apoA-I Concentrations Research Articles

The state of lipid exchange in persons living in the territory of environmental illusion

Introduction. Currently, it is important to consider the issues of diagnosing nonspecific disorders occurred due to exposure of residents to chemicals in cities with chemical industry enterprises on the territory.
 Materials and methods. Working 30–60 year men, permanently residing downwind from the industrial site of LLC “Usolekhimprom” in the territory exposed to mercury in the city of Usolye-Sibirskoye, were examined.
 Results. The maximum concentration of total cholesterol (TCH) was 8.7 mmol/L, cholesterol (CH) of low density lipoproteins (LDL) – 6.0 mmol/L, triglycerides (TG) – 2.3 mmol/L, phospholipids – 5.5 mmol/L. The minimum content of high-density lipoprotein cholesterol (HDL cholesterol) was 0.5 mmol/L. In terms of the prevalence of disorders, hypercholesterolemia held the first place – 63% of cases, the second – a high level of LDL cholesterol – 59%, the third – an increase in ApoB – 45%. Hyperphospholipidemia occurred in 35%, hypertriglyceridemia – in 23%. Reduced HDL cholesterol was recorded in 5.3%. Low concentration of Apo A1 was registered in 20% of cases. A high level of atherogenic index was common among 16%. The prevalence of high LDL-CH was consistent with that of hypercholesterolemia, as evidenced by the correlation coefficient between the indices (R=0.77) and between the level of TCH and Apo B (R=0.80). A HDL cholesterol high level does not always indicate the antiatherogenic ability of lipoproteins, and therefore the revealed low prevalence of hypoalphacholesterolemia in the examined individuals (lower than in Russia - 16%) does not indicate antiatherogenic changes. The triglyceridemia level was associated with the ApoB concentration, which indicates its contribution to the development of proatherogenic disorders. A possible mechanism of hyperphospholipidemia is the formation of a compensatory-adaptive stimulus to the phospholipids synthesis in response to hypercholesterolemia and hypertriglyceridemia.
 Limitations. Male persons. Age 30–60 years.
 Conclusion. In persons living in the ecological trouble zone, a high frequency of lipid metabolism disorders was revealed. This fact can be considered as one of the main predisposing factors for the development of cardiovascular diseases in this cohort.

Microarray analysis identifies human apoA-IMilano and apoA-II as determinants of the liver gene expression related to lipid and energy metabolism

The phenotype of individuals carrying the apolipoprotein A-IMilano (apoA-IM), the mutant form of human apoA-I (apoA-I), is characterized by very low concentrations of HDL and apoA-I, and hypertriglyceridemia. Paradoxically, these subjects are not found to be at increased risk of premature cardiovascular disease compared to controls. Besides, various in vitro and in vivo studies have demonstrated that apoA-IM possesses greater anti-atherosclerotic activity compared to apoA-I. The molecular mechanisms explaining the apoA-IM carrier's phenotype and the apoA-IM higher efficacy are still not fully elucidated. To investigate such mechanisms, we crossed previously generated apoA-I (A-I k-in) or apoA-IM knock-in mice (A-IM k-in) with transgenic mice expressing human apoA-II but lacking murine apoA-I (hA-II) to generate hA-II/A-I k-in, and hA-II/A-IM k-in, respectively. These genetically modified mice completely reproduced the apoA-IM carrier's phenotype, including hypoalphalipoproteinemia and hypertriglyceridemia. Furthermore, by using the microarray methodology, we investigated the intrinsic differences in hepatic gene expression among these k-in mouse lines. The expression of 871, 1,018, 1129 and 764 genes was significantly altered between 1) hA-II/A-I and hA-II/A-IM k-in; 2) A-IM and hA-II/A-IM k-in; 3) A-I and A-IM; 4) A-I and hA-II/A-I k-in liver samples, respectively. Bioinformatics analysis highlighted that the hepatic expression of two genes, Elovl6 and Gatm, related to fatty acid/lipid and energy metabolism, respectively, is influenced by the presence of the apoA-IM natural variant and/or apoA-II.

