ApoE Polymorphism Research Articles

Role of APOE and IL18RAP gene polymorphisms in cervical spondylotic myelopathy in Indian population

Cervical spondylotic myelopathy (CSM) is a progressive degenerative spine disease. It is not clear why certain patients develop symptomatic myelopathy whereas others do not, even in the presence of radiographic features of cervical stenosis. Genetic predisposition has been suggested, supported by familial occurrence of CSM. In this study we explored the demographic and radiographic features of CSM in Indian population and studied the association between polymorphisms in interleukin18RAP and apo-lipoprotein genes in CSM. A total of 100 CSM patients and 100 healthy control subjects were included in this study. Genotyping of APOE (rs7412 and rs429358) and IL18RAP (rs1420106 and rs917997) gene polymorphisms was performed by Taqman allelic discrimination assay. Comparison of allelic frequencies, ε2 versus ε3 (OR = 4.4, 95%CI = 1.23–15.73, P = 0.002) and ε2 versus ε4 (OR = 6.67, 95%CI = 1.58–28.04, P = 0.009) showed a statistically significant association for the risk of CSM. There was no significant association between different genotypes with sex, T2 signal intensity change and Nurick grade. Only patients having multiple level cervical prolapsed intervertebral disc (PIVD) on MRI, had a higher proportion of the ε2 allele as compared to controls (p = <0.0001). No significant association was found between IL18RAP gene polymorphisms (rs1420106 and rs917997) with the risk of CSM. ε2 allele was associated with the risk of CSM in Indian population. There was no significant association between the two single nucleotide polymorphisms (SNPs) of IL18RAP gene with risk of CSM.

Association of ApoE haplotype with clinical evidence of pituitary adenoma

PurposeTo evaluate the association of the presence, invasiveness, hormonal activity and recurrence of pituitary adenoma (PA) with ApoE genotypes and alleles. Materials and methodsOur study group included 142 patients with PA and the control group included 256 healthy individuals. The genotyping of ApoE (rs7412 and rs429358) was performed using a real-time PCR method. ResultsAfter statistical analysis we found that ApoE genotype E2/E3 was associated with 2.6-fold increased odds of active PA (OR = 2.609; 95%CI: 1.380–4.932; p = 0.003), while the presence of ApoE E3/E3 decreased odds of active PA by 65% (OR = 0.343; 95%CI: 0.205–0.575; p < 0.001). The frequency of the allele ε3 was lesser in the PA group (74.3% vs. 83%, p = 0.003) when compared to controls but it was statistically significantly more frequent in the invasive PA than in the noninvasive PA subgroup (80.4% vs. 65.5%, p = 0.005). The ApoE E2/E4 genotype was more frequent in the noninvasive PA subgroup (10.3% vs. 0%, p = 0.003) than in the invasive PA subgroup. The ApoE E4/E4 genotype was more frequent in the recurrent than in the non-recurrent PA subgroup (6.6% vs. 0%, p = 0.006). No associations between ApoE polymorphisms and Ki-67 labelling index were found. ConclusionThe ApoE E2/E3 genotype is associated with the presence of PA while the ApoE genotype E2/E4 is associated with noninvasive PA development. The allele ε3 could possibly have a protective effect against PA. The genotype E4/E4 is associated with the development of recurrent PA.

Evaluation of genetic association of 40 SNPs in candidate genes with cholesterol gallstone disease in north Indian population

