ravi S. Pandey
- The Jackson Laboratory for Genomic MedicineFarmingtonConnecticutUSA
| | - Scott A. Persohn
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | - Charles P. Burton
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | - Ethan W. Miner
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | - Kierra Eldridge
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | | | - Kate E. Foley
- The Jackson LaboratoryBar HarborMaineUSA
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | - Gregory W. Carter
- The Jackson LaboratoryBar HarborMaineUSA
- The Jackson Laboratory for Genomic MedicineFarmingtonConnecticutUSA
| | | | - Paul R. Territo
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
- Department of MedicineDivision of Clinical PharmacologyIndiana University School of MedicineIndianapolisIndianaUSA
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Tian F, Qian Z, Zhang Z, Liu Y, Wu G, Wang C, McMillin SE, Bingheim E, Lin H. Air pollution, APOE genotype and risk of dementia among individuals with cardiovascular diseases: A population-based longitudinal study. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 347:123758. [PMID: 38492747 DOI: 10.1016/j.envpol.2024.123758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/18/2024]
Abstract
Individuals with cardiovascular disease (CVD) are particularly vulnerable to dementia, but it remains unclear whether air pollution exposure links with higher risk of dementia among those with CVD. The data were derived from the UK Biobank study (UKB). Dementia-free participants with CVD at baseline were included. Air pollution exposure was assessed through land use regression models, including particulate matter (PM2.5, PM2.5-10, and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOX). A Cox proportional hazards model was used to investigate the associations between air pollution exposure and incident dementia among individuals with CVD. Air pollution was associated with dementia among individuals with CVD, and the hazard ratios of dementia associated with each interquartile range (IQR) μg/m3 increase in air pollution were 1.07 (95% CI: 1.02, 1.12) for PM2.5, 1.10 (95% CI: 1.04, 1.15) for PM10, 1.08 (95% CI: 1.03, 1.14) for NO2 and 1.05 (95% CI: 1.00, 1.09) for NOx. Associations between air pollution and all-cause dementia were found to be significant among individuals with hypertension. Adverse effects of air pollution were also observed for Alzheimer's dementia (AD) and vascular dementia (VaD), with a higher effect for AD. Observed associations remained similar in subgroups of APOE ε4 carriers and noncarriers, although there was a higher risk difference across different air pollution concentration among these individuals carrying APOE ε4. Air pollution emerges as a critical risk factor for dementia among individuals with CVD, regardless of genetic susceptibility indicated by the APOE genotype. Notably, individuals with hypertension might be susceptible to the adverse effects of air pollution, leading to a higher incidence of dementia. Understanding these impacts on dementia among individuals with CVD may promote better targeted prevention and clinical management strategies.
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Affiliation(s)
- Fei Tian
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhengmin Qian
- Department of Epidemiology and Biostatistics, College for Public Health & Social Justice, Saint Louis University, Saint Louis, MO, 63104, USA
| | - Zilong Zhang
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yuewei Liu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Gan Wu
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chongjian Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | | | - Elizabeth Bingheim
- Department of Epidemiology and Biostatistics, College for Public Health & Social Justice, Saint Louis University, Saint Louis, MO, 63104, USA
| | - Hualiang Lin
- Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
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Shi YM, Ou D, Li JT, Bao L, Liu XD, Zhang W, Ding H. Genetically Predicted Apolipoprotein E Levels with the Risk of Panvascular Diseases: A Mendelian Randomization Study. Cardiovasc Toxicol 2024; 24:385-395. [PMID: 38536640 DOI: 10.1007/s12012-024-09846-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 02/28/2024] [Indexed: 04/07/2024]
Abstract
The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10-3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10-4] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10-2]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10-2]. (Bonferroni threshold p < 0.0026, PFDR < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.
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Affiliation(s)
- Yi-Ming Shi
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Dian Ou
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Jia-Ting Li
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Le Bao
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Xiao-Dan Liu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Wei Zhang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China.
| | - Huang Ding
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China.
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Onos K, Lin PB, Pandey RS, Persohn SA, Burton CP, Miner EW, Eldridge K, Kanyinda JN, Foley KE, Carter GW, Howell GR, Territo PR. Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.13.571584. [PMID: 38168292 PMCID: PMC10760108 DOI: 10.1101/2023.12.13.571584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
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Affiliation(s)
- Kristen Onos
- The Jackson Laboratory, Bar Harbor, ME 04609 USA
| | - Peter B. Lin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
- Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
| | - Ravi S. Pandey
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Scott A. Persohn
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Charles P. Burton
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Ethan W. Miner
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Kierra Eldridge
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | | | - Kate E. Foley
- The Jackson Laboratory, Bar Harbor, ME 04609 USA
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Gregory W. Carter
- The Jackson Laboratory, Bar Harbor, ME 04609 USA
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | | | - Paul R. Territo
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 USA
- Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis IN 46202 USA
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Zhang W, Wang R, Shi F. Peripheral apolipoprotein is an independent factor for enlarged perivascular space in small vessel disease. Clin Neurol Neurosurg 2024; 238:108185. [PMID: 38422746 DOI: 10.1016/j.clineuro.2024.108185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/05/2024] [Accepted: 02/18/2024] [Indexed: 03/02/2024]
Abstract
OBJECTIVE The purpose of this study is to the relationship between peripheral apolipoproteins and cerebral small vessel disease (CSVD) imaging markers. METHODS We reviewed the data of a population that above 40 years old with CSVD, while free of known dementia or acute stroke. We evaluated CSVD imaging markers, including white matter hyperintensities (WMHs), enlarged perivascular spaces (EPVS), lacunas, microbleeds by MRI scans, and measured peripheral apolipoproteins. RESULTS After adjusting for age, sex and vascular risk factors,1) apoB and apoB/apoA-1 were related to grade of EPVS in basal ganglia(apoB:r=0.196,p<0.001;apoB/apoA-1:r=0.208,p<0.001), apoE was related to grade of EPVS in centrum semiovale (r=0.125,p=0.040); 2) apoB(OR=1.739, 95%CI=1.357-2.061, p<0.001), apoB/apoA-1(OR=1.116, 95%CI=1.037-1.761, p=0.005) and apoE(OR=1.287, 95%CI=1.036-1.599, p=0.023) were independent factors of presence of severer EPVS in basal ganglia, apoE was an independent factor of presence of severer EPVS in centrum semiovale (OR=1.235, 95%CI=1.021-1.494, p=0.029). CONCLUSION Our findings demonstrated peripheral apolipoproteins, including apoB, apoB/apoA-1, and apoE, were independent factor for EPVS in CSVD.
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Affiliation(s)
- Wenhua Zhang
- Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, 453# Tiyuchang Road, Hangzhou, China.
