Polymorphism Of Apolipoprotein Research Articles

Apolipoprotein E Gene ε4 Allele is Associated with Atherosclerosis in Multiple Vascular Beds.

Atherosclerosis is a systemic disease that can involve multiple vascular beds. The risk factors for atherosclerosis in multiple vascular beds remain unclear. Apolipoprotein E (APOE) is involved in inflammation and lipid deposition in the process of atherosclerosis. The objective of this study was to investigate whether APOE polymorphisms are associated with atherosclerosis in multiple vascular beds. A total of 416 patients with atherosclerosis in single vascular bed and 658 patients with atherosclerosis in multiple vascular beds were included. APOE genotypes were detected and the differences of APOE genotypes between the groups were compared. Logistic regression analysis was performed to analyze the relationship between APOE genotypes and atherosclerosis in multiple vascular beds. APOE E3/E4 genotype frequency was lower in the patients with atherosclerosis in multiple vascular beds than that of patients with atherosclerosis in single vascular bed (11.4% vs 17.8%, P=0.004). There was no significant difference in age and gender distribution, proportion of history of smoking, alcohol consumption, hypertension, and diabetes mellitus between the two groups (all P>0.05), and among patients with different APOE alleles (all P>0.05). Logistic regression analysis indicated that APOE E3/E4 genotype (E3/E4 vs E3/E3: odds ratio (OR) 0.598, 95% confidence interval (CI): 0.419-0.854, P=0.005), and APOE ε4 allele (ε4 vs ε3: OR 0.630, 95% CI: 0.444-0.895, P=0.010) associated with atherosclerosis in multiple vascular beds. APOE ε4 allele is associated with atherosclerosis in multiple vascular beds.

Association of polymorphism of apolipoprotein e gene with acute myocardial infarction and its short term clinical outcome

Abstract Background/Introduction Myocardial infarction (MI) is a multifactorial disease influenced by environmental and genetic factors. Apolipoprotein E (ApoE) is a protein incorporated into serum lipoproteins directing their catabolism via binding to receptors. It is a structural component of both chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE is thought to play a central role in atherosclerosis by participating in overall plasma cholesterol homeostasis. In addition to other classical risk factors, positive family history of cardiovascular disease (CVD) has been found to be significantly and independently associated with MI in epidemiological studies (1). Besides traditional cardiovascular risk factors it is likely that additional genetic factors like ApoE gene polymorphism may interact with environmental factors to determine overall cardiovascular risk of an individual to develop MI. Purpose The purpose of our study was to determine the risk of association of variants of ApoE gene with Acute Myocardial Infarction. Moreover, we also wanted to study the impact of ApoE gene polymorphism in short term major adverse cardiac events (MACE) in patients with MI not willing for coronary intervention. Methods In this case control study a total of 200 consecutively admitted AMI patients admitted to the coronary care unit of our hospital were enrolled to the study along with 200 age and gender matched controls admitted during the same time period . ApoE gene polymorphism was detected by DNA extraction, DNA amplification by PCR in a DNA thermal cycler followed by restriction enzyme digestion(2). Chi square test was used to investigate the difference in genotype and allele frequencies in casend controls and also between observed and expected frequencies in the realm of Hardy-Weinberg equilibrium. Odds Ratio (OR) with 95 % confidence interval and p values were calculated while analysing the association of different genotypes of ApoE genetic polymorphism with the disease and MACE. Logistic regression analysis was carried out amongst the groups under consideration to find the unadjusted OR and adjusted OR of the genotypes in relation to the disease.p<0.05 was considered as significant Analysis was done in SPSS software. Results Besides the traditional risk factors Apo E4 allele (OR 2.298, CI 1.305-4.044 ) and Apo E3/E4 genotype (OR 2.116, CI 1.008-4.443, p=0.048) showed strong of association with the disease. There was a higher population of Apo E3/E4 genotypes and Apo E2/E3 genotypes with MACE events (25.6% and 28.6%), while the common ApoE3/E3 genotypes had a MACE event of 10.5 %. However, the difference was not significant (p=0.071, Χ 2 =8.63 df =4). Similarly, ApoE4 allele showed a non significantly higher MACE events (p=0.22, Χ 2 =3.01 df =4) Conclusion ApoE4 allele and ApoE3/E4 genotype are strongly and independently associated with AMI.RISK FACTORS AND RISK OF MIGenotype and MACE

Effects of APOE isoforms in diabetic nephropathy patients of South India.