BackgroundIn north Indian population, Gallbladder Stone Disease (GSD) affects 7% of population, with majority of stones containing >50% cholesterol. In general, GSD susceptibility has been suggested to include the combination of predisposing alleles of multiple lithogenic (LITH) genes and environmental factors. Materials and methodsStudy included 610 GSD patients (USG positive) and 315 healthy controls. A panel of 48 SNPs was prepared for candidate genes based on pathobiology of GSD, MAF in Hapmap and 1000 genome database, and Tagger SNPs in Linkage Disequilibrium. Genotyping was carried out by Sequenom Mass ARRAY platform and statistical analyses were performed using SPSS version 16.0, Bonferroni adjustment was applied for multiple testing corrections. Potential functional consequences of the exonic polymorphisms were determined using Polyphen2, SIFT score and interaction networks of associated genes by GENEMANIA. ResultsGenotypes of 40 out of 48 SNPs followed Hardy Weinberg Equilibrium in controls and subjected to present analysis. We observed significant associations of genotypes/alleles of FGFR4, CYP7A1, APOE, TM4SF4, NR1H2, IL10, PLCE1, CYP1A1, SLC10A2, MMP2, CYP8B1, Gab1 with GSD whereas remaining SNPs revealed no association.Analysis after gender stratification and Bonferroni correction revealed that in males SNPs in TM4SF4, PLCE1 and Gab1 were significantly associated with GSD while in females APOE and CYP8B1 polymorphisms were significantly associated with GSD.All but three significantly associated SNPs were intronic. The potential functional consequences of associated exonic SNPs by Polyphen2 predicted probable damaging effects of FGFR4 and APOE variants, while PLCE1 SNP showed benign effect. Further SIFT score predicted probable tolerated effects of FGFR4 and PLCE1, while APOE variant showed deleterious effect. ConclusionsOur study suggests that FGFR4, CYP7A1, APOE, TM4SF4, NR1H2, IL10, PLCE1, CYP1A1, SLC10A2, MMP2, CYP8B1 genetic variants confer significant risk for gallstone disease in North Indian population. The association of many genes with disease risk was found to be sex-specific.

Possible interactions between sex steroids and plasma lipoprotein metabolism in multiple sclerosis

Introduction: Sex hormones may modulate the clinical course of multiple sclerosis (MS) [1]. Sex steroids interact with cholesterol metabolism and the serum lipid profile has been associated with progression of disability in MS patients [2]. We hypothesized that the putative associations between lipoprotein metabolism and severity of MS could be modulated by sex steroids exposure. The aim of this study was to investigate whether oral contraceptives (OC) use changes the lipoprotein profile associated with disability in patients with MS. Materials and methods: Clinical data was collected from 133 women with the diagnosis of relapsing-remitting MS prior to the start of disease-modifying therapies. Patients who were using OC after disease onset (DO) (OC+, n = 57) were compared to those who never used OC or discontinued its intake before DO (OC−, n = 76). In both cohorts of subjects, the associations between the apolipoprotein E (ApoE) polymorphism and plasma lipid levels and the Expanded Disability Status Score (EDSS) and the Multiple Sclerosis Severity Score (MSSS) were evaluated using a hierarchic multiple regression analysis after adjustment for confounders. Approval for the study by the local Ethical Committee was obtained and all participants signed a written informed consent. Results: In patients carrying the E3/E3 phenotype of ApoE (73.7%), EDSS and MSSS were lower in OC + in comparison with OC- subgroup of patients (p < 0.01). In this population, LDL and total cholesterol were associated with EDSS (p = 0.005 and p = 0.041, respectively), and LDL and the triglyceride/high density lipoprotein ratio with MSSS (p = 0.029 and p = 0.016, respectively) in OC + patients. ApoE levels were associated with EDSS (p = 0.012) and MSSS (p = 0.025) in OC- subgroup of patients. Discussion and conclusions: OC use changes the serum lipoprotein profile associated with disability in patients with MS. These results suggest that lipoprotein metabolism could be involved in the modulatory effects of sex steroids in the disease.

Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups.

The apolipoprotein E-C1-C4-C2 gene cluster at 19q13.32 encodes four amphipathic apolipoproteins. The influence of APOE common polymorphisms on plasma lipid/lipoprotein profile, especially on LDL-related traits, is well recognized; however, little is known about the role of other genes/variants in this gene cluster. In this study, we evaluated the role of common and uncommon/rare genetic variation in this gene region on inter-individual variation in plasma lipoprotein levels in non-Hispanic Whites (NHWs) and African blacks (ABs). In the variant discovery step, the APOE, APOC1, APOC4, APOC2 genes were sequenced along with their flanking and hepatic control regions (HCR1 and HCR2) in 190 subjects with extreme HDL-C/TG levels. The next step involved the genotyping of 623 NHWs and 788 ABs for the identified uncommon/rare variants and common tagSNPs along with additional relevant SNPs selected from public resources, followed by association analyses with lipid traits. A total of 230 sequence variants, including 15 indels were identified, of which 65 were novel. A total of 70 QC-passed variants in NHWs and 108 QC-passed variants in ABs were included in the final association analyses. Single-site association analysis of SNPs with MAF>1% revealed 20 variants in NHWs and 24 variants in ABs showing evidence of association with at least one lipid trait, including several variants exhibiting independent associations from the established APOE polymorphism even after multiple-testing correction. Overall, our study has confirmed known associations and also identified novel associations in this genomic region with various lipid traits. Our data also support the contribution of both common and uncommon/rare variation in this gene region in affecting plasma lipid profile in the general population.