| | - Ruiming Wang
- Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, 453# Tiyuchang Road, Hangzhou, China
| | - Fangying Shi
- Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, 453# Tiyuchang Road, Hangzhou, China
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Hu S, Cai J, Chen S, Wang Y, Ren L. Identification of novel biomarkers and immune infiltration characteristics of ischemic stroke based on comprehensive bioinformatic analysis and machine learning. Biochem Biophys Rep 2024; 37:101595. [PMID: 38371524 PMCID: PMC10873872 DOI: 10.1016/j.bbrep.2023.101595] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 02/20/2024] Open
Abstract
Background Ischemic stroke (IS) is one of most common causes of disability in adults worldwide. However, there is still a lack of effective and reliable diagnostic markers and therapeutic targets in IS. Furthermore, immune cell dysfunction plays an important role in the pathogenesis of IS. Hence, in-depth research on immune-related targets in progressive IS is urgently needed. Methods Expression profile data from patients with IS were downloaded from the Gene Expression Omnibus (GEO) database. Then, differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to identify the significant modules and differentially expressed genes (DEGs). Key genes were obtained and used in functional enrichment analyses by overlapping module genes and DEGs. Next, hub candidate genes were identified by utilizing three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine-recursive feature elimination (SVM-RFE). Subsequently, a diagnostic model was constructed based on the hub genes, and receiver operating characteristic (ROC) curves were constructed to validate the performances of the predictive models and candidate genes. Finally, the immune cell infiltration landscape of IS was explored with the CIBERSORT deconvolution algorithm. Results A total of 40 key DEGs were identified based on the intersection of the DEGs and module genes, and we found that these genes were mainly enriched in the regulation of lipolysis in adipocytes, neutrophil extracellular trap formation and complement and coagulation cascades. Based on the results from three advanced machine learning algorithms, we obtained 7 hub candidate genes (ABCA1, ARG1, C5AR1, CKAP4, HMFN0839, SDCBP and TLN1) as diagnostic biomarkers of IS and developed a reliable nomogram with high predictive performance (AUC = 0.987). In addition, immune cell infiltration dysregulation was implicated in IS, and compared with those in the normal group, IS patients had increased fractions of gamma delta T cells, monocytes, M0 macrophages, M2 macrophages and neutrophils and clearly lower percentages of naive B cells, CD8 T cells, CD4+ memory T cells, follicular helper T cells, regulatory T cells (Tregs) and resting dendritic cells. Furthermore, correlation analysis indicated a significant correlation between the hub genes and immune cells in progressive IS. Conclusion In conclusion, our study identified 7 hub genes as diagnostic biomarkers and established a reliable model to predict the occurrence of IS. Meanwhile, we explored the immune cell infiltration pattern and investigated the relationship between candidate genes and immune cells in the pathogenesis of IS. Hence, our study provides new insights into the diagnosis and treatment of IS.
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Affiliation(s)
- Shiyu Hu
- Neurology Department of Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Jingjing Cai
- Neurology Department of Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Sizhan Chen
- Neurology Department of Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
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11
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Lombardi G, Pancani S, Bagnoli S, Vannetti F, Nacmias B, Sorbi S, Cecchi F, Macchi C. Understanding the interplay between APO E polymorphism and cognition in the Italian oldest old: results from the "Mugello study". Neurol Sci 2024; 45:539-546. [PMID: 37710144 DOI: 10.1007/s10072-023-07073-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/09/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Recent data suggest that the deleterious effect on general health and cognition of ε4 allele of Apolipoprotein E (ApoE) observed in the elderly population, may attenuate in extreme aging. This study aimed to describe the ApoE genotype distribution and its relationship with cognition in a group of nonagenarians living in the Mugello area, Italy. MATERIAL AND METHODS Cognition was evaluated using the Mini-Mental-State-Examination (MMSE). DNA was extracted from blood samples to determine ApoE genotyping. Participants were classified into three ApoE groups (ε2, ε3, ε4). Logistic and linear regression models were created, to assess the relationship between ApoE genotype group and dementia diagnosis and cognitive performance, respectively. RESULTS 169 subjects were included. ApoE ε3 was the most prevalent genotype (76.3%). Dementia prevalence was 26.6% and it was not associated with the presence of ApoE ε4. Participants of ε4 group were significantly more likely to have lower cognitive performances than ε2 and ε3, independently of a dementia diagnosis. DISCUSSION Results support that ApoE genotype no longer plays a role in the health condition of the oldest old, however, an interaction is detectable between ApoE polymorphism and cognitive performances at this extreme age.
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Affiliation(s)
- Gemma Lombardi
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
| | - Silvia Pancani
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy.
| | - Silvia Bagnoli
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
| | - Federica Vannetti
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
| | - Benedetta Nacmias
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
| | - Sandro Sorbi
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
| | - Francesca Cecchi
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - Claudio Macchi
- IRCCS Fondazione Don Carlo Gnocchi Onlus, Via Di Scandicci 269, 50143, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
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12
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Motawi TK, Sadik NAH, Shaker OG, Ghaleb MMH, Elbaz EM. Expression, Functional Polymorphism, and Diagnostic Values of MIAT rs2331291 and H19 rs217727 Long Non-Coding RNAs in Cerebral Ischemic Stroke Egyptian Patients. Int J Mol Sci 2024; 25:842. [PMID: 38255915 PMCID: PMC10815378 DOI: 10.3390/ijms25020842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/24/2023] [Accepted: 12/30/2023] [Indexed: 01/24/2024] Open
Abstract
Cerebral ischemic stroke (CIS) is a severe cerebral vascular event. This research aimed to evaluate the role of single-nucleotide polymorphisms (SNPs) of the lncRNAs MIAT rs2331291 and H19 rs217727 and epigenetic methylation in the expression patterns of serum lncRNA H19 in CIS Egyptian patients. It included 80 CIS cases and 40 healthy subjects. Serum MIAT expression levels decreased, whereas serum H19 expression levels increased among CIS compared to controls. For MIAT rs2331291, there were significant differences in the genotypic and allelic frequencies between the CIS and healthy subjects at p = 0.02 and p = 0.0001, respectively. Our findings illustrated a significantly increased MIAT T/T genotype frequency in hypertensive CIS compared to non-hypertensive CIS at p = 0.004. However, H19 rs217727 gene frequency C/C was not significantly higher in non-hypertensive CIS than in hypertensive CIS. The methylation of the H19 gene promoter was significantly higher in CIS patients compared to healthy subjects. The level of MIAT was positively correlated with serum H19 in CIS. Receiver operating characteristics (ROC) analysis revealed that serum MIAT and H19 have a high diagnostic potential for distinguishing CIS subjects from healthy ones. In conclusion, the MIAT-rs2331291 polymorphism might serve as a novel potential indicator of CIS.
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Affiliation(s)
- Tarek K. Motawi
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | | | - Olfat G. Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | | | - Eman M. Elbaz
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
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13
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Thomford NE, Anyanful A, Ateko RO, Blackhurst D, Biney RP, Boadi D, Nyarko SB, Ekor M, Kyei GB. Apolipoprotein E genetic variation, atherogenic index and cardiovascular disease risk assessment in an African population: An analysis of HIV and malaria patients in Ghana. PLoS One 2023; 18:e0284697. [PMID: 37134097 PMCID: PMC10155972 DOI: 10.1371/journal.pone.0284697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/05/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Apolipoprotein E is involved in lipid transport and clearance of lipoprotein through low-density lipoprotein receptors (LDLR). ApoE variation has been linked to cardiovascular disease (CVD) risk. There are 3 isoforms of ApoE which originate from two non-synonymous single nucleotide polymorphisms denoted as ε2, ε3 and ε4. The ε2 isoform is implicated in higher levels of atherogenic lipoprotein with the ε4 isoform causing LDLR downregulation. This leads to variable effects and differential CVD risk. Malaria and HIV are life-threatening diseases affecting several countries globally especially in sub-Saharan Africa. Parasite and viral activities have been implicated in lipid dysregulation leading to dyslipidaemia. This study examined ApoE variation and CVD risk assessment in malaria and HIV patients. METHODS We compared 76 malaria-only, 33 malaria-HIV coinfected, 21-HIV-only and 31 controls from a tertiary health facility in Ghana. Fasting venous blood samples were taken for ApoE genotyping and lipid measurements. Clinical and laboratory data were collected with ApoE genotyping performed using Iplex Gold microarray and PCR-RFLP. Cardiovascular disease risk was calculated using the Framingham BMI and cholesterol risk and Qrisk3 tools. RESULTS The frequency of C/C genotype for rs429358 was 9.32%, whiles T/T genotype for rs7412 was found in 2.48% of all participants. ε3/ε3 was the most distributed ApoE genotype accounting for 51.55% of the total participants whiles ε2/ε2 was found in 2.48% of participants, with 1 in malaria-only and 3 in HIV-only patients. There was a significant association between ε4+ and high TG (OR = 0.20, CI; 0.05-0.73; p = 0.015), whiles ε2+ was significantly associated with higher BMI (OR; 0.24, CI; 0.06-0.87; p = 0.030) and higher Castelli Risk Index II in females (OR = 11.26, CI; 1.37-92.30; p = 0.024). A higher proportion of malaria-only participants had a moderate to high 10-year CVD risk. CONCLUSION Overall malaria patients seem to have a higher CVD risk though the means through which this occurs may be poorly understood. ε2/ε2 genotypes was observed in our population at a lower frequency. Further studies are vital to determine CVD risk in malaria and how this occurs.