Diabetic nephropathy (DN) is a grave complication and the most common renal dysfunction of diabetes mellitus. Genetic factors, including Apolipoprotein E (APOE) isoforms, have been implicated in the pathogenesis of DN. A total of 577 type 2 Diabetes mellitus subjects were categorized into diabetes non-nephropathic (Controls: n = 321), diabetes nephropathic (DN: n = 256) groups. Demographic, clinical, and biochemical parameters including age, BMI, lipid profiles (TC, LDL-C, HDL-C, TG), glucose metabolism (plasma glucose, HbA1c, serum insulin), renal function (UACR, PCR), and blood pressure (SBP, DBP) were assessed. APOE variant frequencies were determined using restriction fragment length polymorphism (RFLP) analysis, validated against Hardy-Weinberg equilibrium (HWE), and statistically correlated with each clinical and biochemical parameter. The DN group had an increased prevalence of hypertension, fatty liver, and dyslipidemia compared to the Control group. Biochemical analyses revealed elevated levels of TC (213.41mg/dL vs. 189.32mg/dL), LDL-C (134.46mg/dL vs. 107.56mg/dL), and reduced HDL-C (58.13mg/dL vs. 65.32mg/dL) in DN cases compared to Controls (all p < 0.0001). The APOE variants distribution showed a significant increase in E2 allele frequency (69.1% vs. 15.3%) and corresponding homozygous genotype (E2/2: 42.2% vs. 5.6%) in DN cohorts. The study found a higher frequency of E2 allele in the DN group compared to Controls, though no statistically significant risk of DN was linked to this allele. The results suggest a potential association for APOE polymorphisms, requiring broader studies to clarify the role of APOE polymorphisms in DN susceptibility.

Association of apolipoprotein E gene polymorphism with gallstone disease in Iraqi Kurdish women

Gallstone disease (GSD) is a worldwide problem; the frequency of GSD varies greatly amongst different ethnic groups, possibly due to environmental and genetic factors. One circulating lipoprotein involved in lipid metabolism is apolipoprotein E (APOE). The APOE gene is polymorphic, has three distinct alleles, APOE2, APOE3, and APOE4. The an APOE polymorphism is linked to a variety of diseases, including Alzheimer's and type-two diabetes, so this study aimed to assess the relationship among various APOE genotypes and alleles with gallstone cases in Iraqi Kurdish women. The present case-control study involved 81 cases with laparoscopic cholecystectomy for gallstone disease and 80 healthy women without GSD. Genomic DNA samples were taken from blood to find the genotype of APOE using allele-specific sequence-primers and a method based on polymerase chain reaction (PCR). lipid profiles were examined using an automated biochemical analyzer. SPSS and GraphPad Prism 9.1.1 software were used to conduct the statistical analysis. No significant relationships were found between healthy people and GSD patients in genotype and allele frequencies. However, the genotype for E3/E4 and the APOE4 allele in GSD patients were higher than the controls (9.88% vs. 5.0% and 4.94% vs. 2.5%, respectively; P &lt;0.05) but statistically nonsignificant. serum levels of cholesterol, low-density lipoproteins, and very low-density lipoproteins were higher, and the levels of serum high-density lipoprotein was lower than controls. These findings revealed no connection between the examined polymorphisms and gallstone cases. Additionally, it was demonstrated that gallstone disease and lipid parameters had a favorable relationship. Keywords: Apolipoprotein E, APOE, Gallstone disease, Genotype, Polymorphisms.

Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor.

Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

Lipoprotein(a) and diet: consuming sugar-sweetened beverages lowers lipoprotein(a) levels in obese and overweight adults

