Apolipoprotein E Gene Research Articles

Cognitive decline in older adults with epilepsy: The Cardiovascular Health Study.

Cognitive decline is a major concern for older adults with epilepsy. Whether and how much faster older adults with epilepsy experience cognitive decline beyond expected age-related cognitive change remain unclear. We sought to estimate and compare rates of cognitive decline in older adults with and without epilepsy. The Cardiovascular Health Study is a population-based longitudinal cohort study of 5888 US adults aged 65+. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate average rates of decline in 3MS and DSST scores by epilepsy status (prevalent, incident, or no epilepsy), adjusted for risk factors associated with cognitive decline. The rate of decline in 3MS was significantly faster in prevalent epilepsy (P<.001) and after incident epilepsy (P=.002) compared with no epilepsy. Prevalent epilepsy and apolipoprotein E gene (APOE) ε4 (ApoE4) had a synergistic interaction, whereby prevalent epilepsy and ApoE4 together were associated with 1.51 points faster annual decline in 3MS than would be expected if prevalent epilepsy and ApoE4 did not interact (P<.001). Older adults with prevalent epilepsy had a significantly lower initial DSST score and faster rate of decline compared to those with no epilepsy (P<.001). Faster decline in global cognitive ability seen in this study validates concerns of patients. ApoE4 allele status was an effect modifier of the relationship between cognitive decline and prevalent epilepsy. Further research is warranted to explore biological mechanisms and possible interventions to mitigate cognitive decline.

The Association Between Apolipoprotein E Gene Polymorphism and In-Stent Restenosis After Extracranial and Intracranial Artery Stenting

Background and Purpose: Neo-atherosclerosis plays a vital role in the incidence of in-stent restenosis (ISR) after extracranial and intracranial artery stenting, and Apolipoprotein (ApoE) gene polymorphism has been reported to be closely related to the occurrence and development of atherosclerosis. The present study aims to investigate the association between ApoE gene polymorphism and ISR after extracranial and intracranial artery stenting. Methods: A total of 169 patients with successful stent implantation were included in this study. ApoE genotypes were obtained during the postoperative follow-up. Color Doppler ultrasonography of cervical artery or head and neck CT angiography (CTA) was performed on the 1,3,6 and 12 months and then yearly in the clinical follow-up. Multivariate Cox regression analysis of independent risk factors was performed to evaluate the ISR. Kaplan-Meier curves were generated to compare the restenosis –free rate among the patients with different ApoE genotypes. Results: Of the 169 patients, 43 (43/169, 25.4%) developed ISR after a mean follow-up period of 10.4 months (1–35 months). Multivariate analysis showed that genotype E4/E4 (hazard ratio 3.305, P = 0.031, 95% confidence interval 1.118–9.773) and degree of stenosis >90% (hazard ratio 5.083, P = 0.001, 95% confidence interval 1.938–13.327) were significant determinants of ISR. Conclusion: ApoE gene polymorphism is closely related to the incidence of ISR after extracranial and intracranial artery stenting, and the genotype E4/E4 is an independent risk factor for ISR.

Association of APOE E2 and low-density lipoprotein with depressive symptoms in Chinese senile schizophrenia inpatients: A cross-sectional study

BackgroundSchizophrenia is considered to occur due to both environmental and genetic factors. Depressive symptoms and apolipoprotein E (APOE) gene polymorphisms are involved in the pathogenesis of schizophrenia. However, the effect of APOE gene polymorphism on depressive symptoms has never been investigated among Chinese elderly schizophrenia patients. ObjectiveThis cross-sectional study aimed to determine the effect of APOE gene polymorphism on blood lipid metabolism and depressive symptoms among elderly schizophrenia patients. MethodA total of 301 elderly schizophrenia patients (161 males, age ranges from 60 to 92 years, with an average age of 67.31 ± 6.667) were included in the study. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). APOE gene polymorphisms were determined by polymerase chain reaction (PCR). Correlations between GDS and serum low-density lipoprotein (LDL) levels with APOE genotypes were assessed. ResultsThe concentration of LDL in the APOE E2 group was significantly lower than those in the APOE E3 and APOE E4 groups, and the GDS scores in the APOE E2 and APOE E3 groups were higher than those in the APOE E4 group. Using partial correlation analysis and controlling the duration of disease and hyperlipidemia, we found that GDS scores were significantly correlated with LDL (r = −0.179, p = 0.025). ConclusionsThe APOE E2 genotype is associated with more depressive symptoms and lower serum LDL in elderly Chinese schizophrenia patients, and there is a negative correlation between depressive symptoms and LDL.