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Affiliation(s)
- Nicholas Ekow Thomford
- Department of Medical Biochemistry, Pharmacogenomics and Genomic Medicine Group, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Akwasi Anyanful
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Richmond Owusu Ateko
- Department of Chemical Pathology, University of Ghana Medical School University of Ghana, Legon, Accra, Ghana
- Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Dee Blackhurst
- Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Robert Peter Biney
- Department of Pharmacology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Dennis Boadi
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Samuel Badu Nyarko
- Department of Medical Biochemistry, Pharmacogenomics and Genomic Medicine Group, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Martins Ekor
- Department of Pharmacology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - George Boateng Kyei
- Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States of America
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14
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Satizabal CL, Himali JJ, Beiser AS, Ramachandran V, Melo van Lent D, Himali D, Aparicio HJ, Maillard P, DeCarli CS, Harris WS, Seshadri S. Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study. Neurology 2022; 99:e2572-e2582. [PMID: 36198518 PMCID: PMC9754651 DOI: 10.1212/wnl.0000000000201296] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 08/10/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype. METHODS We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes. RESULTS We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers. DISCUSSION Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.
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Affiliation(s)
- Claudia L Satizabal
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD.
| | - Jayandra Jung Himali
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Alexa S Beiser
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Vasan Ramachandran
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Debora Melo van Lent
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Dibya Himali
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Hugo J Aparicio
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Pauline Maillard
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Charles S DeCarli
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - William S Harris
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
| | - Sudha Seshadri
- From the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., J.J.H., D.M.L., S.S.), UT Health San Antonio, San Antonio, TX; Department of Population Health Sciences (C.L.S., J.J.H.), UT Health San Antonio, San Antonio, TX; Department of Neurology (C.L.S., J.J.H., A.S.B., D.M.L., H.J.A., S.S.), Boston University School of Medicine, Boston, MA; The Framingham Heart Study (C.L.S., J.J.H., A.S.B., V.R., D.M.L., D.H., H.J.A., S.S.), Framingham, MA; Department of Biostatistics (J.J.H., A.S.B.), Boston University School of Public Health, Boston, MA; Department of Medicine (V.R.), Boston University School of Medicine, Boston, MA; Department of Epidemiology (V.R.), Boston University School of Public Health, Boston, MA; Center for Computing and Data Sciences (V.R.), Boston University, Boston, MA; Imaging of Dementia and Aging Laboratory and Center for Neurosciences (P.M., C.S.D.), Davis, CA; Department of Neurology (C.S.D.), UC Davis School of Medicine, Sacramento, CA; Sanford School of Medicine (W.S.H.), University of South Dakota, Sioux Falls, SD; and Fatty Acid Research Institute (W.S.H.), Sioux Falls, SD
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15
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Fatty Acid Levels and Their Inflammatory Metabolites Are Associated with the Nondipping Status and Risk of Obstructive Sleep Apnea Syndrome in Stroke Patients. Biomedicines 2022; 10:biomedicines10092200. [PMID: 36140306 PMCID: PMC9496373 DOI: 10.3390/biomedicines10092200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 11/17/2022] Open
Abstract
Background: This paper discusses the role of inflammation in the pathogenesis of nondipping blood pressure and its role in the pathogenesis of obstructive sleep apnea syndrome. The aim of the study was to assess the impact of free fatty acids (FAs) and their inflammatory metabolites on the nondipping phenomenon and the risk of sleep apnea in stroke patients. Methods: Sixty-four ischemic stroke patients were included in the prospective study. Group I consisted of 33 patients with a preserved physiological dipping effect (DIP), while group II included 31 patients with the nondipping phenomenon (NDIP). All subjects had FA gas chromatography and inflammatory metabolite measurements performed with the use of liquid chromatography, their 24 h blood pressure was recorded, and they were assessed with the Epworth sleepiness scale (ESS). Results: In the nondipping group a higher level of C16:0 palmitic acid was observed, while lower levels were observed in regard to C20:0 arachidic acid, C22:0 behenic acid and C24:1 nervonic acid. A decreased leukotriene B4 level was recorded in the nondipping group. None of the FAs and derivatives correlated with the ESS scale in the group of patients after stroke. Correlations were observed after dividing into the DIP and NDIP groups. In the DIP group, a higher score of ESS was correlated with numerous FAs and derivatives. Inflammation of a lower degree and a higher level of anti-inflammatory mediators from EPA and DHA acids favored the occurrence of the DIP. A high level of C18: 3n6 gamma linoleic acid indicating advanced inflammation, intensified the NDIP effect. Conclusions: We demonstrated potential novel associations between the FA levels and eicosanoids in the pathogenesis of the nondipping phenomenon. There are common connections between fatty acids, their metabolites, inflammation, obstructive sleep apnea syndrome and nondipping in stroke patients.
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16
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Xi X, Li H, Chen S, Lv T, Ma T, Jiang R, Zhang P, Wong WH, Zhang X. Unfolding the genotype-to-phenotype black box of cardiovascular diseases through cross-scale modeling. iScience 2022; 25:104790. [PMID: 35992073 PMCID: PMC9386115 DOI: 10.1016/j.isci.2022.104790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/26/2022] [Accepted: 07/14/2022] [Indexed: 12/01/2022] Open
Abstract
Complex traits such as cardiovascular diseases (CVD) are the results of complicated processes jointly affected by genetic and environmental factors. Genome-wide association studies (GWAS) identified genetic variants associated with diseases but usually did not reveal the underlying mechanisms. There could be many intermediate steps at epigenetic, transcriptomic, and cellular scales inside the black box of genotype-phenotype associations. In this article, we present a machine-learning-based cross-scale framework GRPath to decipher putative causal paths (pcPaths) from genetic variants to disease phenotypes by integrating multiple omics data. Applying GRPath on CVD, we identified 646 and 549 pcPaths linking putative causal regions, variants, and gene expressions in specific cell types for two types of heart failure, respectively. The findings suggest new understandings of coronary heart disease. Our work promoted the modeling of tissue- and cell type-specific cross-scale regulation to uncover mechanisms behind disease-associated variants, and provided new findings on the molecular mechanisms of CVD.