Apolipoprotein A1 Inhibits Adipogenesis Progression of Human Adipose-Derived Mesenchymal Stem Cells.

According to the reports, the most vital characteristic of obesity is an aberrant accumulation of triglycerides (TG) in the adipocyte. On the other hand, circulating concentrations of apolipoprotein A1 (apoA1) have been demonstrated to be strongly correlated with the prevalence and the pathological development of obesity. Nevertheless, the underlying mechanisms whereby apoA1 modulates the pathogenesis of obesity is still not fully elucidated. Adipose-derived mesenchymal stem cells (AMSCs, isolated from the hospitalized patients were combined with 15 μg/ml recombined human apoA1 protein. The effects of apoA1 on modulating the intracellular levels of TG and the expression contents of adipogenic related cytokines were also analyzed. Furthermore, whether apoA1 modulated the adipogenesis progression via sortilin was also explored in the current research. During the adipogenesis progression, apoA1 could significantly lower the quantity of intracellular lipid droplets (LDs). Meanwhile, apoA1 could decrease the intracellular levels of TG and down-regulate the expression contents of several vital adipogenic related cytokines, such as CCAAT enhancer-binding proteins α/β (C/EBPα/β), fatty acid synthetase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, the inhibitory effect of apoA1 was further verified to be induced through upregulating the SORT1 gene expression which subsequently increased sortilin protein. Consistent with these findings, silencing the SORT1 gene expression could induce the loss-of-function (LOF) of apoA1 in modulating the adipogenesis progression of AMSCs. In conclusion, apoA1 could suppress the adipogenesis progression of human AMSCs through, at least partly, up-regulating the SORT1 gene expression which subsequently increases the sortilin protein content. Thereby, the present research sheds light on a novel pathogenic mechanism by which apoA1 regulates adipogenesis progression and proposes that apoA1 embraces the function to treat obesity in clinical practice.

ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio as candidate pre-treatment biomarkers of pathomorphological response to neoadjuvant therapy in gastric and esophago-gastric junction adenocarcinoma.

<b><br>Introduction:</b> Neoadjuvant chemotherapy (NAC) is a part of the current standard of care in a locally advanced gastric adenocarcinoma (GA) and esophagogastric junction adenocarcinoma (EGJA), but only patients with good pathomorphological response (pR) to NAC benefit from prolonged overall survival.</br> <b><br>Aim:</b> The study aims to evaluate ApoA-I and ApoB as candidate pre-treatment biomarkers of pR to NAC in patients with GA and EGJA.</br> <b><br>Materials and methods:</b> Serum samples were collected from 18 patients with GA and 9 with EGJA before the initiation of NAC to determine the ApoA-I and ApoB levels. After NAC tumor regression grade (TRG) was evaluated in resected specimens according to the Mandard's tumor regression grading system and correlated with pre-treatment ApoA-I and ApoB serum concentration, and ApoB-to-ApoA-I serum concentration ratio.</br> <b><br>Results:</b> We found a positive correlation of ApoA-I level and pR (95% CI: -0.863 to -0.467; P < 0.0001), a negative correlation of ApoB level and pR (95% CI: 0.445 to 0.857; P < 0.0001), a negative correlation of ApoB-to-ApoA-I ratio and pR (95% CI: 0.835 to 0.964; P < 0.0001).</br> <b><br>Conclusions:</b> ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio are candidate pre-treatment predictors of pR to NAC in GA and may help to guide personalized therapy.</br>Our work fits into the dynamically developing trend of personalized treatment. It describes a potentially important rationale for further evaluation of apolipoprotein A-I and apolipoprotein B as predictors of cancer response to neoadjuvant therapy.

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.

Type IIx muscle fibers are related to poor body composition, glycemic and lipidemic blood profiles in young females: the protective role of type I and IIa muscle fibers.