Lipoprotein(a) [Lp(a)] contributes to cardiovascular disease risk. A genetically determined size polymorphism in apolipoprotein(a) [apo(a)], determined by the number of Kringle (K) repeats, inversely regulates Lp(a) levels. Nongenetic factors including dietary saturated fat influence Lp(a) levels. However, less is known about the effects of carbohydrates including dietary sugars. In this double-blind, parallel arm study among 32 overweight/obese adults, we investigated the effect of consuming glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks on Lp(a) level and assessed the role of the apo(a) size polymorphism. The mean (±SD) age of participants was 54 ± 8 years, 50% were women, and 75% were of European descent. Following the 10-week intervention, Lp(a) level was reduced by an average (±SEM) of −13.2% ± 4.3% in all participants (P = 0.005); −15.3% ± 7.8% in the 15 participants who consumed glucose (P = 0.07); and −11.3% ± 4.5% in the 17 participants who consumed fructose (P = 0.02), without any significant difference in the effect between the two sugar groups. Relative changes in Lp(a) levels were similar across subgroups of lower versus higher baseline Lp(a) level or carrier versus noncarrier of an atherogenic small (≤22K) apo(a) size. In contrast, LDL-C increased. In conclusion, in older, overweight/obese adults, consuming sugar-sweetened beverages reduced Lp(a) levels by ∼13% independently of apo(a) size variability and the type of sugar consumed. The Lp(a) response was opposite to that of LDL-C and triglyceride concentrations. These findings suggest that metabolic pathways might impact Lp(a) levels.

PON1, APOE and SDF-1 Gene Polymorphisms and Risk of Retinal Vein Occlusion: A Case-Control Study.

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3'G(801)A] for SDF-1 gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Impact of APOE-ε alleles on brain structure and cognitive function in healthy older adults: A VBM and DTI replication study.

The Apolipoprotein E (APOE) gene has been established in the Alzheimer's disease (AD) literature to impact brain structure and function and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. The current study aimed to replicate and expand the multimodal approach employed by Honea et al. Structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and neuropsychological measures were used to investigate the impact of APOE-ε status on grey matter structure, white matter integrity, and cognitive functioning. Data were obtained from the Alzheimer's Disease Initiative Phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-ε2+ N = 17, APOE-ε3ε3 N = 64, APOE-ε4+ N = 35). Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity, respectively, between APOE-ε2+ and APOE-ε3ε3 controls, and again between APOE-ε4+ and APOE-ε3ε3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with age, sex and education as regressors of no interest. Cognitive scores were correlated (Pearson r) with imaging metrics within groups. No significant differences were seen across groups, within groups in MRI metrics, or cognitive performance (p>0.05, corrected for multiple comparisons). The current study partially replicated and extended previous findings from an earlier multimodal study (Honea 2009). Future studies should clarify APOE mechanisms in healthy ageing by adding other imaging, cognitive, and lifestyle metrics and longitudinal design in larger sample sizes.

APOE-E4 allele as a potential marker for implantation failure: A comparison between fertile women, ART success and RIF patients.

Apolipoprotein E (APOE) is the most important precursor for the production of steroid hormones and is also involved in regulating the function of steroid hormones, hence playing a significant role in reproductive processes. So, APOE gene expression may be correlated with the implantation process. This study tries to make a better clarification of the correlation between APOE gene polymorphisms and recurrent implantation failure (RIF), where we compared the frequency of APOE polymorphisms in RIF patients, assisted reproductive treatment (ART) success cases and fertile women. In all, 100 women with successful ART who got pregnant (fetal heart rate positive) in their first or second cycle of invitro fertilization or intracytoplasmic sperm injection, 100 infertile RIF cases, and 100 normal fertile control cases with at least one live birth were included in present study. Following DNA extraction, genotypes were determined through polymerase chain reaction-restriction fragment length polymorphism method using HhaI restriction enzyme. Finally, statistical analysis was performed by chi-squared (χ2) test in SPSS software (P < 0.05). The RIF group showed significantly higher frequency for E3/E4 genotype (29%) compared with the other two control groups (fertile = 15%, ART success [ART+] = 13%) (P = 0.007). There was also a significantly higher frequency of the E4 allele in the RIF group (14.5%) compared with both of the control groups (fertile = 7.5%, ART+ = 6.5%) (P = 0.018). APOE4 is correlated with recurrent failure in the process of embryo implantation and, accordingly, it may potentially be considered a possible risk factor to the implantation process. The presence of E4 can be proposed as a predictive indicator in determining the results of assisted reproductive techniques.