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Affiliation(s)
- Xi Xi
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing 100084, China
| | - Haochen Li
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - Shengquan Chen
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing 100084, China
| | - Tingting Lv
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Tianxing Ma
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing 100084, China
| | - Rui Jiang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing 100084, China
| | - Ping Zhang
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Wing Hung Wong
- Departments of Statistics and Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
| | - Xuegong Zhang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing 100084, China
- School of Medicine, Tsinghua University, Beijing 100084, China
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17
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Jiang W, Li J, Cai Y, Liu W, Chen M, Xu X, Deng M, Sun J, Zhou L, Huang Y, Wu S, Cheng X. The Novel lncRNA ENST00000530525 Affects ANO1, Contributing to Blood-Brain Barrier Injury in Cultured hCMEC/D3 Cells Under OGD/R Conditions. Front Genet 2022; 13:873230. [PMID: 35754821 PMCID: PMC9213740 DOI: 10.3389/fgene.2022.873230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/19/2022] [Indexed: 11/13/2022] Open
Abstract
Ischemic stroke (IS) is a major neurological disease with high fatality and residual disability burdens. Long noncoding RNAs (lncRNAs) have been found to play an important role in IS. However, the roles and significance of most lncRNAs in IS are still unknown. This study was performed to identify differentially expressed (DE) lncRNAs using a lncRNA microarray in whole blood samples of patients suffering from acute cerebral ischemia. Bioinformatics analyses, including GO, KEGG pathway enrichment analysis, and proximity to putative stroke risk location analysis were performed. The novel lncRNA, ENST00000530525, significantly decreased after IS. Furthermore, we evaluated lncRNA ENST00000530525 expression in cultured hCMEC/D3 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions using fluorescent in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (RT-qPCR) analysis. To investigate the function of lncRNA ENST00000530525, its over-expression (OE) and negative control (NC) plasmids were transfected into hCMEC/D3 cells, and cell viability was detected by a cell counting kit-8 (CCK-8) assay after OGD/R. LncRNA ENST00000530525 and ANO1 expression were investigated using RT-qPCR and immunofluorescence. For blood-brain barrier (BBB) permeability, FITC-dextran transendothelial permeability assay and tight junction (TJ) protein immunofluorescence assays were performed. There were 3352 DE lncRNAs in the blood samples of acute IS patients. The validation results were consistent with the gene chip data. The GO and KEGG results showed that these lncRNAs were mainly related to oxygen and glucose metabolism, leukocyte transendothelial migration, mitophagy and cellular senescence. Among these, lncRNA ENST00000530525 was the most highly downregulated lncRNA and it was mapped within the IS-associated gene anoctamin-1 (ANO1). We further found that lncRNA ENST00000530525 was downregulated in hCMEC/D3 cells under 4 h OGD and 20 h reoxygenation (OGD4/R20) conditions. Upregulating lncRNA ENST00000530525 by plasmid transfection decreased cell viability while increasing ANO1 expression and it contributed to BBB injury in hCMEC/D3 cells after OGD4/R20. The lncRNA ENST00000530525 might play deleterious roles in post-stroke pathogenesis. These results show that some DE lncRNAs in humans participate through characteristic roles in post-stroke pathogenesis; thus, the roles and significance of some novel lncRNAs in IS warrant further study.
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Affiliation(s)
- Wen Jiang
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Jie Li
- Department of Anesthesiology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuefang Cai
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Wenchen Liu
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mei Chen
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoying Xu
- Department of Anatomy, Sun Yat-Sen School of Medicine, Sun Yat-Sen University, Shenzhen, China
| | - Minzhen Deng
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingbo Sun
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.,Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China
| | - Lihua Zhou
- Department of Anatomy, Sun Yat-Sen School of Medicine, Sun Yat-Sen University, Shenzhen, China
| | - Yan Huang
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.,Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China
| | - Shuang Wu
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Xiao Cheng
- Department of Second Institute of Clinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, China.,Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine/The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China
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18
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Ereqat S, Cauchi S, Eweidat K, Elqadi M, Ghatass M, Sabarneh A, Nasereddin A. Association of DNA methylation and genetic variations of the APOE gene with the risk of diabetic dyslipidemia. Biomed Rep 2022; 17:61. [PMID: 35719839 PMCID: PMC9198989 DOI: 10.3892/br.2022.1544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/05/2022] [Indexed: 11/06/2022] Open
Abstract
Apolipoprotein E (APOE) is a key regulator of lipoprotein metabolism, and consequently, affects the plasma and tissue lipid contents. The aim of the present study was to investigate the parallel effects of APOE genetic variants and promoter methylation levels of six CpGs on the risk of diabetic dyslipidemia. A total of 204 Palestinian type 2 diabetes (T2D) patients (mean age ± SD: 62.7±10.2) were enrolled in the present study (n=96 with dyslipidemia and n=108 without dyslipidemia). Next generation sequencing was performed to analyze five single nucleotide polymorphisms: Two variants rs7412 and rs429358 that determine APOE ε alleles, and three variants in the promoter region (rs769446, rs449647, and rs405509). For all subjects, the most common genotype was ε3/ε3 (79.4%). No statistical differences were observed in the APOE ε polymorphisms and the three promoter variants among T2D patients with and without dyslipidemia (P>0.05). A comparison of lipid parameters between ε3/ε3 subjects and ε4 carriers in both groups revealed no significant differences in the mean values of LDL-C, HDL-C, TG, and TC levels (P>0.05). Six CpG sites in the APOE promoter on chromosome 19:44905755-44906078 were identified, and differential DNA methylation in these CpGs were observed between the study groups. Logistic regression analysis revealed a significant association of DNA methylation level at the six CpGs with an increased risk of diabetic dyslipidemia (odds ratio, 1.038; 95% confidence interval, 1.012-1.064; P=0.004). In conclusion, the present study revealed that DNA methylation levels in six CpGs in the APOE promoter region was associated with the risk of diabetic dyslipidemia independently of the APOE ε4 variant which could be a potential therapeutic target to reverse the methylation of the APOE promoter.
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Affiliation(s)
- Suheir Ereqat
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Al‑Quds University, Abu Dis P144, Palestine
| | - Stéphane Cauchi
- Centre National de la Recherche Scientfique (CNRS), Unité Mixte de Recherche UMR8204 Lille, France
| | - Khaled Eweidat
- Faculty of Medicine, Al‑Quds University, East Jerusalem, Abu Dis P144, Palestine
| | - Muawiyah Elqadi
- Faculty of Medicine, Al‑Quds University, East Jerusalem, Abu Dis P144, Palestine
| | - Manal Ghatass
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Al‑Quds University, Abu Dis P144, Palestine
| | - Anas Sabarneh
- Palestine Medical Complex, Laboratories Division, Ramallah P606, Palestine
| | - Abedelmajeed Nasereddin
- Biochemistry and Molecular Biology Department, Faculty of Medicine, Al‑Quds University, Abu Dis P144, Palestine
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19
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Xie YL, Li JX, Ji WZ, Yao YL. Distribution characteristics of ApoE gene polymorphism in the Tibetan population of Qinghai. EUR J INFLAMM 2022. [DOI: 10.1177/1721727x221095381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective: To understand the distribution characteristics of the relative frequencies of apolipoprotein E (APOE) alleles in Tibetans of Qinghai province, to provide a basis for subsequent research. Method: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the APOE genotypes and analyze the distribution characteristics in 96 indigenous Tibetans randomly selected from the Medical Examination Center of Qinghai Provincial People’s Hospital, and the results of this study were compared with those of other ethnic groups in China. Results: The frequencies of E2, E3, and E4 alleles in the 96 subjects were 1.563%, 89.062%, and 9.375%, respectively, and the genotype frequencies were E2/E2 (0%), E2/E3 (3.125%), E2/E4 (0%), E3/E3 (78.125%), E3/E4 (18.750%), and E4/E4 (0%), respectively. The frequency distribution of the ε2 allele in the Tibetan population was lower than that of the Northern Han, Southern Hakka, Hui, Mongolian, and Dai populations of China. The frequency distribution of the ε4 allele in the Tibetan population was of no significant difference compared with that of the Northern Han, Southern Hakka, Hui, and Mongolian populations, but was higher than that of the Dai population. The frequency distribution of the ε3 allele in the Tibetan population was of no significant difference compared with that of the Northern Han, Mongolian, and Dai populations, but higher than that of the Southern Hakka and Mongolian populations. Conclusion: There are ethnic differences in the frequency distribution of the three common alleles of APOE.