Effects of Apolipoprotein E Polymorphism on Cerebral Oxygen Saturation After Traumatic Brain Injury.

Objective: To investigate the effects of the apolipoprotein E gene (APOE) on the cerebral oxygen saturation of patients after traumatic brain injury (TBI).Methods: Clinical data of 114 patients with TBI and 54 normal people were collected. The APOE genotypes of all subjects were determined by quantitative fluorescent polymerase chain reaction (QF-PCR). The regional cerebral oxygen saturation (rScO2) of TBI patients and normal people were monitored by near-infrared spectroscopy (NIRS).Results: The mean rScO2 of patients was (55.06 ± 7.60)% in the early stage of TBI, which was significantly lower than that of normal people (67.21 ± 7.80)% (P < 0.05). Single-factor and multifactor logistic regression analyses showed APOEε4 was an independent risk factor that caused the early decline of rScO2 in TBI patients. Furthermore, in the TBI group, the rScO2 of APOEε4 carriers (52.23 ± 8.02)% was significantly lower than that of non-ε4 carriers (60.33 ± 7.12)% (P < 0.05). But in the normal group, no significant differences in rScO2 were found between APOEε4 carriers and non-carriers.Conclusion: The rScO2 may be significantly decreased after TBI, and APOEε4 may be a risk factor for decreased rScO2 in the early stage of TBI.

Blood Transcriptome Response to Environmental Metal Exposure Reveals Potential Biological Processes Related to Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease which is manifested by a progressive and irreversible decline of cognition, memory loss, a shortened attention span, and changes in personality. Aging and genetic pre-dispositions, particularly the presence of a specific form of apolipoprotein E (APOE), are main risk factors of sporadic AD; however, a large body of evidence has shown that multiple environmental factors, including exposure to toxic metals, increase the risk for late onset AD. Lead (Pb) and cadmium (Cd) are ubiquitous toxic metals with a wide range of applications resulting in global distribution in the environment and exposure of all living organisms on earth. In addition to being classified as carcinogenic (Cd) and possibly carcinogenic (Pb) to humans by the International Agency for Research on Cancer, both compounds disrupt metal homeostasis and can cause toxic responses at the cellular and organismal levels. Pb toxicity targets the central nervous system and evidence for that has emerged also for Cd. Recent epidemiological studies show that both metals possibly are etiological factors of multiple neurodegenerative diseases, including Alzheimer's disease (AD). To further explore the association between metal exposure and AD risk we applied whole transcriptome gene expression analysis in peripheral blood leukocytes (PBLs) from 632 subjects of the general population, taken from the EnviroGenomarkers project. We used linear mixed effect models to associate metal exposure to gene expression after adjustment for gender, age, BMI, smoking, and alcohol consumption. For Pb exposure only few associations were identified, including a downregulation of the human eukaryotic translation initiation factor 5 (eIF5). In contrast, Cd exposure, particularly in males, revealed a much stronger transcriptomic response, featuring multiple pathways related to pathomolecular mechanisms of AD, such as endocytosis, neutrophil degranulation, and Interleukin−7 signaling. A gender stratified analysis revealed that the Cd responses were male-specific and included a downregulation of the APOE gene in men. This exploratory study revealed novel hypothetical findings which might contribute to the understanding of the neurotoxic effects of chronic Pb and Cd exposure and possibly improve our knowledge on the molecular mechanisms linking metal exposure to AD risk.

Diagnosis Test Meta-Analysis for Apolipoprotein E in Alzheimer's Disease.