LPA Gene Copy Number Variation and APOE Gene Polymorphism in Young Acute Myocardial Infarction

INTRODUCTION: An early onset of acute myocardial infarction (AMI) and a strong family history suggest the possibility of its genetic predisposition. Lipoprotein(a) (LPA) and Apolipoprotein E (APOE) genes are known to be involved in lipid metabolism which may contribute to the development of atherosclerosis leading to AMI. This study aims to assess the association between LPA gene copy number variation (CNV) and APOE gene polymorphism in young AMI patients. MATERIALS AND METHODS: A total of 40 DNAs were extracted from the buffy coat. APOE genotyping and detection of LPA gene CNV were performed using multiplex PCR technique and digital PCR. After tabulation of the results of the current study, meta-analyses were performed from selected studies among Asian populations using the Comprehensive Meta-analysis version 3 software program. RESULTS: No significant association was found between CNV of the LPA gene and the polymorphism of the APOE gene with Young AMI patients in the current study. However, our meta-analysis confirmed that the E4 allele increased the risk for CAD with the E3/E4 genotype [p=0.000, OR= 1.60 (95% CI: 1.41-1.83) significantly increased risk of CAD and individuals with E3/E3 genotype [p=0.000, OR=0.73 (95% CI: 0.66-0.81) were protective against CAD. The gain of LPA CNV was higher in YAMI [n=5 (25%)] than in control [n=2 (10%)] but they are not significant. CONCLUSION: There is no association between the LPA gene CNV and the presence of APOE polymorphism in young AMI, but our meta-analysis confirmed that the E4 allele increased the risk for CAD.

Generation of human induced pluripotent stem cell line (XWHNi004-A) from a male with APOE gene mutation

Genetic polymorphism of apolipoprotein E (APOE) confers differential susceptibility to Alzheimer's disease (AD), and APOE ɛ4 variants is the most powerful risk factor for this disease. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line carrying the APOE ɛ4/ɛ4 genotype from peripheral blood mononuclear cells (PBMCs) isolated from a male with a family history of AD utilizing non-integrative Sendai virus vector. The iPSC maintains their original genotype, highly express endogenous pluripotency markers, displays a normal karyotype, and retains the ability to differentiate into cells representative of the three germ layers.

Serum Apo Lipoprotein E, Apo Lipoprotein E Gene Polymorphisms, and Parkinson's Disease.

A central role for apolipoprotein E (APOE) has been suggested in modulating processes of neurodegeneration. To study the association between serum APOE levels, APOE gene polymorphisms, and Parkinson's disease (PD). Fifty-five patients with PD and 30 healthy subjects were enrolled. PD patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr scale, and Schwab-England Activities of Daily Living scale. Serum APOE level and genotyping for APOE polymorphisms were done for PD patients and controls using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. Mean serum APOE level was significantly higher in PD patients compared with healthy controls. APOE ε2/4 genotype was present in a significantly higher proportion of patients compared with controls. APOE ε4 allele was significantly associated with a higher score on the "mentation, behavior, and mood section" of UPDRS compared with ε2 allele. APOE ε2 allele was significantly associated with a shorter disease duration compared with ε3 and ε4 alleles. Mean serum APOE level was significantly higher in patients presenting predominantly by rigidity and bradykinesia compared with those presenting predominantly by tremors. Serum APOE level was positively correlated with mean scores of "mentation, behavior, and mood section" of UPDRS and disease duration. Serum APOE level was a significant predictor for the scores of "mentation, behavior, and mood section" of UPDRS. APOE ε2/4 genotype might be a susceptibility variant for PD. There may be a possible role for APOE in modulating the process of neurodegeneration in PD.

Apolipoprotein E Polymorphisms in Andean Population of Jujuy, Argentina.

The pleiotropic nature of the apolipoprotein E (APOE) gene is associated with complex diseases in different populations. We analyzed APOE polymorphisms in 76 individuals from Jujuy - Argentina using NGS technology. The observed genotypes align with the expected Hardy-Weinberg equilibrium. APOE3 was the most common allele, followed by APOE4 and APOE2. The allele distribution pattern is consistent with findings in previously studied populations of Native Americans and Asians. The E4 allele's low frequency, always observed in a heterozygous state, raises questions regarding its relevance in explaining dementia and longevity associated with this marker in the Central Andes.