ε3/4 genotype of the apolipoprotein E is associated with higher risk of Alzheimer's disease in patients with type 2 diabetes mellitus

As a progressive and chronic disease, type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia with rising prevalence worldwide. The ε4 allele of the apolipoprotein E (ApoE) gene may be risk factor of severe peripheral neuropathy in T2DM patients. The association of ApoE polymorphism and Alzheimer's disease (AD) in T2DM patients remains largely unknown. Totally 156 T2DM patients with AD and 145 T2DM patients were included. The genotypes and allele frequency of ApoE were analyzed to explore the role of ApoE in AD in T2DM patients. The levels of total cholesterol (TC), triglyeride (TG), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) were detected to further investigate mechanism of ApoE. Genotype frequency ratio of genotype ε3/4, ε4/4 and allele ε4 among the T2DM patients with AD was obviously increased. The TC, TG and LDL-C levels of T2DM patients with ε3/4 genotype were higher than those with ε3/3 or ε2/3 genotype and the ε3/4 genotype, while the HDL-C level was on the contrary, suggesting that ε3/4 genotype elevated blood lipid levels in T2DM patients with AD, thus increasing the risk of AD in T2DM patients. ApoE polymorphism was associated with AD in T2DM patients. ApoE ε3/4 genotype was possibly to serve as a risk factor for AD in T2DM patients by enhancing the blood lipid levels.

Association Between ApoE Polymorphism in Obesity Markers in Healthy Adults Who Follow the Greek Orthodox Fasting Rules

Aim: To examine the association between ApoE genetic polymorphisms and BMI.Methods: This case control study of randomly selected, free living individuals from North Greece investigated whether traditional Greek Orthodox dietary practices could affect obesity markers independent of genetic influences, by examining the Waist circumference (WC), waist hip ratio (WHR) and % fat mass (% FM), were measured in healthy adults who follow the rules of Greek Orthodox fasting compared to those who did not. 382 subjects (246 women and 136 men) were included in the analysis, 161 fasters and 220 non-fasters as a control group. Results: Age affected obesity markers in all participants with more obesity in the older subjects. ApoE alleles did not differ between fasting and controls. When fasters where classified as obese and non-obese, there was no association with age (p&gt;0,077). In the control group, BMI and WC were associated with age and gender and WHR with apoE alleles (p&lt;0.001). In the fasting group these correlations are not observed (p=0.545 and p=0.365 respectively). Interactions between independent variables (sex, age apoE alleles and fasting status) and their influence on BMI, %BF and WHR. ApoE alleles and age significantly influence WHR (p=0.014). Conclusions: In the present study we found that the effect of ApoE alleles on adiposity was associated with age. In conclusion, even if genetic risks factor influence the susceptibility to obesity and cardiometabolic disorders, lifestyle changes may ameliorate these effects.

The Influence of Genetic Factors and Cognitive Reserve on Structural and Functional Resting-State Brain Networks in Aging and Alzheimer's Disease.

Magnetic resonance imaging (MRI) offers significant insight into the complex organization of neural networks within the human brain. Using resting-state functional MRI data, topological maps can be created to visualize changes in brain activity, as well as to represent and assess the structural and functional connections between different brain regions. Crucially, Alzheimer’s disease (AD) is associated with progressive loss in this connectivity, which is particularly evident within the default mode network. In this paper, we review the recent literature on how factors that are associated with risk of dementia may influence the organization of the brain network structures. In particular, we focus on cognitive reserve and the common genetic polymorphisms of APOE and BDNF Val66Met.