The aim of the present study was to investigate the association between muscle fiber composition, body composition, resting glycemic-lipidemic blood profiles, in apparently healthy, young, active females. Thirty-four young healthy female volunteers were allocated into two groups, depending on their Vastus Lateralis type IIx muscle fibers percent cross-sectional area (%CSA; H: high type IIx %CSA; L: low type IIx %CSA). Body composition was determined via dual-energy X-ray absorptiometry. Venous blood samples were collected for the determination of resting serum glucose, Insulin, Apo-A1, HOMA-IR, triglycerides (TG), total cholesterol (TC), High-density lipoprotein (HDL-C), and Low-density lipoprotein (LDL-C) concentrations. Nutritional intake was also evaluated. Individuals of the H group have significantly higher body mass, body fat percentage-mass, and resting blood indices of glycemic and lipidemic profiles, compared to those of L group (p < 0.001). Increased type IIx and low type I, IIa muscle fibers %CSAs were linked with poorer body composition, glycemic and lipidemic blood profiles (r: - 0.722 to 0.740, p < 0.001). Linear regression analyses revealed that the impact of muscle fibers %CSA (B coefficients ranged between - 0.700 and 0.835) on the above parameters, was at least, of the same or even of greater magnitude as that of body composition and daily nutritional intake (B: - 0.700 to 0.666). Increased type IIx and low Type I, IIa %CSAs are associated with poorer body composition and glycemic-lipidemic profiles in young healthy females. The contribution of the muscle fiber %CSA on health status seems to be comparable to that of nutrition and body composition.

Low-grade inflammation is associated with a heterogeneous lipoprotein subclass profile in an apparently healthy population sample

Background and aimsPrevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters.MethodsWe utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models.ResultsAPRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile.ConclusionOur findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.

Associations of Serum Apolipoprotein A1 and High Density Lipoprotein Cholesterol With Glucose Level in Patients With Coronary Artery Disease.

This study determined the associations of apolipoprotein A1 (ApoA1), high-density lipoprotein cholesterol (HDL-C), and HDL-C/ApoA1 ratio with fasting blood glucose (FBG) and evaluated the mediating effects of high-sensitivity C-reactive protein (hsCRP) and body mass index (BMI). A cross-sectional study with 4805 coronary artery disease (CAD) patients was performed. In multivariable analyses, higher ApoA1, HDL-C, and HDL-C/ApoA1 ratio were associated with significantly lower FBG level (Q [quartile] 4 vs Q1: 5.67 vs 5.87mmol/L for ApoA1; 5.64 vs 5.98mmol/L for HDL-C; 5.63 vs 6.01mmol/L for HDL-C/ApoA1 ratio). Moreover, inverse associations of ApoA1, HDL-C, and HDL-C/ApoA1 ratio with abnormal FBG (AFBG) were found with odd ratios (95% confidence interval) of .83 (.70-.98), .60 (.50-.71), and .53 (.45-.64) in Q4 compared with Q1. Path analyses indicated that "ApoA1 (or HDL-C)-FBG" associations were mediated by hsCRP and "HDL-C-FBG" association was mediated by BMI. Our data suggested that higher ApoA1, HDL-C, and HDL-C/ApoA1 ratio were favorably associated with a lower FBG level in CAD patients and these associations might be mediated by hsCRP or BMI. Collectively, higher concentrations of ApoA1, HDL-C, and HDL-C/ApoA1 ratio might decrease the risk of AFBG.