Role of Apolipoproteins in Neurodegenerative Diseases

Since lipids are insoluble in water, they are carried in the blood as particles called lipoproteins. Lipoproteins consisting of lipids and proteins are multicomponent complexes. The classification of lipoproteins, which are divided into several main groups such as low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL) and chylomicrons, is based on their density, size, lipid and apolipoprotein content. Apolipoproteins are the protein component of lipoproteins that carry lipids from the blood to various tissues of the body for metabolism and utilisation. Apolipoproteins play an important role in lipid metabolism. They regulate many metabolic enzymes and interact with lipoprotein receptors. Numerous studies have shown that apolipoprotein phenotype, different allelic polymorphism and apolipoprotein gene mutation can affect metabolism and utilisation of blood lipids and consequently trigger the onset and development of atherosclerosis, hyperlipidaemia, cerebrovascular and cardiovascular diseases. Furthermore, apolipoproteins have been associated with neurodegenerative diseases and different apolipoprotein polymorphisms have been evaluated as risk factors or protective agents in different neurodegenerative diseases. This review presents evidence from some studies linking apolipoproteins with Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration disease.

Extracranial carotid artery atherosclerotic plaque and APOE polymorphisms: a systematic review and meta-analysis.

Carotid atherosclerotic plaque is an important independent risk factor for stroke. Apolipoprotein E (APOE) influences cholesterol levels and certain isoforms are associated with increased carotid atherosclerosis, though the exact association between APOE and carotid plaque is uncertain. The study aimed to evaluate the association between APOE and carotid plaque. A systematic review was performed to retrieve all studies which examined the association between carotid plaque and APOE. This study was conducted in accordance with the PRISMA guidelines. Independent readers extracted the relevant data from each study including the type of imaging assessment, plaque definition, frequency of APOE E4 carrier status and type of genotyping. Meta-analyses with an assessment of study heterogeneity and publication bias were performed. Results were presented in a forest plot and summarized using a random-effects model. After screening 838 studies, 17 studies were included for systematic review. A meta-analysis of 5 published studies showed a significant association between ε4 homozygosity and carotid plaque [odds ratio (OR), 1.53; 95% CI, 1.16, 2.02; p = .003]. Additionally, there was a significant association between patients possessing at least one ε4 allele, heterozygotes or homozygotes, and carotid plaque (OR, 1.25; 95% CI, 1.03, 1.52; p = .03). Lastly, there was no association between ε4 heterozygosity and carotid plaque (OR, 1.08; 95% CI, 0.93, 1.26; p = .30). APOE ε4 allele is significantly associated with extracranial carotid atherosclerotic plaque, especially for homozygous individuals.

Association of Apolipoprotein E Gene Polymorphism with Type 2 Diabetic Nephropathy in the Southern Chinese Population.

Common polymorphisms within the apolipoprotein E (APOE) gene are rs429358 and rs7412, which result in three major alleles (ɛ2, ɛ3, and ɛ4) and six genotypes (E2/E2, E2/E3, E3/E3, E3/E4, E4/E4, and E2/E4). Although APOE gene polymorphisms have been suggested to be associated with the development of diabetic nephropathy (DN), their potential association remains unclear in different regions. This study aims to unveil the genetic effects of APOE gene polymorphisms on DN susceptibility and serum lipid profiles in southern Chinese population. A total of 306 DN patients and 483 type 2 diabetic patients as controls were included in the study. The APOE gene polymorphisms were analyzed by polymerase chain reaction (PCR) microarray gene chip. Relevant medical records and information of these participants were collected. There were statistically significant differences (p < 0.05) in gender, SBP, hypertension, hyperuricemia, UTP, TG and HDL-C between DN patients and controls. DN patients exhibited a higher frequency of the ε2 allele and E2/E3 genotype than controls (p < 0.001). Logistic regression analysis indicated that the ε2 allele and E2/E3 genotype were independent risk factors (adjusted OR: 3.237, 95% CI: 1.789-5.854, p < 0.001; adjusted OR: 3.453, 95% CI: 1.873-6.368, p < 0.001), while the ε3 allele or E3/E3 genotype might serve as protective role (adjusted OR: 0.395, 95% CI: 0.255-0.612, p < 0.001) for development of DN. Our study indicates a correlation between APOE polymorphisms and DN in the southern Chinese Hakka population. Specifically, individuals carrying the APOE ε2 allele and E2/E3 genotype are at a higher risk of developing DN. Conversely, those with the APOE ε3 allele and E3/E3 genotype have a lower risk of DN in southern Chinese population.