Objective To evaluate the diagnostic value of apolipoprotein E (APOE) gene in Alzheimer's disease (AD). Methods Databases including PubMed, EMBASE, Google Scholar, Wanfang Med online, China National Knowledge Infrastructure (CNKI), and China Biomedical Literature Database (CBM) were searched for literatures in English or Chinese. No limitations on the date. The sensitivity, specificity, likelihood ratio, and diagnostic odds ratio were pooled for meta-analysis. The symmetric receiver operator characteristic curve (SROC) and Fagan's Nomogram were drawn, and metaregression and subgroup analysis were used to explore the source of heterogeneity. Results A total of 13 studies, including 2662 cases and 8843 controls, were analyzed. The combined sensitivity (SEN) was 0.62 (95% CI (0.58-0.66)), specificity (SPE) was 0.84 (95% CI (0.81-0.86)), the positive likelihood ratio was 3.8 (95% CI (3.3-4.3)), and the negative likelihood ratio was 0.45 (95% CI (0.41-0.49)). The area under the ROC curve was 0.80, and the diagnostic ratio (DOR) was 8. Neither publication bias was detected in Deeks' funnel plot, nor threshold effect was shown in the SROC. Metaregression analysis showed that the diagnostic methods, experimental design, and sample size contributed to the heterogeneity in SEN, while the diagnostic methods, experimental design, blind evaluation on test results, and sample size contributed to the heterogeneity in SPE. When the pretest probability was set as 50%, the posterior probability in Fagan's Nomogram was 79%, the positive likelihood ratio (LRP) was 5, and the negative likelihood ratio (LRN) was 0.42. Conclusions AD could neither be confirmed nor excluded by the APOE genotype test. The sensitivity and specificity of the APOE gene test were relatively low in the diagnosis of AD. The diagnostic value of APOE ε4 gene in AD was moderate; it might play an important role in the prevention of AD.

Nonlinear interaction between APOE ε4 allele load and age in the hippocampal surface of cognitively intact individuals.

The 4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE 4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE 4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE 4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE 4 and AD in a similar way.

Association of Apolipoprotein E Gene Polymorphism with Ischemic Stroke in Coronary Heart Disease Patients Treated with Medium-intensity Statins.

ObjectiveTo study the association of apolipoprotein E(APOE) gene polymorphism with ischemic stroke (IS) in coronary heart disease (CHD) patients treated with medium-intensity statins.MethodsThe retrospective study was performed on 662 samples including 169 CHD subjects complicated with IS, 296 subjects with CHD, and 197 control subjects. The APOE gene was obtained from case files. Univariable and multivariable logistic regression analyses were utilized to recognize the possible risks of CHD and IS.ResultsThe frequency of ε3-ε4 genotype was increased in the CHD group (p=0.013) and CHD-IS group (p=0.001), the frequency of ε4 allele was also increased in the CHD group (p=0.047) and the CHD-IS group (p=0.009) compared with control group. ε3-ε4 genotype was the independent risk for CHD and CHD-IS after adjusting for traditional risk factors with adjusted odds ratio (AOR) 2.210, 95%CI: 1.263–3.867, p=0.005) and (AOR 2.794, 95%CI: 1.539–5.072, p=0.002). The ε4 allele was also significantly associated with CHD (AOR 2.126, 95%CI: 1.265–3.575,=0.004) and CHD-IS (AOR 2.740, 95%CI: 1.569–4.784, p=0.001).ConclusionThese results demonstrated that ε4 allele influenced the development of CHD with or without IS, especially for the genotype of ε3-ε4. CHD patients carrying the ε3-ε4 genotype and the ε4 allele were significantly associated with the incidence of IS, even if medium-intensity statins had been used.

Allelic Distribution of Genes for Apolipoprotein E and MTHFR in Patients with Alzheimer’s Disease and Their Epistatic Interaction

Background:Genetic risk factors play an important role in the pathogenesis of Alzheimer’s disease (AD). However, the gene-gene interaction (epistasis) between specific allelic variants is only partially understood.Objective:In our study, we examined the presence of the ɛ4 allele of apolipoprotein E (APOE) and the presence of C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with AD and controls. We also evaluated the epistatic interaction between MTHFR and the APOE variants.Methods:A total of 564 patients with AD and 534 cognitively unimpaired age-matched controls were involved in the study.Results:The presence of the ɛ4 allele of APOE increases the risk of developing AD in a dose-dependent manner (OR 32.7: homozygotes, 15.6: homozygotes + heterozygotes, 14.3: heterozygotes). The combination of genotypes also increases the risk of developing AD in a dose-dependent manner: OR 18.3 (APOE 4/X and 4/4 + CT rs1801133), OR 19.4 (APOE 4/X and 4/4 + CT rs1801133 + AC rs1801131), OR 22.4 (APOE 4/X and 4/4 + TT rs1801133), and OR 21.2 (APOE 4/X and 4/4 + CC rs1801131). Homozygotes for variant alleles of MTHFR as well as patients with AD had significantly higher levels of homocysteine than homozygotes for standard alleles or controls.Conclusion:Homozygotes for APOE4 and carriers of APOE4 with TT genotype of rs1801133 were found to be at the highest risk of developing AD. These findings suggest that the epistatic interaction of specific gene variants can have a significant effect on the development of AD.