408-P: Associations between Apolipoprotein B (apoB): Apolipoprotein A1 (apoA1) Ratio and Metabolic and Kidney Disease in Youth with Type 1 Diabetes

ApoA1 is a major protein component of high-density lipoprotein (HDL) and apoB the main protein component of low-density lipoprotein (LDL). The ratio between apoB and apoA1 (ApoB:ApoA1) is often used to measure cardiovascular disease (CVD) risk in adults, yet little is known about its relationship with insulin resistance, central adiposity and early kidney disease, important CVD risk factors, in youth with T1D. In a study of 50 youth with type 1 diabetes, glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed using iohexol and p-aminohippurate clearance, and urine albumin-to-creatinine ratio (UACR) was also measured. Central adiposity was assessed using DXA and insulin sensitivity was estimated (eIS). Intraglomerular pressure was estimated using the Gomez equations. The study participants were 16±3.0 years old, 50% were female, and their average HbA1c was 8.7±1.3%. They had an average T1D duration of 5.7±2.6 years, with UACR levels of 6[5-14] mg/g and GFR of 189±40 ml/min. Concentrations of apoA1 and apoB were quantified by targeted nuclear magnetic resonance spectroscopy. ApoA1 (185±35 vs. 150±36 mg/dl, p=0.001) and apoB (108±29 vs. 90±27 mg/dl, p=0.03) were higher in girls vs. boys, but the apoB:apoA1 ratio was similar between the sexes (p=0.59). ApoB correlated with PGLO (r: 0.42, p=0.01), log UACR (r: 0.33, p=0.02), and trunk mass (r: 0.34, p=0.02), whereas ApoB:ApoA1 correlated with GFR (r: 0.44, p=0.002), PGLO (r: 0.48, p=0.01), log UACR (r: 0.38, p=0.008), trunk mass (r: 0.45, p=0.001), BMI (r: 0.40, p=0.004) and inversely with eIS (-0.44, p=0.001). The ratio of apoB to apoA1 associated with markers of metabolic and kidney disease in youth with T1D. Further research is needed to fully understand the mechanisms behind these associations and to identify potential strategies for preventing or mitigating cardiovascular disease in young persons with T1D. Disclosure L.Remmers: None. C.Birznieks: None. D.Carrasco: None. S.Gross: None. J.K.Snell-bergeon: None. L.A.Hall: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. K.L.Tommerdahl: None.

#5795 THE APOPROTEIN E (APOE) POLYMORPHISM AND PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9) IN HEMODIALYSIS (HD) PATIENTS

