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Atherosclerosis Nov 2014Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).
METHODS AND RESULTS
We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.
CONCLUSIONS
In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.
Topics: Adult; Aged; Alleles; Apolipoprotein E4; Cohort Studies; Coronary Disease; Female; Gene-Environment Interaction; Genotype; Heterozygote; Humans; Male; Middle Aged; Risk Factors; Smoking
PubMed: 25173947
DOI: 10.1016/j.atherosclerosis.2014.07.038 -
Alzheimer's & Dementia : the Journal of... Jan 2023The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological... (Meta-Analysis)
Meta-Analysis
White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.
INTRODUCTION
The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps.
METHODS
A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke.
RESULTS
Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier.
DISCUSSION
Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.
Topics: Humans; White Matter; Reproducibility of Results; Magnetic Resonance Imaging; Cognitive Dysfunction; Alzheimer Disease
PubMed: 35319162
DOI: 10.1002/alz.12642 -
Drugs & Aging Jan 2015Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, as newly-developed oral hypoglycaemic agents, were evaluated as a possible therapy for AD.
AIM
We systematically evaluated the efficacy and safety of PPAR-γ agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD.
METHODS
A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95% CIs. The results were pooled using a random-effects model.
RESULTS
Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, especially for patients with comorbid diabetes (MD -3.47, 95% CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) ε4 non-carriers (MD -0.31, 95% CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-γ agonist treatment (RR 4.14, 95% CI 2.37-7.23).
CONCLUSIONS
There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-γ agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.
Topics: Alzheimer Disease; Cognitive Dysfunction; Humans; Hypoglycemic Agents; PPAR gamma; Pioglitazone; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones
PubMed: 25504005
DOI: 10.1007/s40266-014-0228-7 -
Journal of Neurotrauma Apr 2021There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have...
There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non-apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood-brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6-12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.
Topics: Apolipoproteins E; Brain Injuries, Traumatic; Brain-Derived Neurotrophic Factor; Cytokines; Genetic Association Studies; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Treatment Outcome
PubMed: 29799308
DOI: 10.1089/neu.2017.5583 -
Journal of Exercise Rehabilitation Apr 2021The presence of apolipoprotein (Apo) E4 is a genetic risk factor in cognitive impairment. Physical exercise contributes to slowing cognitive impairment in older adults,... (Review)
Review
The presence of apolipoprotein (Apo) E4 is a genetic risk factor in cognitive impairment. Physical exercise contributes to slowing cognitive impairment in older adults, but little is known about the influence of exercise on ApoE4 carriers and noncarriers. The objective of systematic review is to study the role of physical exercise in older adults' ApoE4 carriers and noncarriers. A systematic literature search was carried out in five international databases: PubMed, Web of Science, PeDro, Scopus, and SPORTDiscus. A total of nine randomized controlled trials were included with a sample size of 2,025 subjects (901 ApoE4 carriers). The exercise reported a significant improvement on cognitive performance in older adults' ApoE4 noncarriers (standardized mean difference [SMD]=0.653; 95% confidence interval [CI], 0.29-1.00; chi=35.36; degrees of freedom [ ]=7; <0.0001; =80%). It was also reported that a total program duration greater than 50 sessions generated different and significant effects on cognitive performance in older adults' ApoE4 noncarriers (SMD=0.878; 95% CI, 0.14-1.61; chi=31.82; =3; <0.0001; =91%). The results reported that high intensity generated a differential effect on cognitive performance in older adults' ApoE4 carriers versus noncarriers (SMD=0.963; 95% CI, 0.25-1.67; chi=18.11; =3; <0.0004; =83%). The effect of physical exercise on cognitive performance in older adults is conditioned by the presence or not of ApoE4.
PubMed: 34012932
DOI: 10.12965/jer.2142130.065 -
Progress in Neuro-psychopharmacology &... Jul 2019The comorbidity of major depressive disorder (MDD) and stroke are common in clinic. There is a growing body of evidence suggesting a bi-directional relationship between... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The comorbidity of major depressive disorder (MDD) and stroke are common in clinic. There is a growing body of evidence suggesting a bi-directional relationship between stroke and depression. However, the mechanisms underlying the relationship between MDD and stroke are poorly investigated. Considering that both MDD and stroke can be heritable and are influenced by multiple risk genes, shared genetic risk factors between MDD and stroke may exist.
OBJECTIVE
The objective is to review the existing evidence for common genetic risk factors for both MDD and stroke and to outline the possible pathophysiological mechanisms mediating this association.
METHODS
A systematic review and meta-analysis was performed. Gene association studies regarding stroke and depression were searched in the database PubMed, CNKI, and Chinese Biomedical Literature Database before December 2018. Statistical analysis was performed using the software Revman 5.3.
RESULTS
Genetic polymorphisms of 4 genes, methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein E (ApoE) have been demonstrated to associate with the increased risk for both MDD and stroke, while the association between identified polymorphisms in angiotensin converting enzyme (ACE) and serum paraoxonase (PON1) with depression is still under debate, for the existing studies are insufficient in sample size. These results suggest the possible pathophysiological mechanisms that are common to these two disorders, including immune-inflammatory imbalance, increased oxidative and nitrative stress, dysregulation of lipoprotein and lipid metabolism, and changes of cerebrovascular morphology and function. Other associated genes with few or conflicting results have also been included, and a few studies have investigated the effects of the described polymorphisms on MDD and stroke comorbidity, such as post stroke depression.