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Affiliation(s)
- Yan-Ling Xie
- Department of Endocrinology, Qinghai Provincial People’s Hospital, China
| | - Jian-Xun Li
- Department of Endocrinology, Qinghai Provincial People’s Hospital, China
| | - Wei-Zhong Ji
- Department of Neurology, Qinghai Provincial People’s Hospital, China
| | - Yong-Li Yao
- Department of Endocrinology, Qinghai Provincial People’s Hospital, China
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20
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Ren XL, Liu Y, Chu WJ, Li ZW, Zhang SS, Zhou ZL, Tang J, Yang B. Blood levels of omega-6 fatty acids and coronary heart disease: a systematic review and metaanalysis of observational epidemiology. Crit Rev Food Sci Nutr 2022; 63:7983-7995. [PMID: 35380474 DOI: 10.1080/10408398.2022.2056867] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Individual omega-6 polyunsaturated fatty acids (PUFAs), principally linoleic acid (LA) and arachidonic acid (AA), may have differential impacts on cardiovascular risk. We aimed to summarize the up-to-date epidemiology evidence on the relationship between blood levels of omega-6 PUFAs and the risk of coronary heart disease (CHD). Population-based studies determining PUFA levels in blood were identified until May 2021 in PubMed, Embase, Web of Science, and Cochrane Library. Random-effects meta-analyses of cohorts comparing the highest versus lowest category were conducted to combine study-specific risk ratios (RRs) with 95% confidence intervals (CIs). Blood levels of omega-6 PUFAs were compared between the CHD case and non-case, presented as a weight mean difference (WMD). Twenty-one cohorts and eleven case-control studies were included. The WMD was -0.71 (95% CI: -1.20, -0.21) for LA and 0.08 (95% CI: -0.28, 0.43) for AA. LA levels were inversely associated with total CHD risk (RR: 0.85, 95% CI: 0.71, 1.00), but not AA. Each one-SD increase in LA levels resulted in 10% reductions in the risk of fatal CHD (RR: 0.90, 95% CI: 0.86, 0.95), but not in non-fatal CHD. Such findings highlight that the current recommendation for optimal intakes of omega-6 PUFAs (most LA) may offer a coronary benefit in primary prevention.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2056867 .
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Affiliation(s)
- Xiao-Li Ren
- The Laboratory Animal Center, Wenzhou Medical University, Wenzhou, China
- Institute of Lipids Medicine, Wenzhou Medical University, Wenzhou, China
| | - Yang Liu
- The 1st School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Wei-Jie Chu
- The 1st School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Ze-Wang Li
- The 1st School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Shuang-Shuang Zhang
- The 1st School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Zhi-Liang Zhou
- Institute of Lipids Medicine, Wenzhou Medical University, Wenzhou, China
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jun Tang
- Institute of Lipids Medicine, Wenzhou Medical University, Wenzhou, China
- Department of Food Science & Nutrition, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Lipids Medicine, Wenzhou Medical University, Wenzhou, China
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
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21
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Abstract
Although a relationship between traditional cardiovascular risk factors and stroke has long been recognized, these risk factors likely play a role in other aspects of brain health. Clinical stroke is only the tip of the iceberg of vascular brain injury that includes covert infarcts, white matter hyperintensities, and microbleeds. Furthermore, an individual's risk for not only stroke but poor brain health includes not only these traditional vascular risk factors but also lifestyle and genetic factors. The purpose of this narrative review is to summarize the state of the evidence on traditional and nontraditional vascular risk factors and their contributions to brain health. Additionally, we will review important modifiers that interact with these risk factors to increase, or, in some cases, reduce risk of adverse brain health outcomes, with an emphasis on genes and biomarkers associated with Alzheimer disease. Finally, we will consider the importance of social determinants of health in brain health outcomes.
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Affiliation(s)
- Rebecca F Gottesman
- Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, MD (R.F.G.)
| | - Sudha Seshadri
- Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UTHSA, San Antonio, TX (S.S.).,Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.)
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22
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Basavaraju P, Balasubramani R, Kathiresan DS, Devaraj I, Babu K, Alagarsamy V, Puthamohan VM. Genetic Regulatory Networks of Apolipoproteins and Associated Medical Risks. Front Cardiovasc Med 2022; 8:788852. [PMID: 35071357 PMCID: PMC8770923 DOI: 10.3389/fcvm.2021.788852] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/22/2021] [Indexed: 12/22/2022] Open
Abstract
Apolipoproteins (APO proteins) are the lipoprotein family proteins that play key roles in transporting lipoproteins all over the body. There are nearly more than twenty members reported in the APO protein family, among which the A, B, C, E, and L play major roles in contributing genetic risks to several disorders. Among these genetic risks, the single nucleotide polymorphisms (SNPs), involving the variation of single nucleotide base pairs, and their contributing polymorphisms play crucial roles in the apolipoprotein family and its concordant disease heterogeneity that have predominantly recurred through the years. In this review, we have contributed a handful of information on such genetic polymorphisms that include APOE, ApoA1/B ratio, and A1/C3/A4/A5 gene cluster-based population genetic studies carried throughout the world, to elaborately discuss the effects of various genetic polymorphisms in imparting various medical conditions, such as obesity, cardiovascular, stroke, Alzheimer's disease, diabetes, vascular complications, and other associated risks.
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Affiliation(s)
- Preethi Basavaraju
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Rubadevi Balasubramani
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Divya Sri Kathiresan
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Ilakkiyapavai Devaraj
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Kavipriya Babu
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Vasanthakumar Alagarsamy
- Biomaterials and Nano-Medicine Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| | - Vinayaga Moorthi Puthamohan
- Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
- *Correspondence: Vinayaga Moorthi Puthamohan
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23
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Lozano S, Padilla V, Avila ML, Gil M, Maestre G, Wang K, Xu C. APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population. Genes (Basel) 2021; 12:genes12111768. [PMID: 34828374 PMCID: PMC8619821 DOI: 10.3390/genes12111768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 11/16/2022] Open
Abstract
Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene’s associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer’s Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10−4) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings.
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Affiliation(s)
- Stephanie Lozano
- Department of Science, Graduate College of Biochemistry and Molecular Biology, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
| | - Victoria Padilla
- Department of Health and Biomedical Science, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA; (V.P.); (M.L.A.)
| | - Manuel Lee Avila
- Department of Health and Biomedical Science, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA; (V.P.); (M.L.A.)
| | - Mario Gil
- Department of Psychological Science, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA;
- Department of Neuroscience, School of Medicine, University of Texas Rio Grande Valley, Harlingen, TX 78539, USA
| | - Gladys Maestre
- Neuroscience and School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78539, USA;
| | - Kesheng Wang
- Health Sciences Center, Department of Family and Community Health, School of Nursing, West Virginia University, Morgantown, WV 26506, USA
- Correspondence: (K.W.); (C.X.); Tel.: +1-304-581-1912 (K.W.); +1-956-882-4193 (C.X.)
| | - Chun Xu
- Department of Health and Biomedical Science, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA; (V.P.); (M.L.A.)
- Correspondence: (K.W.); (C.X.); Tel.: +1-304-581-1912 (K.W.); +1-956-882-4193 (C.X.)