BRIDGING THE GAP BETWEEN NEUROLOGY AND PSYCHIATRY-ATYPICAL PRESENTATION OF COMMON NEURODEGENERATIVE DISORDERS: Session 418

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories both in Alzheimer's as well as in Parkinson's disease. Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Recently subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau (t-tau) and phosphorylated tau181 (p-tau), MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. We will review the typical and atypical forms of AD from these varied perspectives to help improve diagnostic confidence among clinicians. Special attention will be given to language variant of Alzheimer's disease. A predominant deficit in the language domain is a key feature of primary progressive aphasia but language impairment is commonly present in Alzheimer's disease. International diagnostic criteria for PPA and its three variants (agrammatic, logopenic, semantic) were published relatively recently in 2011. Since then, studies have investigated the validity of these criteria in classifying patients which includes clinical symptoms, neurocognitive presentations, distinct MRI signatures, and neuropathological differences. In this session, we will review the subtypes of PPA using the above parameters to assist clinicians in diagnosis of these conditions. Special attention will be given of logopenic PPA a syndrome frequently seen in atypical Alzheimer's disease. Another common neurodegenerative disorder, Parkinson's disease (PD) conceptualized as predominantly movement disorder presents with myriad of atypical features predominantly psychiatric in nature. Psychosis is one of the most debilitating symptoms of PD, as it is an independent risk factor for nursing home placements, increased caregiver distress and mortality. Visual hallucinations are the most common psychotic manifestation in PD. Auditory, olfactory, tactile and gustatory hallucinations are infrequently found and usually coexist with visual ones. Delusions occur in about 5% of Parkinson's disease patients. Cognitive correlates of hallucinations and delusions appear to be different in PD. They may have distinct pathogenic mechanisms and possibly anatomical substrates. Global cognitive deficits including attention, frontal executive dysfunction, visuospatial abnormalities, language and verbal memory were associated with the presence of hallucinations in Parkinson's disease, but did not correlate with the presence of delusions. APOE and glucocerebrosidase gene (GBA) mutations and polymorphisms found to be associated with a distinct cognitive profile of changes characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. During this session new findings on pathognomonic, cognitive and genetic correlates of psychosis in PD will be presented.

Serum Lipoprotein Profile Is Associated With Protective Effects of Oral Contraceptive Use on Multiple Sclerosis Severity: A Cross-Sectional Study.

Background: The mechanisms underlying the influence of sex hormones in multiple sclerosis (MS) are uncertain. Sex steroids interact with cholesterol metabolism and the serum lipid profile has been associated with the severity of the disease. We hypothesized that the putative associations between lipoprotein metabolism and MS could be modulated by sex steroids exposure. The aim of this study was to investigate whether oral contraceptives (OC) use changes the lipoprotein profile associated with disability in patients with multiple sclerosis.Methods: Clinical data was collected from 133 relapsing-remitting multiple sclerosis (RRMS) women with a mean of 6.5 years of disease duration and prior to the start of disease-modifying therapies. Patients who were using OC after disease onset (DO) (OC+, n = 57) were compared to those who never used OC or discontinued its intake before DO (OC–, n = 76). In both cohorts of subjects, the associations between the apolipoprotein E (ApoE) polymorphism, and plasma lipid levels, and the annualized relapse rate (RR), the Expanded Disability Status Score (EDSS), and the Multiple Sclerosis Severity Score (MSSS) were evaluated using a hierarchic multiple regression analysis after adjustment for confounders.Results: Low density lipoprotein (LDL) levels were associated with higher EDSS (p = 0.010) and MSSS (p = 0.024) in the whole studied cohort. In E3/E3 phenotype carriers (73.7%), EDSS and MSSS were lower in OC+ in comparison with OC– subgroup of patients (p < 0.01). LDL and total cholesterol were associated with EDSS (p = 0.005 and p = 0.043, respectively), and LDL and the triglyceride/high density lipoprotein ratio with MSSS (p = 0.011 and p = 0.048, respectively) in OC+ patients. In OC– subgroup of patients, ApoE levels were associated with EDSS (p = 0.012) and MSSS (p = 0.031). No significant interactions between the lipid variables or OC use and RR were observed.Conclusions: Serum lipid profile is associated with protective effects of OC use on disability of RRMS patients. Lipoprotein metabolism may be involved in the modulatory effects of sex steroids on the severity of the disease.