Abstract Background and Aims The apoE polymorphism and PCSK9 play an important role in lipid metabolism in healthy subjects, however, its role in HD patients remains unclear. We investigated the apoE polymorphism and PCSK9 as well as a lipid profile to clarify the impact of these factors on prognosis in HD patients. We also examined the association of cardiovascular (CVD) events in dead HD patients and clinical features. Method HD patients (n = 296, m/f; 207/89, DM; 152, age; 69.8±12.1, HD duration; 68.7±72.0 months) were subjected to this study. Written informed consent was obtained from each patient. Of these patients 85 subjects (m/f; 61/24, DM; 54, HD duration; 98.6±53.5 months) died during this study (from June 2011 to December 2022). Blood samples were collected to analyze the apoE genotypes by the invader method, serum concentrations of PCSK9-heterodimers and PCSK9-free fragments were measured using ELISA (BML Co. Ltd., Tokyo, Japan) and serum concentrations of apoA1, apoA2, apoB, apo C2, apoC3 and apoE were estimated using turbidimetric immunoassay. For the death cases we used multivariable logistic regression to control for the potentially confounding roles of type 2 diabetes mellitus (DM), apoE genotypes, and serum concentrations of PCSK9-heterodimers, PCSK9-free segments, apoA1, apoA2, apoB, apo C2, apoC3 and apoE. Survival probabilities in dead HD patients with CVD events according to the apoE genotypes were analyzed using the Kaplan-Meier curves. A p value less than 0.05 was considered statistically significant. Results The spoE allele frequencies in HD patients (n = 296) were ɛ2; 0.044, ɛ3; 0.870 and ɛ4; 0.086, whereas those in Japanese healthy controls were ɛ2; 0.036, ɛ3; 0.848 and ɛ4; 0.116 (Eto M., et al. Clin Genet 30:422-427, 1986.), demonstrating the ɛ2 frequency in HD patients had a trend to be higher than that in Japanese healthy controls (p = 0.096). The serum concentrations of PCSK9-heterodimers and PCSK9-free fragments in female HD patients (n = 89, 227.0±88.0 ng/ml and 41.9±19.1 ng/ml, respectively) were significantly higher than those in male HD patients (n = 207, 195.9±70.3 ng/ml, p = 0.001, and 35.8±15.3 ng/ml, p&amp;lt;0.004, respectively) . The serum concentrations of PCSK9-heterodimers in HD patients with DM (n = 152); 213.8±77.6 ng/ml showed a trend to be higher than those in HD patients without DM (n = 144); 196.3±76.1 ng/ml (p = 0.05). The multivariable logistic regression analysis demonstrated the serum concentration of apoA1 and apoE polymorphism showed statistically significant impact on CVD events in dead HD patients (Table 1). The Kaplan-Meier analysis revealed the apoE polymorphism had a significant impact on the survival probability in dead HD patients with CVD events (Figure 1). Conclusion Recent studies reported the association between apoE2 and renal insufficiency in Japanese type2 DM. ApoE2 may be one of the attributable factors that lead to the end stage kidney disease. PCSK9-heterodimers bind to LDL cholesterol receptors (LDLr) and prevent LDLr from shuttling back to the surface and instead target it for degradation, however, PCSK9-free segments have weaker effects to bind to LDLr. Significance of higher serum concentrations of PCSK9-heterodimers andPCSK9-free fragments in female HD patients than male HD patients depends on future investigation. ApoE2 and the serum concentration of apoA1 contribute to CVD events. The prognosis of the HD patients with apoE2 or apoE4 were poorer than that with apoE3/3. The apoE polymorphism and PCSK9 may be key factors in lipid metabolism as well as prognosis of HD patients.

Metrologically Traceable Quantification of 3 Apolipoprotein E Isoforms in Cerebrospinal Fluid.

APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application. To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results. The assay of each isoform in human CSF was precise (≤11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of Ɛ4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers. Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.

Analysis of genetic variants related to oxidative stress in patients with Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is one of the common neurodegenerative diseases with an incompletely understood pathomechanism. In AD, generation of oxidative stress is observed as a result of dysfunction of the mitochondrial respiratory chain. The effect of this disturbance is the production of reactive oxygen species (ROS). The SOD2 gene is involved in the elimination of ROS. Glutathione S‐transferases (GST) are a group of enzymes with antioxidant properties that protect cells from ROS damage. GSTP1 gene variants may impair the activity of these enzymes. APOE gene, is also related to the regulation of oxidative stress. In AD patients with APOE E4, higher levels of lipid peroxidation are found. The precise nature of the association between oxidative stress and hallmarks of AD pathology is unknown.The aim of the study was to analyze of genetic variants of SOD2 c.47T&gt;C (exon 2) and GSTP1 c.341C&gt;T (exon 6) genes in AD patients, control subjects related to AD cases (CR), and controls subjects without family history of AD (CU). The APOE E4 allele was included in the studies.MethodThe studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The SOD2 and GSTP1 genetic variants were determined by HRM and sequencing. The apoE concentration was determined by the ELISA method.ResultVariant CC c.47T&gt;C SOD2 was more frequent in CR, while CT in CU. The TT variant of this gene tended to occur more frequently in patients with AD. In AD, the TT variant was more common in the subject without E4 allele (p&lt;0.05). The CC and CT variants of the c.341C&gt;T GSTP1 gene occurred with equal frequency in AD and CR. The TT variant of this gene was not found in the examined subjects. Regardless of the genetic variant of APOE, SOD2, GSTP1, a significantly higher level of apoE was found in CR.ConclusionGenes involved in the regulation of oxidative stress may play an important role in the pathogenesis of AD.