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Li L, Xu W, Tan CC, Cao XP, Wei BZ, Dong CW, Tan L. A gene-environment interplay between omega-3 supplementation and APOE ε4 provides insights for Alzheimer's disease precise prevention amongst high-genetic-risk population. Eur J Neurol 2021; 29:422-431. [PMID: 34710256 DOI: 10.1111/ene.15160] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND PURPOSE The present study aimed to explore whether and how omega-3 (ω-3) supplementation could interact with genetic factors to modulate cognitive functions, amyloid pathologies, and Alzheimer's disease (AD) risk. METHODS A total of 1,670 non-demented participants (mean age 73 years, 47% females, 41% APOE ε4 carriers) were followed up for 10 years. Hierarchical regressions, linear mixed-effects models, and Cox proportional hazards models were used to examine the interaction effects of ω-3 supplementation with APOE ε4 and polygenic hazard scores, after adjusting for age, gender, education, cognitive diagnosis, insomnia, depression, anxiety, and cardiovascular risk score. RESULTS Individuals who progress to AD during the follow-up tend to take a shorter duration of ω-3 at baseline than those stable, for whom the difference remained significant only amongst APOE ε4 carriers (p < 0.01). The interaction term (APOE ε4 × ω-3) accounted for a significant amount of variance in cognition and cerebral amyloid burden. Long-term ω-3 use protected cognition (especially memory function) and lowered amyloid burden and AD risk only amongst APOE ε4 carriers. Mediation analysis suggested that amyloid pathologies, brain reserve capacities, and brain metabolism mediated the relationships of ω-3 use with memory and global cognition for APOE ε4 (+) carriers. Similar interaction and mediation effects were also indicated amongst high-risk subjects defined by polygenic hazard scores. CONCLUSIONS Long-term ω-3 intake may have a role in AD prevention in genetically at-risk populations.
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Affiliation(s)
- Lin Li
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.,Department of Neurology, Linyi People's Hospital, Qingdao University, Qingdao, China
| | - Wei Xu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Xi-Peng Cao
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Bao-Zhen Wei
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Cheng-Wen Dong
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
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25
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Kosti RI, Kasdagli MI, Kyrozis A, Orsini N, Lagiou P, Taiganidou F, Naska A. Fish intake, n-3 fatty acid body status, and risk of cognitive decline: a systematic review and a dose-response meta-analysis of observational and experimental studies. Nutr Rev 2021; 80:1445-1458. [PMID: 34605891 DOI: 10.1093/nutrit/nuab078] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
CONTEXT Randomized controlled trials (RCTs) testing supplementation with eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids have failed to provide evidence supporting a suggested inverse association between fish intake and dementia risk. OBJECTIVE Dose-response analyses were conducted to evaluate associations between fish intake, all-cause dementia or Alzheimer's Disease (AD), and the effect of EPA/DHA supplementation on cognitive performance. DATA SOURCES PubMed, Scopus and Web of Science databases were searched for original research evaluating either associations between fish intake and dementia or AD, or the impact of EPA and/or DHA supplementation on the risk of cognitive decline. DATA EXTRACTION Data were collected on study characteristics and methods; number of cases/deaths (for observational studies); categories of exposure; model covariates; risk estimates from the most-adjusted model; type and dosage of supplementation (from RCTs); fatty acid levels in blood; and differences in cognition test results before and after supplementation. Risk of bias was assessed through the ROBINS-E and RoB2.0 tools for observational and experimental studies, respectively. DATA ANALYSIS Weighted mixed-effects models were applied, allowing for the inclusion of studies with 2 levels of exposure. Based on findings with low/moderate risk of bias, fish intake of up to 2 portions (250 g) per week was associated with a 10% reduction (95% confidence interval [CI]: 0.79, 1.02, Ν = 5) in all-cause dementia and a 30% reduction (95% CI: 0.54, 0.89, Ν = 3) in AD risk. Changes in EPA and DHA body status had a positive impact on participants' executive functions, but not on their overall cognitive performance. CONCLUSION The protection offered by fish intake against cognitive decline levels off at intakes higher than 2 portions/week and likely relates to the impact of EPA and DHA on the individual's executive functions, although there remain questions about the mechanisms linking the short- and long-term effects. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42019139528.
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Affiliation(s)
- Rena I Kosti
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, Trikala, Greece
| | - Maria I Kasdagli
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Kyrozis
- 1st Neurology Clinic, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicola Orsini
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Fani Taiganidou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Androniki Naska
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Wang Y, Du X, Zhao R, Niu J, Wang H, Li J. Association of APOE polymorphisms with lipid-lowering efficacy of statins
in atherosclerotic cardiovascular diseases. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2021. [DOI: 10.47102/annals-acadmedsg.2020505] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: Apolipoprotein E (APOE) gene is a promising candidate for the diagnosis of
hyperlipoproteinaemia and atherosclerosis. Polymorphisms in APOE have been reported to result in
differential efficacies of statins in atherosclerotic cardiovascular diseases.
Method: We classified APOE genotypes of 225 patients treated with atorvastatin and analysed the
relationship between genotypes and blood lipid levels.
Results: The baseline levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C)
were significantly lower in APOE ε4 than APOE ε3 carriers. Levels of TC and LDL-C decreased
significantly after 1 month of atorvastatin treatment. Statins have a higher significant effect in reducing
TC and LDL-C levels in APOE ε4 genotype.
Conclusion: Polymorphism in APOE is related to the efficacy of atorvastatin in reducing the levels
of TC and LDL-C.
Keywords: Apolipoprotein E, lipid-lowering efficacy, polymorphism, statin, total cholesterol
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Affiliation(s)
- Yuexi Wang
- Affiliated Hospital of Inner Mongolia Medical University, China
| | - Xiaohong Du
- Shanghai BaiO Technology Company Ltd., Shanghai, China
| | - Ruifen Zhao
- Affiliated Hospital of Inner Mongolia Medical University, China
| | - Juan Niu
- Affiliated Hospital of Inner Mongolia Medical University, China
| | - Haixu Wang
- Affiliated Hospital of Inner Mongolia Medical University, China
| | - Jing Li
- Affiliated Hospital of Inner Mongolia Medical University, China
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27
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Role of polyunsaturated fatty acids in ischemic stroke - A perspective of specialized pro-resolving mediators. Clin Nutr 2021; 40:2974-2987. [PMID: 33509668 DOI: 10.1016/j.clnu.2020.12.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 12/14/2020] [Accepted: 12/26/2020] [Indexed: 12/17/2022]
Abstract
Polyunsaturated fatty acids (PUFAs) have been proposed as beneficial for cardiovascular health. However, results from both epidemiological studies and clinical trials have been inconsistent, whereas most of the animal studies showed promising benefits of PUFAs in the prevention and treatment of ischemic stroke. In recent years, it has become clear that PUFAs are metabolized into various types of bioactive derivatives, including the specialized pro-resolving mediators (SPMs). SPMs exert multiple biofunctions, such as to limit excessive inflammatory responses, regulate lipid metabolism and immune cell functions, decrease production of pro-inflammatory factors, increase anti-inflammatory mediators, as well as to promote tissue repair and homeostasis. Inflammation has been recognised as a key contributor to the pathophysiology of acute ischemic stroke. Owing to their potent pro-resolving actions, SPMs are potential for development of novel anti-stroke therapy. In this review, we will summarize current knowledge of epidemiological studies, basic research and clinical trials concerning PUFAs in stroke prevention and treatment, with special attention to SPMs as the unsung heroes behind PUFAs.