4 Impact of APOE-ε Alleles on Brain Structure and Function in Healthy Older Adults: A VBM and DTI Replication Study

Objective:The Apolipoprotein E (APOE) gene has been established in the Alzheimer’s disease (AD) literature to impact brain structure and function and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and neuropsychological measures present as useful, non-invasive tools to investigate the impact of APOE-e allele status on grey matter structure, white matter integrity, and cognitive functioning, respectively. Nonetheless, studies to date have revealed mix findings and few studies have taken a multimodal approach to investigating APOE’s effects. Thus, the objective of the current study was to replicate and expand upon the multimodal neuroimaging study conducted by Honea et al. (2009), that examined the impact of APOE-e4 presence on brain structure and cognitive function in healthy older adults, with the addition of APOE-e2 carriers and cognitive composite measures. The aim of the current replication study was to identify reliable changes to grey matter volume and white matter integrity in healthy older adults as it relates to APOE-e allele presence and cognitive performance. This represents one of the first studies to investigate both the risk and protective effects of APOE-e alleles (e4 and e2 respectively) on measures of cognitive performance, GMV and white matter integrity in healthy older adults.Participants and Methods:Data were obtained from the Alzheimer’s Disease Initiative phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-e2+ N= 17, APOE-e3e3 N= 64, APOE-e4+ N=35). Voxel-based morphometry (VBM) and tract based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity respectively between APOE-e2+ and APOE-e3e3 controls, and again between APOE-e4+ and APOE-e3e3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with covariates of age, sex, education, and cognitive scores were correlated with imaging metrics within groups (Pearson r) to examine associations between cognitive performance and brain structure.Results:Consistent with findings from Honea et al. (2009), no significant differences were seen across APOE groups, within-groups in MRI metrics, or cognitive performance (p&gt;0.05, corrected for multiple comparisons). Taking a similar approach to Honea and company, nonsignificant, trend-level results were examined (p&lt;0.2, corrected for multiple comparisons) and suggested: 1) Decreased GMV and increased mean diffusivity (MD) were present in APOE-e4+ compared to APOE-e3e3 and 2) Increased GMV and fractional anisotropy (FA) were present in APOE-e2+ compared to APOE-e3e3.Conclusions:The current study replicated and extended previous findings. Trend-level findings across both the current and replicated study suggests there may be subtle neurostructural differences in healthy aging as a function of APOE-e4 status. The current study additionally found potential subtle differences in GMV and white matter integrity in APOE-e2 carriers at the trend-level, consistent with previous reports of APOE-e2 's protective effects against neurodegeneration. Although these findings should be interpreted with caution, trend-level effects seen in the current study are consistent with previous research and may hold important implications for APOE neuromechanisms.

P01.04.B LONG-TERM COGNITIVE TOXICITY IN SMALL CELL LUNG CANCER POPULATION: EARLY CLINICAL, NEUROIMAGING, AND SEROLOGICAL BIOMARKERS

Abstract BACKGROUND Small cell lung cancer patients (SCLC) are treated with platinum-based chemotherapy, thoracic radiation, and some of them will also receive prophylactic cranial irradiation (PCI). Following therapy, nearly 45% of SCLC will exhibit moderate to severe cognitive impairment (CI). The aim of our study was to identify early biomarkers including clinical, serological and changes in brain structure associated with an increased risk of CI in SCLC population. MATERIAL AND METHODS Fifty-two SCLC were prospectively recruited from January 2019-December 2022 at our institution and evaluated at diagnosis using a neuropsychological battery (NPS), a structural MRI (T1-weighted), and serological markers including: a) cytokines (interleukin 1, 2, 6, 8, 10 and TNF alpha) and b) single nucleotide polymorphisms (SNP) of apolipoprotein E (APOE), multidrug resistance protein (MDR1) and brain-derived neurotrophic factor (BDNF). They were also clinically and NPS evaluated at 1-month following chemotherapy-before PCI, at 3-6 months, at one-year and at 2-3 years post-PCI. Voxel-based morphometry (T1-VBM) was used to analyze gray matter (GM) integrity. RESULTS Of the 52 patients included, 70% were male, median age was 65 years (46-82). Most (94%) had an ECOG PS ≤1. Half had hypertension (52%) and dyslipidemia (46%); one third (36%) moderate alcoholism and 25% were diabetic. Nearly half (54%) had limited stage and received cisplatin-based chemotherapy (52%). One third (29%, n=15) exhibited brain metastasis (BM): 4 at baseline (8%) and the other during follow-up (21%). Regarding smoking, median packs per year was 45 (12-100). Twenty-nine (56%) received cranial radiation, most of them (n=22, 42%) PCI (25Gy). Median overall survival was 18 months (2.5, 71); twenty-one (40%) were alive at the end of the study.Nearly half of our cohort (48%, n=25) exhibited CI: 31% (n=16) at baseline and another 17% (n= 9) during follow-up. CI group performed significantly worse in all the domains explored, especially in verbal memory (p &amp;lt; 0.001) and executive functioning (p &amp;lt; 0.001). Only smoking habit resulted significantly different between groups: CI patients were heavier smokers (p=0.04). VBM analysis showed that CI group exhibited significant GM damage in anterior and mid cingulate, superior, and inferior temporal gyrus, precuneus and fusiform gyrus. GM volume positively correlated with measures of cognitive functioning at baseline (all correlations, p &amp;lt;0.04). We found no differences regarding cytokines levels or SNPs of APOE, MDR1 and BDNF between groups. CONCLUSION This study confirms that nearly half of the SCLC population exhibit CI. Of greater interest, however, is the fact that most of them already exhibit CI before therapy that seem to correlate with GM alterations previously described in this population. In addition, smoking seems to be the most important clinical risk factor.