Presence of the apolipoprotein E-\u03b54 allele is associated with an increased risk of sepsis progression

Growing evidence indicated that single nucleotide polymorphisms (SNPs) in the apolipoprotein E (APOE) gene are related to increase the risk of many inflammatory-related diseases. However, few genetic studies have associated the APOE gene polymorphism with sepsis. This study was to investigate the clinical relevance of the APOE gene polymorphism in the onset and progression of sepsis. A multicenter case–control association study with a large sample size (601 septic patients and 699 healthy individuals) was conducted. Clinical data showed that the APOEε4 allele was overrepresented among all patients with septic shock (p = 0.031) compared with sepsis subtype, suggesting that APOEε4 allele may associated with increased susceptibility to the progression of sepsis. Moreover, the APOE mRNA levels decreased after lipopolysaccharide (LPS) stimulation in cells in culture. Then 21 healthy individuals to extract PBMC for genotype grouping (APOE4+ group 8; APOE4− group 13) was selected to evaluate the effect on APOE level, and results showed that the expression level of APOE in APOE4+ group and APOE4− group did not differ in mRNA levels after an LPS challenge, but the protein levels in APOE4+ group decreased slower than that in APOE4− group, and this process was accompanied by the upregulation of proinflammatory cytokines. These results provide evidence that the APOEε4 allele might be associated with the development of sepsis and a potential risk factor that can be used in the prognosis of sepsis.

Superior short-term memory in APOE ε2 carriers across the age range

The Apolipoprotein-E (APOE) gene is now known to be associated with individual differences in cognitive health in ageing. However, while the APOE ε4 allele confers significantly increased risk of developing Alzheimer’s disease (AD), the APOE ε2 allele is hypothesized to be protective against the development of AD. This is in line with neuroimaging and pathological findings associated with ε2 APOE allele, which go in the opposite direction to those observed in AD-related pathology. However, the precise impact of this allele on cognition remains inconclusive, with some small-cohort studies raising the possibility of an advantageous memory performance in these individuals. Here, we tested short-term memory (STM) performance in a large cohort of individuals, 300 of which were ε2/ε3 carriers. Their performance was compared to 554 ε3/ε3 carriers. We included participants from a wide age range spanning young, middle-aged and elderly adults. All of them performed a STM task that has previously been shown to be sensitive to subtle changes in memory in various patient and at-risk cohorts. Individuals carrying the APOE-ε2 allele exhibited a significant memory advantage, regardless of STM task difficulty and across all ages. The observed memory advantage was present across the age range, suggestive of a phenotypical effect of this allele on cognition, possibly independent of any effects of this genetic allele that occur later life in these individuals.

ApoE Lipidation as a Therapeutic Target in Alzheimer's Disease.

Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments.

A Likelihood Ratio Test for Gene-Environment Interaction Based on the Trend Effect of Genotype Under an Additive Risk Model Using the Gene-Environment Independence Assumption.

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data.

Apolipoprotein E expression pattern in human induced pluripotent stem cells during in vitro neural induction.

Apolipoprotein E (APOE) is a multifunctional protein that plays significant roles in important cellular mechanisms in peripheral tissues and is as well expressed in the central nervous system, notably by adult neural stem cells (NSCs) in the hippocampus. Evidence from animal studies suggest that APOE is critical for adult NSC maintenance. However, whether APOE has the potential to play a similar role in human NSCs has not been directly investigated. To address this question, we conducted a focused study characterising APOE gene and protein expression in an in vitro model of neural differentiation utilising human induced pluripotent stem cells. We found that APOE gene expression was dramatically decreased as the cells became more differentiated, indicating that APOE expression levels reflect the degree of cellular differentiation during neural induction. Furthermore, qualitative analysis results of immunocytochemistry showed that intracellular localisation of APOE protein becomes more pronounced as neural differentiation progresses. Taken together, our findings suggest a potential role for APOE in human NSC maintenance and justify further investigations being carried out to understand whether changes in APOE levels can directly impact the neurogenic capacity of human stem cells.

APOE and dementia - resequencing and genotyping in 105,597 individuals.

IntroductionThe mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well‐characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia.MethodsThe APOE gene was sequenced in 10,369 individuals, and nine amino acid–changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly.ResultsRisk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10−4 and P = 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33.DiscussionWe found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.

Should Lipoprotein(a) be Measured in Youth?