Apolipoprotein E Polymorphism and Oxidative Stress in Peripheral Blood-Derived Macrophage-Mediated Amyloid-Beta Phagocytosis in Alzheimer's Disease Patients.

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aβ phagocytosis needs to be analyzed. Aβ phagocytosis assay has been performed using FITC-labeled Aβ and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aβ by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aβ-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.

Association between selected cholesterol-related gene polymorphisms and Alzheimer's disease in a Turkish cohort.

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer's disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257AD patients (mean age: 75.9years ± 10.4) and 414 controls (mean age: 62.2years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the 'TT' genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p < 0.001) and individuals carrying the CH25H 'T' allele had an increased risk for AD (OR 3.07, 95% CI 2.13-4.44, p = 2.20e-09) independently from age, gender and APOE ε4 allele. Moreover, this risk was excessively increased (OR 14.04, 95% CI 6.99-28.23, p = 9.78e-14) in the presence of APOE ε4 allele. The 'ins/ins' genotype of APOC1 rs11568822 was significantly more frequent in the AD group compared to controls (p = 1.95e-08). However, this increased AD risk in 'ins/ins' carriers was found to be dependent on their APOE ε4 carrier status. No significant associations were found in allele and genotype distributions of APOA5, APOD, LDLR and SORL1 gene polymorphisms. Our results suggest that the association between APOC1 'ins/ins' genotype and AD risk can be explained by linkage disequilibrium with the APOE locus. CH25H rs13500 polymorphism is associated with an AD risk in the Turkish population and CH25H might have a role in the pathogenesis of AD together with, and independently from APOE.

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan.

The central nervous system (CNS) is the cellular substrate for the integration of complex, dynamic, constant, and simultaneous interactions among endogenous and exogenous stimuli across the entire human lifespan. Numerous studies on aging-related brain diseases show that some genes identified as risk factors for some of the most common neurodegenerative diseases - such as the allele 4 of APOE gene (APOE4) for Alzheimer’s disease (AD) - have a much earlier neuro-anatomical and neuro-physiological impact. The impact of APOE polymorphism appears in fact to start as early as youth and early-adult life. Intriguingly, though, those same genes associated with aging-related brain diseases seem to influence different aspects of the brain functioning much earlier actually, that is, even from the neonatal periods and earlier. The APOE4, an allele classically associated with later-life neurodegenerative disorders as AD, seems in fact to exert a series of very early effects on phenomena of neuroplasticity and synaptogenesis that begin from the earliest periods of life such as the fetal ones.We reviewed some of the findings supporting the hypothesis that APOE polymorphism is an early modifier of various neurobiological aspects across the entire human lifespan - from the in-utero to the centenarian life - during both normal and pathological conditions of the brain.

The effect of apolipoprotein E polymorphism on serum metabolome \u2013 a population-based 10-year follow-up study

Apolipoprotein E (apoE) is the key regulator of plasma lipids, mediating altered functionalities in lipoprotein metabolism – affecting the risk of coronary artery (CAD) and Alzheimer’s diseases, as well as longevity. Searching pathways influenced by apoE prior to adverse manifestations, we utilized a metabolome dataset of 228 nuclear-magnetic-resonance-measured serum parameters with a 10-year follow-up from the population-based Young Finns Study cohort of 2,234 apoE-genotyped (rs7412, rs429358) adults, aged 24–39 at baseline. At the end of our follow-up, by limiting FDR-corrected p < 0.05, regression analyses revealed 180/228 apoE-polymorphism-related associations with the studied metabolites, in all subjects – without indications of apoE x sex interactions. Across all measured apoE- and apoB-containing lipoproteins, ε4 allele had consistently atherogenic and ε2 protective effect on particle concentrations of free/esterified cholesterol, triglycerides, phospholipids and total lipids. As novel findings, ε4 associated with glycoprotein acetyls, LDL-diameter and isoleucine – all reported biomarkers of CAD-risk, inflammation, diabetes and total mortality. ApoE-subgroup differences persisted through our 10-year follow-up, although some variation of individual metabolite levels was noticed. In conclusion, apoE polymorphism associate with a complex metabolic change, including aberrations in multiple novel biomarkers related to elevated cardiometabolic and all-cause mortality risk, extending our understanding about the role of apoE in health and disease.