Associations of apolipoproteinA1, high density lipoprotein cholesterol with hemoglobin glycation index and triglyceride-glucose index in Chinese adults with coronary artery disease

AimsScarce data explored the associations of apolipoproteins with hemoglobin glycation index (HGI) and triglyceride-glucose (TyG) index. This study determined associations of serum apolipoproteinA1 (ApoA1) and high density lipoprotein cholesterol (HDL-C) with HGI and TyG index in coronary artery disease (CAD) patients. MethodsA total of 10,803 CAD patients were included in this cross-sectional pilot study. Serum concentrations of ApoA1 and HDL-C were measured. Analyses of covariance were used to compare the mean differences in glucose metabolism indices (e.g., HGI, TyG index, hemoglobin glycation [HbA1c], fasting blood glucose [FBG]) among the quartiles of ApoA1, HDL-C and HDL-C/ApoA1 ratio. ResultsIn multivariate analysis, higher ApoA1, HDL-C and HDL-C/ApoA1 ratio were associated with significantly lower HGI (Quartile [Q]4 vs. Q1: −0.032 % vs. 0.017 % for ApoA1; −0.072 % vs. 0.079 % for HDL-C; −0.083 % vs. 0.085 % for HDL-C/ApoA1 ratio). Intermediate ApoA1 level was inversely associated with TyG index (Q2 vs. Q1: 296.278 vs. 306.794). The mean TyG index were significantly decreased with increased HDL-C and HDL-C/ApoA1 ratio (Q4 vs. Q1: 298.584 vs. 309.221 for HDL-C; 300.405 vs. 315.218 for HDL-C/ApoA1 ratio). Moreover, the inverse associations of ApoA1, HDL-C and HDL-C/ApoA1 ratio with HbA1c and FBG also were observed. In path analysis, the associations of HDL-C and HDL-C/ApoA1 ratio with TyG index were mediated by obesity. ConclusionThis study provided further support for the hypoglycemic effects of ApoA1 and HDL-C in patients with CAD. Replication of these findings is warranted in further longitudinal studies in different populations.

A Machine Learning Model to Aid Detection of Familial Hypercholesterolemia

BackgroundPeople with monogenic familial hypercholesterolemia (FH) are at an increased risk of premature coronary heart disease and death. With a prevalence of 1:250, FH is relatively common; but currently there is no population screening strategy in place and most carriers are identified late in life, delaying timely and cost-effective interventions. ObjectivesThe purpose of this study was to derive an algorithm to identify people with suspected monogenic FH for subsequent confirmatory genomic testing and cascade screening. MethodsA least absolute shrinkage and selection operator logistic regression model was used to identify predictors that accurately identified people with FH in 139,779 unrelated participants of the UK Biobank. Candidate predictors included information on medical and family history, anthropometric measures, blood biomarkers, and a low-density lipoprotein cholesterol (LDL-C) polygenic score (PGS). Model derivation and evaluation were performed in independent training and testing data. ResultsA total of 488 FH variant carriers were identified using whole-exome sequencing of the low-density lipoprotein receptor, apolipoprotein B, apolipoprotein E, proprotein convertase subtilisin/kexin type 9 genes. A 14-variable algorithm for FH was derived, with an area under the curve of 0.77 (95% CI: 0.71-0.83), where the top 5 most important variables included triglyceride, LDL-C, apolipoprotein A1 concentrations, self-reported statin use, and LDL-C PGS. Excluding the PGS as a candidate feature resulted in a 9-variable model with a comparable area under the curve: 0.76 (95% CI: 0.71-0.82). Both multivariable models (w/wo the PGS) outperformed screening-prioritization based on LDL-C adjusted for statin use. ConclusionsDetecting individuals with FH can be improved by considering additional predictors. This would reduce the sequencing burden in a 2-stage population screening strategy for FH.

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype

Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues – one in the hinge region and one in the C-terminal region – and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.