Should Lipoprotein(a) be Measured in Youth?

Alzheimer's Disease Susceptibility Gene Apolipoprotein E (APOE) and Blood Biomarkers in UK Biobank (N = 395,769).

Alzheimer's disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential associations between APOE genotypes and biomarkers. Several biomarkers significantly associated with APOEɛ4 'risk' and ɛ2 'protective' genotypes (versus neutral ɛ3/ɛ3). Most associations supported previous data: for example, ɛ4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p < 0.001) and ɛ2 with lower LDL (b = -0.456 SDs, p < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ4 and increased insulin-like growth factor (IGF-1) (b = 0.017, p < 0.001) where lower levels have been previously suggested as an AD risk factor. These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.

Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank.

BackgroundThe three main alleles of the APOE gene (ε4, ε3 and ε2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach.MethodsWe used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype ε3ε3 as a reference. Data was restricted to 337,484 white British participants (aged 37–73 years).FindingsAfter correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, ε3ε4 and ε4ε4 genotypes associated with increased odds of AD (p ≤ 7.6 × 10−46), hypercholesterolaemia (p ≤ 7.1 × 10−17) and ischaemic heart disease (p ≤ 2.3 × 10−4), while ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10−10) compared to ε3ε3. In contrast, ε4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ≤ 5.2 × 10−4) while ε2ε2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ≤ 6.1 × 10−4). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes.InterpretationPheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions.FundingNational Health and Medical Research Council of Australia.

Molecular Evolution of Apolipoprotein Multigene Family and the Original Functional Properties of Serum Apolipoprotein (LAL2) in Lampetra japonica.

Apolipoprotein (APO) genes represent a large family of genes encoding various binding proteins associated with plasma lipid transport. Due to the long divergence history, it remains to be confirmed whether these genes evolved from a common ancestor through gene duplication and original function, and how this evolution occurred. In this study, based on the phylogenetic tree, sequence alignment, motifs, and evolutionary analysis of gene synteny and collinearity, APOA, APOC, and APOE in higher vertebrates may have a common ancestor, lamprey serum apolipoprotein LAL1 or LAL2, which traces back to 360 million years ago. Moreover, the results of immunofluorescence, immunohistochemistry, and flow cytometry show that LAL2 is primarily distributed in the liver, kidney, and blood leukocytes of lampreys, and specifically localized in the cytoplasm of liver cells and leukocytes, as well as secreted into sera. Surface plasmon resonance technology demonstrates that LAL2 colocalizes to breast adenocarcinoma cells (MCF-7) or chronic myeloid leukemia cells (K562) associated with lamprey immune protein (LIP) and further enhances the killing effect of LIP on tumor cells. In addition, using quantitative real-time PCR (Q-PCR) and western blot methods, we found that the relative mRNA and protein expression of lal2 in lamprey leukocytes and sera increased significantly at different times after stimulating with Staphylococcus aureus, Vibrio anguillarum, and Polyinosinic-polycytidylic acid (Poly I:C). Moreover, LAL2 was found to recognize and bind to gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli) and play an important role in the antibacterial process. All in all, our data reveals a long, complex evolutionary history for apolipoprotein genes under different selection pressures, confirms the immune effect of LAL2 in lamprey sera against pathogens, and lays the foundation for further research regarding biological functions of lamprey immune systems.

The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans.

Cardiovascular disease (CVD) is the leading cause of death globally. It is well-established based on evidence accrued during the last three decades that high plasma concentrations of cholesterol-rich atherogenic lipoproteins are causatively linked to CVD, and that lowering these reduces atherosclerotic cardiovascular events in humans (1–9). Historically, most attention has been on low-density lipoproteins (LDL) since these are the most abundant atherogenic lipoproteins in the circulation, and thus the main carrier of cholesterol into the artery wall. However, with the rise of obesity and insulin resistance in many populations, there is increasing interest in the role of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants, with accumulating evidence showing they too are causatively linked to CVD. Plasma triglyceride, measured either in the fasting or non-fasting state, is a useful index of the abundance of TRLs and recent research into the biology and genetics of triglyceride heritability has provided new insight into the causal relationship of TRLs with CVD. Of the genetic factors known to influence plasma triglyceride levels variation in APOC3- the gene for apolipoprotein (apo) C-III - has emerged as being particularly important as a regulator of triglyceride transport and a novel therapeutic target to reduce dyslipidaemia and CVD risk (10).