CONCLUSION
These findings suggest that shared genetic pathways may contribute to the comorbidity of MDD and stroke. Studies to evaluate the shared genetic variations between MDD and stroke may provide insights into the molecular mechanisms that trigger disease progression.
Topics: Apolipoproteins E; Aryldialkylphosphatase; Depression; Genetic Predisposition to Disease; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Peptidyl-Dipeptidase A; Risk Factors; Stroke
PubMed: 30898617
DOI: 10.1016/j.pnpbp.2019.03.003 -
Alzheimer's Research & Therapy Nov 2020Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have... (Review)
Review
Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.
Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Atrophy; Cognition; Humans
PubMed: 33148345
DOI: 10.1186/s13195-020-00712-4 -
Pharmacogenomics 2016We evaluated the evidence of pharmacogenetic associations with statins in a systematic review. (Review)
Review
AIM
We evaluated the evidence of pharmacogenetic associations with statins in a systematic review.
METHODS
Two separate outcomes were considered of interest: modification of low-density lipoprotein cholesterol (LDL-C) response and modification of risk for cardiovascular events.
RESULTS
In candidate gene studies, 141 loci were claimed to be associated with LDL-C response. Only 5% of these associations were positively replicated. In addition, six genome-wide association studies of LDL-C response identified common SNPs in APOE, LPA, SLCO1B1, SORT1 and ABCG2 at genome-wide significance. None of the investigated SNPs consistently affected the risk reduction for cardiovascular events.
CONCLUSION
Only five genetic loci were consistently associated with LDL-C response. However, as effect sizes are modest, there is no evidence for the value of genetic testing in clinical practice.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Adaptor Proteins, Vesicular Transport; Apolipoproteins E; Cardiovascular Diseases; Cholesterol, LDL; Genetic Loci; Genome-Wide Association Study; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipoprotein(a); Liver-Specific Organic Anion Transporter 1; Neoplasm Proteins; Organic Anion Transporters; Polymorphism, Single Nucleotide
PubMed: 26670324
DOI: 10.2217/pgs.15.158 -
Cortex; a Journal Devoted To the Study... May 2024The ε4 allele of the apolipoprotein E (APOE4) gene is an established risk factor for Alzheimer's disease but its impact on cognition in healthy adults across the... (Review)
Review
The ε4 allele of the apolipoprotein E (APOE4) gene is an established risk factor for Alzheimer's disease but its impact on cognition in healthy adults across the lifespan is unclear. One cognitive domain that is affected early in the course of Alzheimer's disease is spatial cognition, yet the evidence for APOE-related changes in spatial cognition is mixed. In this meta-analysis we assessed the impact of carrying the APOE4 allele on five subdomains of spatial cognition across the lifespan. We included studies of healthy human participants where an APOE4-carrier group (heterozygous or homozygous) could be compared to a homozygous group of APOE3-carriers. We identified 156 studies in total from three databases (Pubmed, Scopus and Web of Science) as well as through searching cited literature and contacting authors for unpublished data. 122 studies involving 32,547 participants were included in a meta-analysis, and the remaining studies are included in a descriptive review. APOE4 carriers scored significantly lower than APOE3 carriers (θˆ = -.08 [-.14, -.02]) on tests of spatial long-term memory; this effect was very small and was not modulated by age. On other subdomains of spatial cognition (spatial construction, spatial working memory, spatial reasoning, navigation) there were no effects of genotype. Overall, our results demonstrate that the APOE4 allele exerts little influence on spatial cognitive abilities in healthy adults.
PubMed: 38878339
DOI: 10.1016/j.cortex.2024.05.006 -
BioMed Research International 2019The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the clinical benefit of terpenoids in humans are scarce. This systematic review and meta-analysis evaluated the effects of terpenoid administration on atherosclerotic lesion area in ApoE -/- mice.
METHODS
A comprehensive literature search using PubMed, Embase, and the Cochrane Library databases was performed to identify studies that assessed the effects of terpenoids on atherosclerosis in ApoE -/- mice. The primary outcome was atherosclerotic lesion area, and study quality was estimated using SYRCLE's risk of bias tool.
RESULTS
The meta-analysis included 25 studies. Overall, terpenoids significantly reduced atherosclerotic lesion area when compared to vehicle control (<0.00001; SMD: -0.55; 95% CI: -0.72, -0.39). In terpenoid type and dose subgroup analyses, sesquiterpenoid (=0.002; SMD -0.93; 95% CI: -1.52, -0.34), diterpenoid (=0.01; SMD: -0.30; 95% CI: -0.54, -0.06), triterpenoid (<0.00001; SMD: -0.66; 95% CI: -0.94, -0.39), tetraterpenoid (<0.0001; SMD: -1.81; 95% CI: -2.70, -0.91), low dose (=0.0001; SMD: -0.51; 95% CI: -0.76, -0.25), medium dose (0.0001; SMD: -0.48; 95% CI: -0.72, -0.24), and high dose (=0.002; SMD: -1.07; 95% CI: -1.74, -0.40) significantly decreased atherosclerotic lesion area when compared to vehicle control. PROSPERO register number is CRD42019121176.
CONCLUSION
Sesquiterpenoid, diterpenoid, triterpenoid, and tetraterpenoid have potential as antiatherosclerotic agents with a wide range of doses. This systematic review provides a reference for research programs aimed at the development of terpenoid-based clinical drugs.
Topics: Animals; Aortic Diseases; Atherosclerosis; Disease Models, Animal; Mice; Mice, Knockout, ApoE; PubMed; Terpenes
PubMed: 31392210
DOI: 10.1155/2019/2931831