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28
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Cao X, Guo Y, Wang Y, Wang H, Liu D, Gong Y, Wang J, Chen X, Zhang W. Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice. Sci Rep 2020; 10:18601. [PMID: 33139746 PMCID: PMC7606505 DOI: 10.1038/s41598-020-75576-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 10/16/2020] [Indexed: 12/17/2022] Open
Abstract
To investigate the effects of a high-fat diet (HFD) and apolipoprotein E (Apoe) deficiency on retinal structure and function in mice. Apoe KO mice and wild-type C57BL/6J mice were given a low-fat diet (LFD) or a HFD for 32 weeks. Blood glucose, serum lipids, body weight and visceral fat weight were evaluated. Retinal sterol quantification was carried out by isotope dilution gas chromatography-mass spectrometry. The cholesterol metabolism related genes SCAP-SREBP expressions were detected by qRT-PCR. Retinal function was recorded using an electroretinogram. The thickness of each layer of the retina was measured by optical coherence tomography. Fundus fluorescein angiography was performed to detect retinal vasculature changes. Immunohistochemical staining was used to determine the expression of NF-κB, TNF-α and VEGFR2 in the retina among HFD, HFD Apoe-/-, LFD Apoe-/- and WT mice retinas. HFD feeding caused the mice to gain weight and develop hypercholesterinemia, while Apoe-/- abnormalities also affected blood lipid metabolism. Both HFD and Apoe deficiency elevated retinal cholesterol, especially in the HFD Apoe-/- mice. No up-regulated expression of SCAP-SREBP was observed as a negative regulator. Impaired retinal functions, thinning retinas and abnormal retinal vasculature were observed in the peripheral retinas of the HFD and Apoe-/- mice compared with those in the normal chow group, particularly in the HFD Apoe-/- mice. Moreover, the expression of NF-κB in the retinas of the HFD and Apoe-/- mice was increased, together with upregulated TNF-α mRNA levels and TNF-α expression in the layer of retinal ganglion cells of the peripheral retina. At the same time, the expression level of VEGFR2 was elevated in the intervention groups, most notably in HFD Apoe-/- mice. HFD or Apoe gene deletion had certain adverse effects on retinal function and structure, which were far below the combined factors and induced harm to the retina. Furthermore, HFD caused retinal ischemia and hypoxia. Additionally, Apoe abnormality increased susceptibility to ischemia. These changes upregulated NF-κB expression in ganglion cells and activated downstream TNF-α. Simultaneously, they activated VEGFR2, accelerating angiogenesis and vascular permeability. All of the aforementioned outcomes initiated inflammatory responses to trigger ganglion cell apoptosis and aggravate retinal neovascularization.
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Affiliation(s)
- Xiupeng Cao
- Tianjin Medical University, Tianjin, China.,Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China.,Nankai University Affiliated Eye Hospital, Tianjin, China
| | - Yatu Guo
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China. .,Nankai University Affiliated Eye Hospital, Tianjin, China.
| | - Yuchuan Wang
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China.,Nankai University Affiliated Eye Hospital, Tianjin, China
| | - Hao Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin, China
| | - Dong Liu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin, China
| | - Yibo Gong
- Tianjin Medical University, Tianjin, China.,Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China.,Nankai University Affiliated Eye Hospital, Tianjin, China
| | - Jue Wang
- Tianjin Medical University, Tianjin, China.,Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China.,Nankai University Affiliated Eye Hospital, Tianjin, China
| | - Xia Chen
- Tianjin Medical University, Tianjin, China. .,Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China. .,Nankai University Affiliated Eye Hospital, Tianjin, China.
| | - Wei Zhang
- Tianjin Medical University, Tianjin, China. .,Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, China. .,Nankai University Affiliated Eye Hospital, Tianjin, China.
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29
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Zhang W, Zhou F, Huang H, Mao Y, Ye D. Biomarker of dietary linoleic acid and risk for stroke: A systematic review and meta-analysis. Nutrition 2020; 79-80:110953. [PMID: 32862121 DOI: 10.1016/j.nut.2020.110953] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/11/2020] [Accepted: 07/07/2020] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Previous observational studiíes provided conflicting findings on the relationship between linoleic acid (LA) and the risk for stroke. The aim of this study was to evaluate the association of LA levels in blood or adipose tissue samples with risk for stroke. METHODS PubMed, Web of Science, and Embase databases were searched until February 29, 2020 to identify eligible observational studies, including cohort studies, nested case-control studies, case-cohort studies, and case-control studies, reporting the association of LA with the risk for stroke and its subtypes. We pooled hazard ratio (HR) estimates with 95% confidence intervals (CIs) and conducted heterogeneity test. Sensitivity analysis and publication bias test were also carried out. RESULTS Twelve studies from 11 observational articles involving 47 836 individuals were included in the meta-analysis. We observed an inverse association between biomarkers of dietary LA and risk for total stroke (HR, 0.88; 95% CI, 0.83-0.94; P < 0.001). Meta-regression analysis suggested that ethnicity (P = 0.029) and study design (P = 0.049) contributed to between-study heterogeneity. Subgroup analysis showed that the association was statistically significant among studies conducted in white (P < 0.001) and Asian (P = 0.032) populations, and those with cohort (P = 0.001) and case-cohort design (P = 0.007). Moreover, we found that higher LA levels were associated with a reduced risk for ischemic stroke (HR, 0.87; 95% CI, 0.80-0.95; P = 0.001), although no statistically significant association was found between LA levels and the risk for hemorrhagic stroke. CONCLUSIONS The present study supported an inverse association of LA levels with the risk for stroke, particularly ischemic stroke. Racial disparity exists in the association between LA and the risk for stroke, which deserves further studies.
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Affiliation(s)
- Wanting Zhang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Feixiang Zhou
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Huijun Huang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yingying Mao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ding Ye
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
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30
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Huang J, Zuber V, Matthews PM, Elliott P, Tzoulaki J, Dehghan A. Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study. Neurology 2020; 95:e1963-e1970. [PMID: 32817390 PMCID: PMC7682841 DOI: 10.1212/wnl.0000000000010463] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 04/23/2020] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE To explore the causal relationships between sleep, major depressive disorder (MDD), and Alzheimer disease (AD). METHODS We conducted bidirectional 2-sample Mendelian randomization analyses. Genetic associations were obtained from the largest genome-wide association studies currently available in UK Biobank (n = 446,118), Psychiatric Genomics Consortium (n = 18,759), and International Genomics of Alzheimer's Project (n = 63,926). We used the inverse variance-weighted Mendelian randomization method to estimate causal effects and weighted median and Mendelian randomization-Egger for sensitivity analyses to test for pleiotropic effects. RESULTS We found that higher risk of AD was significantly associated with being a "morning person" (odds ratio [OR] 1.01, p = 0.001), shorter sleep duration (self-reported: β = -0.006, p = 1.9 × 10-4; accelerometer based: β = -0.015, p = 6.9 × 10-5), less likely to report long sleep (β = -0.003, p = 7.3 × 10-7), earlier timing of the least active 5 hours (β = -0.024, p = 1.7 × 10-13), and a smaller number of sleep episodes (β = -0.025, p = 5.7 × 10-14) after adjustment for multiple comparisons. We also found that higher risk of AD was associated with lower risk of insomnia (OR 0.99, p = 7 × 10-13). However, we did not find evidence that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and risk of AD. CONCLUSION We found that AD may causally influence sleep patterns. However, we did not find evidence supporting a causal role of disturbed sleep patterns for AD or evidence for a causal relationship between MDD and AD.
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Affiliation(s)
- Jian Huang
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece
| | - Verena Zuber
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece
| | - Paul M Matthews
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece
| | - Paul Elliott
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece
| | - Joanna Tzoulaki
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece
| | - Abbas Dehghan
- From the MRC Centre for Environment and Health (J.H., V.Z., P.E., J.T., A.D.), Department of Epidemiology and Biostatistics, School of Public Health, St. Mary's Campus, Imperial College London, Norfolk Place; UK Dementia Research Institute at Imperial College London (J.H., P.M.M., J.T., A.D.); Imperial College NIHR Biomedical Research Centre (J.H., P.E.); Department of Brain Sciences (P.M.M., P.E.), Faculty of Medicine, Imperial College London; Health Data Research UK-London; and Department of Hygiene and Epidemiology (P.E., J.T.), University of Ioannina Medical School, Greece.