The association between the SLCO1B1, apolipoprotein E, and CYP2C9 genes and lipid response to fluvastatin: a meta-analysis.

The aim of this study was to determine the impact of the SLCO1B1, apolipoprotein E (ApoE), and CYP2C9 genotypes on the lipid-lowering efficacy of fluvastatin. We performed electronic searches on the PubMed, Embase, and Cochrane Library databases to identify studies published through October 2017. Studies that reported the effect estimates with 95% confidence intervals (CIs) of total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein were included so that the different genotype categories could be compared. Weighted mean difference (WMD) was used to summarize the effect estimates. Six studies, involving a total of 1171 individuals, were included in the final analysis. We noted that the patient carrier SLCO1B1 521TT was associated with greater change in TC (WMD: -2.98; 95% CI: -5.12 to -0.84; P=0.006) and LDL (WMD: -5.58; 95% CI: -10.64 to -0.52; P=0.031) compared with 521TC or CC. Furthermore, the patient carrier ApoE*2/*3 showed more change in high-density lipoprotein compared with ApoE*3/*3 (WMD: 18.76; 95% CI: 8.97-28.55; P<0.001) and ApoE*3/*4 or *4/*4 (WMD: 22.51; 95% CI: 0.98-44.04; P=0.040). Finally, the CYP2C9 genotypes showed no correlation with the effects of fluvastatin on TC, triglyceride, and LDL. The findings of this study suggested that the SLCO1B1 and ApoE polymorphisms could influence the lipid-lowering effect of fluvastatin, whereas the CYP2C9 genotypes were not associated with the therapeutic effects of fluvastatin.

Association study between DNA methylation and genetic variation of APOE gene with the risk of coronary artery disease.

Coronary artery disease (CAD) is a common health problem with a high rate of disability and death. Dyslipidemia and altered metabolism of Apo-lipoproteins are involved in the CAD pathogenesis. The current study investigated two common polymorphisms (rs429358 and rs7412) and promoter DNA methylation status of APOE in the Iranian CAD patients and control subjects. Two hundred angiographically documented CAD patients and 200 control subjects were included in the study. The APOE polymorphism analysis was done by PCR-RFLP technique and DNA methylation status was evaluated by methylation specific PCR. The assay of lipid levels was conducted using standard colorimetric protocols. Results indicated that the frequency of ε3/ε4 and ε2/ε3 genotypes was significantly more common in CAD group compared with control group. Relative to wild type genotype (ε3/ε3), CAD patients with ε3/ε4 and ε2/ε3 genotypes displayed significantly higher concentration of total-cholesterol and LDL-cholesterol. The frequency of DNA methylation of APOE was similar between the two studied groups. However, the methylation frequency of APOE gene was significantly higher in triple stenotic vessels relative to single stenotic vessels (P=0.032). In conclusion The present study indicated that the rs429358 and rs7412 polymorphisms are significantly risk factors for development and severity of CAD. Also, APOE methylation status may be involved in the severity but not in the development of CAD.

Association analysis of ApoE gene polymorphisms among Egyptian patients with Alzheimer's disease