Abstract 5456: Application of a multiplex urinalysis test for predicting treatment response in patients with BCG unresponsive bladder cancer: a pilot study

Abstract Introduction and Objective: Recently, we reported that OncuriaTM, a multiplex urinalysis test, could be predictive of BCG treatment response. Furthermore, high-grade BCG unresponsive bladder cancer have limited treatment options. Such patients are offered either radical cystectomy or systemic therapy. One of the systemic therapies include immune-oncology agents, e.g., PD-1 or PD-L1 inhibitors. In this study, we tested the performance of OncuriaTM in a BCG unresponsive cohort to determine if it could predict response to a PDL1 inhibitor. Methods: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 18 subjects who have BCG-unresponsive NMIBC with treatment of atezolizumab monotherapy or atezolizumab BCG combination (provided by Genentech, NCT02792192). The urine samples were collected prior to treatment in both arms. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. Predictive models were previously developed using supervised learning and cross-validation analyses. Model performance was validated using ROC curves. Results: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved sensitivity and specificity of &amp;gt;90%. Conclusion: Previous pilot study found that monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. In this study, we noted the performance of OncuriaTM for the prediction of systemic PDL1 inhibitor treatment response. A limitation of this study includes its small sample size. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients who have not previously responded to intravesical BCG treatment and is considering systemic immune-oncology options. Citation Format: Hideki Furuya, Kaoru Murakami, Ian Pagano, Runpu Chen, Yijun Sun, Nari Kim, Edward E. Kadel, Cheryl V. Wong, Nicole Davarpanah, Charles J. Rosser. Application of a multiplex urinalysis test for predicting treatment response in patients with BCG unresponsive bladder cancer: a pilot study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5456.

PD25-04 APPLICATION OF A MULTIPLEX URINALYSIS TEST FOR PREDICTING TREATMENT RESPONSE IN PATIENTS WITH BCG UNRESPONSIVE BLADDER CANCER: A PILOT STUDY

You have accessJournal of UrologyCME1 Apr 2023PD25-04 APPLICATION OF A MULTIPLEX URINALYSIS TEST FOR PREDICTING TREATMENT RESPONSE IN PATIENTS WITH BCG UNRESPONSIVE BLADDER CANCER: A PILOT STUDY Hideki Furuya, Kaoru Murakami, Ian Pagano, Runpu Chen, Yijun Sun, Nari Kim, Edward Kadel, Cheryl Wong, Nicole Davarpanah, and Charles Rosser Hideki FuruyaHideki Furuya More articles by this author , Kaoru MurakamiKaoru Murakami More articles by this author , Ian PaganoIan Pagano More articles by this author , Runpu ChenRunpu Chen More articles by this author , Yijun SunYijun Sun More articles by this author , Nari KimNari Kim More articles by this author , Edward KadelEdward Kadel More articles by this author , Cheryl WongCheryl Wong More articles by this author , Nicole DavarpanahNicole Davarpanah More articles by this author , and Charles RosserCharles Rosser More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003303.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recently, we reported that OncuriaTM, a multiplex urinalysis test, could be predictive of BCG treatment response. Furthermore, high-grade BCG unresponsive bladder cancer have limited treatment options. Such patients are offered either radical cystectomy or systemic therapy. One of the systemic therapies include immune-oncology agents, e.g., PD-1 or PD-L1 inhibitors. In this study, we tested the performance of OncuriaTM in a BCG unresponsive cohort to determine if it could predict response to a PDL1 inhibitor. METHODS: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 18 subjects who have BCG-unresponsive NMIBC with treatment of atezolizumab monotherapy or atezolizumab BCG combination (provided by Genentech, NCT02792192). The urine samples were collected prior to treatment in both arms. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. Predictive models were previously developed using supervised learning and cross-validation analyses. Model performance was validated using ROC curves. RESULTS: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved sensitivity and specificity of >90%. CONCLUSIONS: Previous pilot study found that monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. In this study, we noted the performance of OncuriaTM for the prediction of systemic PDL1 inhibitor treatment response. A limitation of this study includes its small sample size. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients who have not previously responded to intravesical BCG treatment and is considering systemic immune-oncology options. Source of Funding: NIH/NCI R21CA263230, NIH/NCI R01CA198887 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e730 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hideki Furuya More articles by this author Kaoru Murakami More articles by this author Ian Pagano More articles by this author Runpu Chen More articles by this author Yijun Sun More articles by this author Nari Kim More articles by this author Edward Kadel More articles by this author Cheryl Wong More articles by this author Nicole Davarpanah More articles by this author Charles Rosser More articles by this author Expand All Advertisement PDF downloadLoading ...