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Lipoxins, RevD1 and 9, 13 HODE as the most important derivatives after an early incident of ischemic stroke. Sci Rep 2020; 10:12849. [PMID: 32732956 PMCID: PMC7393087 DOI: 10.1038/s41598-020-69831-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/15/2020] [Indexed: 11/19/2022] Open
Abstract
There is limited information available regarding the association of plasma free fatty acids (FFA) and inflammation mediators with ischemic stroke. At the same time, new treatment strategies are being pursued. The aim of this study was to carry out a thorough analysis of inflammation with multiple FFA-derivative mediators after and ischemic stroke and standard treatment. HPLC separations of 17 eicosanoids were performed using an Agilent Technologies 1,260 liquid chromatograph. The profiles of the esters of fatty acids were labelled by means of gas chromatography. FFA, and eicosanoid profiles in the group of patients after ischemic stroke significantly differed from the profile of the control group. Studies confirmed the involvement of derivative synthesis pathways responsible for the inflammation, especially palmitic acid (9 and 13 HODE), arachidonic acid, EPA and DHA. Arachidonic acid derivatives were synthesised on 5LOX, 15 LOX and COX pathways with the participation of prostaglandins while omega 3 derivatives strengthened the synthesis of resolvins, RevD1 in particular. The ability to accelerate the quenching of inflammation after ischemic stroke seems to be a promising strategy of stroke treatment in its early stage. In this context, our study points to lipoxins, RevD1, and 9, 13 HODE as the most important derivatives.
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32
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Li J, Guasch-Ferré M, Li Y, Hu FB. Dietary intake and biomarkers of linoleic acid and mortality: systematic review and meta-analysis of prospective cohort studies. Am J Clin Nutr 2020; 112:150-167. [PMID: 32020162 PMCID: PMC7326588 DOI: 10.1093/ajcn/nqz349] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 12/31/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Current evidence on associations between intakes of linoleic acid (LA), the predominant n-6 (ω-6) fatty acid, and mortality is inconsistent and has not been summarized by a systematic review and meta-analysis. OBJECTIVE The aim was to perform a systematic review and meta-analysis of prospective cohort studies to examine associations between LA intake and mortality. METHODS We conducted a comprehensive search of MEDLINE and EMBASE databases through 31 July 2019 for prospective cohort studies reporting associations of LA (assessed by dietary surveys and/or LA concentrations in adipose tissue or blood compartments) with mortality from all causes, cardiovascular disease (CVD), and cancer. Multivariable-adjusted RRs were pooled using random-effects meta-analysis. RESULTS Thirty-eight studies reporting 44 prospective cohorts were identified; these included 811,069 participants with dietary intake assessment (170,076 all-cause, 50,786 CVD, and 59,684 cancer deaths) and 65,411 participants with biomarker measurements (9758 all-cause, 6492 CVD, and 1719 cancer deaths). Pooled RRs comparing extreme categories of dietary LA intake (high vs low) were 0.87 (95% CI: 0.81, 0.94; I2 = 67.9%) for total mortality, 0.87 (95% CI: 0.82, 0.92; I2 = 3.7%) for CVD mortality, and 0.89 (95% CI: 0.85, 0.93; I2 = 0%) for cancer mortality. Pooled RRs for each SD increment in LA concentrations in adipose tissue/blood compartments were 0.91 (95% CI: 0.87, 0.95; I2 = 64.1%) for total mortality, 0.89 (95% CI: 0.85, 0.94; I2 = 28.9%) for CVD mortality, and 0.91 (95% CI: 0.84, 0.98; I2 = 26.3%) for cancer mortality. Meta-regressions suggested baseline age and dietary assessment methods as potential sources of heterogeneity for the association between LA and total mortality. CONCLUSIONS In prospective cohort studies, higher LA intake, assessed by dietary surveys or biomarkers, was associated with a modestly lower risk of mortality from all causes, CVD, and cancer. These data support the potential long-term benefits of PUFA intake in lowering the risk of CVD and premature death.
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Affiliation(s)
- Jun Li
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA,Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Marta Guasch-Ferré
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Yanping Li
- Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Frank B Hu
- Address correspondence to FBH (E-mail: )
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A Systems Pharmacology Approach for Identifying the Multiple Mechanisms of Action for the Rougui-Fuzi Herb Pair in the Treatment of Cardiocerebral Vascular Diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:5196302. [PMID: 32025235 PMCID: PMC6982690 DOI: 10.1155/2020/5196302] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/05/2019] [Accepted: 12/12/2019] [Indexed: 02/08/2023]
Abstract
Cardiocerebral vascular diseases (CCVDs) are the main reasons for high morbidity and mortality all over the world, including atherosclerosis, hypertension, myocardial infarction, stroke, and so on. Chinese herbs pair of the Cinnamomum cassia Presl (Chinese name, rougui) and the Aconitum carmichaelii Debx (Chinese name, fuzi) can be effective in CCVDs, which is recorded in the ancient classic book Shennong Bencao Jing, Mingyibielu and Thousand Golden Prescriptions. However, the active ingredients and the molecular mechanisms of rougui-fuzi in treatment of CCVDs are still unclear. This study was designed to apply a system pharmacology approach to reveal the molecular mechanisms of the rougui-fuzi anti-CCVDs. The 163 candidate compounds were retrieved from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP). And 84 potential active compounds and the corresponding 42 targets were obtained from systematic model. The underlying mechanisms of the therapeutic effect for rougui-fuzi were investigated with gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, component-target-disease (C-T-D) and target-pathway (T-P) networks were constructed to further dissect the core pathways, potential targets, and active compounds in treatment of CCVDs for rougui-fuzi. We also constituted protein-protein in interaction (PPI) network by the reflect target protein of the crucial pathways against CCVDs. As a result, 21 key compounds, 8 key targets, and 3 key pathways were obtained for rougui-fuzi. Afterwards, molecular docking was performed to validate the reliability of the interactions between some compounds and their corresponding targets. Finally, UPLC-Q-Exactive-MSE and GC-MS/MS were analyzed to detect the active ingredients of rougui-fuzi. Our results may provide a new approach to clarify the molecular mechanisms of Chinese herb pair in treatment with CCVDs at a systematic level.
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Zeng M, Zhen J, Zheng X, Qiu H, Xu X, Wu J, Lin Z, Hu J. The Role of DNA Methylation in Ischemic Stroke: A Systematic Review. Front Neurol 2020; 11:566124. [PMID: 33193003 PMCID: PMC7652818 DOI: 10.3389/fneur.2020.566124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/28/2020] [Indexed: 02/05/2023] Open
Abstract
Background: Knowledge about the classic risk and protective factors of ischemic stroke is accumulating, but the underlying pathogenesis has not yet been fully understood. As emerging evidence indicates that DNA methylation plays a role in the pathological process of cerebral ischemia, this study aims to summarize the evidence of the association between DNA methylation and ischemic stroke. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials were searched for eligible studies. The results reported by each study were summarized narratively. Results: A total of 20 studies with 7,014 individuals finally met the inclusion criteria. Three studies focused on global methylation, 11 studies on candidate-gene methylation, and six on epigenome-wide methylation analysis. Long-interspersed nuclear element 1 was found to be hypomethylated in stroke cases in two studies. Another 16 studies reported 37 genes that were differentially methylated between stroke cases and controls. Individuals with ischemic stroke were also reported to have higher acceleration in Hanuum 's epigenetic age compared to controls. Conclusion: DNA methylation might be associated with ischemic stroke and play a role in several pathological pathways. It is potentially a promising biomarker for stroke prevention, diagnosis and treatment, but the current evidence is limited by sample size and cross-sectional or retrospective design. Therefore, studies on large asymptomatic populations with the prospective design are needed to validate the current evidence, explore new pathways and identify novel risk/protective loci.
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Affiliation(s)
- Minyan Zeng
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Juanying Zhen
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Xiaodan Zheng
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Hongyan Qiu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiaonan Xu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jun Wu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zhijian Lin
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- *Correspondence: Zhijian Lin
| | - Jun Hu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Jun Hu
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The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity. Genes (Basel) 2019; 10:genes10030222. [PMID: 30884759 PMCID: PMC6471373 DOI: 10.3390/genes10030222] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/01/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer's disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.
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