Mass-spectrometric analysis of APOB polymorphism rs1042031 (G/T) and its influence on serum proteome of coronary artery disease patients: genetic-derived proteomics consequences.

Genetic polymorphisms of apolipoprotein B gene (APOB) may result into serum proteomic perturbance in Coronary Artery Disease (CAD). The current case-control cohort of Pakistani subjects was designed to analyze the genetic influence of APOB rs1042031, (G/T) genotype on serum proteome. Subjects were categorized into two groups: CAD patients (n = 480) and healthy individuals (n = 220). For genotyping, tetra ARMS-PCR was carried out and validated through sequencing, whereas LC/MS-based proteomic analysis of serum samples was performed through label-free quantification. In initial step of genotyping, the frequencies of each genotype GG, GT, and TT were 70%, 27%, and 30% in CAD patients, while in control group, the subjects were 52%, 43%, and 5%, respectively, in CAD patients. The genotypic frequencies in patients vs. control groups found significantly different (p = 0.004), and a strong association of dominant alleles GG with the CAD was observed in both dominant (OR: 2.4 (1.71-3.34), p = 0.001) and allelic genetic models (OR: 2.0 (1.45-2.86), p = 0.001). In second step of label-free quantitation, a total of 40 significant proteins were found with altered expression in CAD patients. The enriched Gene Ontology (GO) terms of molecular functions and pathways of these protein showed upregulated pathways as follows: chylomicron remodeling and assembly, complement cascade activation, plasma lipoprotein assembly, apolipoprotein-A receptor binding, and metabolism of fat-soluble vitamins in G allele carrier of rs1042031 (G > T) vs. mutant T-allele carriers. This study provides better understanding of CAD pathobiology by proteogenomics of APOB. It evidences the influence of APOB rs1042031-dominant (GG) genotype with CAD patients.

Interaction between APOE, APOA1, and LPL Gene Polymorphisms and Variability in Changes in Lipid and Blood Pressure following Orange Juice Intake: A Pilot Study.

Chronic orange juice intake is associated with reduced risk of cardiovascular disease, however, a large inter-individual variability in response to orange juice for lipid profile and blood pressure has been observed. This heterogeneity in responsiveness could be associated with single nucleotide polymorphism (SNP), which has not been previously addressed. This study aims to investigate the influence of SNP in apolipoprotein E (APOE), apolipoprotein A1 (APOA1), mevalonate (MVK), and lipase lipoprotein (LPL) genes in the biological response after chronic orange juice intake. Forty-six volunteers ingested 500 mL daily for 60 days and blood pressure and biochemical parameters are measured. Also, SNPs in APOE, APOA1, MVK, and LPL genes are genotyped in the volunteers that are medium/high excretors of flavanone metabolites. GenotypesCC (APOA1), AA, and GG (LPL) are associated with positive health effects of orange juice and the CC (APOE), GG (APOA1), GG, and AA (LPL) genotypes are associated with no effects of orange juice consumption (p < 0.05). These results identify for the first-time SNP associated with effects of orange juice on lipid levels and blood pressure, results that may provide bases for future precise nutritional recommendations regarding this flavanone-rich food to lower the risk for cardiovascular disease.