BackgroundAlzheimer disease (AD) is one of the leading causes of dementia among elderly. It is a progressive brain disorder associated with unusual behaviors, personality changes, and irreversible decline in thinking ability. Epsilon 4 allele of apolipoprotein E (ApoE) is considered as a major risk factor for AD in several populations. AimWe investigated APOE polymorphisms in a group of Egyptian patients with Alzheimer's disease. Subjects and methodsWe analyzed APOE polymorphisms in 53 Alzheimer patients who were 60 years or older and the study included a control group of 100 individuals. For APOE genotyping, we used conventional PCRs followed by Restriction Fragment Length Polymorphism (RFLP) analysis. Additionally, we performed Real time PCR analysis to confirm the results of RFLP and apply a more accurate method that is fast, simple, and cost-effective. ResultsWe observed that E4 allele was associated with 28.3% of Alzheimer patients as E3/E4 genotype (22.6%) and E4/E4 (17.0%), while we detected it in only 4% of the control group as E3/E4 genotype (8%). E3 allele has been shown in 69.8% of Alzheimer patients and in 93.5% of the control subjects. We have detected E2 allele in 18.9% of the cases and in 25% of the control group. RT-PCR analysis showed the exact patterns of genotype as determined by RFLP. ConclusionThere is a significant association between ApoE4 isomer and Alzheimer dementia in the Egyptian patients.We recommend conducting further studies to screen larger number of patients and confirm that ApoE4 could be considered as a reliable molecular marker for late onset Alzheimer disease (LOAD) among Egyptian elderly.

Role of rs670 variant of APOA1 gene on metabolic response after a high fat vs. a low fat hypocaloric diets in obese human subjects

Background & aimsA common G-to-A transition located 75 base pairs upstream (rs670) from transcription start site of the APOA1 gene has been related with some metabolic parameters. Our aim was to analyze the effects of rs670 APOA1 gene polymorphism on lipid profile and metabolic changes after two different hypocaloric diets. Methods282 obese subjects were randomly allocated during 12 weeks (Diet HF – high fat diet vs. Diet LF – low fat diet). Anthropometric and biochemical status were evaluated. ResultsBody mass index, weight, fat mass, waist circumference, systolic blood pressure, leptin levels and waist circumference decreased in all patients in average after both diets. In A allele carriers after 12 weeks with both diets, insulin levels (Delta diet HF: −5.3 + 1.2 UI/L; P = 0.02 and Delta diet LF: −5.8 + 1.3 UI/L; P = 0.02) and HOMA-IR (Delta diet HF: −2.9 + 0.8 units; P = 0.01 and Delta diet LF: −2.2 + 0.9 units; P = 0.03) improved in a significant way. With the low fat diet, A allele carriers showed a statistical improvement in HDL-cholesterol levels (Delta: 4 + 1 mg/dl; P = 0.03). ConclusionsOur study showed the association of rs670 ApoA1 polymorphism with a decrease of insulin resistance induced by both diets and provided additional evidence on HDL-cholesterol increase after a LF hypocaloric diet in A allele carriers.

Association of APOA5 and APOC3 Genetic Polymorphisms With Severity of Hypertriglyceridemia in Patients With Cutaneous T-Cell Lymphoma Treated With Bexarotene

Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

Prevalence of candidate single nucleotide polymorphisms on p53, IL-11, IL-10, VEGF and APOE in patients with repeated implantation failure (RIF) and pregnancy loss (RPL)

Recurrent pregnancy loss (RPL; defined as the loss of three or more consecutive pregnancies) and recurrent implantation failure (RIF; when implantation is not achieved after at least three cycles of IVF) are two of the major challenges that reproductive medicine faces. Some polymorphisms have been identified as possible causes of an increased risk of these diseases. This paper studies the prevalence of the polymorphisms in p53, VEGF, IL-10, IL-11 and APOE in RIF and RPL patients that determines the risk for these pathologies. A total of 255 patients were selected (89 RPL patients, 77 RIF patients and 89 controls) and genotyped for p53-R72P; IL-11-1082-AG; VEGF-1154-AG; IL-10; APOE-R112C; APOE-R158C. Statistically significant differences were found in the prevalence of the E4 isoform (R122-R158) of the APOE gene in RPL patients (p < 0.05), and in RIF patients, the R72P polymorphism of the p53 gene and the 1154-AG of the VEGF gene showed different distribution (p < 0.05). Regarding the p53 and IL-11 studied polymorphisms, PP of p53 gene and GG of IL-11 are more prevalent in RPL patients without reaching statistical significance. In conclusion, our results suggest patients carrying variants in p53 and VEGF would be at risk of RIF, and those carrying variants in APOE gene would suffer RPL.