NMR derived changes of lipoprotein particle concentrations related to impaired fasting glucose, impaired glucose tolerance, or manifest type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (T2D) and corresponding borderline states, impaired fasting glucose (IFG) and/or glucose tolerance (IGT), are associated with dyslipoproteinemia. It is important to distinguish between factors that cause T2D and that are the direct result of T2D.MethodsThe lipoprotein subclass patterns of blood donors with IFG, IGT, with IFG combined with IGT, and T2D are analyzed by nuclear magnetic resonance (NMR) spectroscopy. The development of lipoprotein patterns with time is investigated by using samples retained for an average period of 6 years. In total 595 blood donors are classified by oral glucose tolerance test (oGTT) and their glycosylated hemoglobin (HbA1c) concentrations. Concentrations of lipoprotein particles of 15 different subclasses are analyzed in the 10,921 NMR spectra recorded under fasting and non-fasting conditions. The subjects are assumed healthy according to the strict regulations for blood donors before performing the oGTT.ResultsUnder fasting conditions manifest T2D exhibits a significant concentration increase of the smallest HDL particles (HDL A) combined with a decrease in all other HDL subclasses. In contrast to other studies reviewed in this paper, a general concentration decrease of all LDL particles is observed that is most prominent for the smallest LDL particles (LDL A). Under normal nutritional conditions a large, significant increase of the concentrations of VLDL and chylomicrons is observed for all groups with IFG and/or IGT and most prominently for manifest T2D. As we show it is possible to obtain an estimate of the concentrations of the apolipoproteins Apo-A1, Apo-B100, and Apo-B48 from the NMR data. In the actual study cohort, under fasting conditions the concentrations of the lipoproteins are not increased significantly in T2D, under non-fasting conditions only Apo-B48 increases significantly.ConclusionIn contrast to other studies, in our cohort of “healthy” blood donors the T2D associated dyslipoproteinemia does not change the total concentrations of the lipoprotein particles produced in the liver under fasting and non-fasting conditions significantly but only their subclass distributions. Compared to the control group, under non-fasting conditions participants with IGT and IFG or T2D show a substantial increase of plasma concentrations of those lipoproteins that are produced in the intestinal tract. The intestinal insulin resistance becomes strongly observable.

A TiO2/Si carrier derived from photovoltaic solid waste to assemble Ag3PO4/Co3(PO4)2/TiO2/Si heterostructure for enhancing visible-light photocatalytic activity

The rapid development of the photovoltaic solar industry has generated a huge amount of retired waste silicon panels. The management and value-added recycling of silicon wafer waste are highly important for both environmental remediation and economic efficiency. In this work, waste solar silicon wafers were ball-milled to obtain silicon powder that was employed to prepare TiO2/Si by hydrothermal synthesis, which then was converted to support Ag3PO4 and Co3(PO4)2 with a co-precipitation method to yield Ag3PO4/Co3(PO4)2/TiO2/Si (APO/CPO/TIO/Si) composite catalyst. The photocatalytic properties of the materials doped with different concentrations of APO or CPO were examined using methyl orange (MO) degradation rate as a performance metric. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), diffuse reflectance spectrometer (DRS), and ultraviolet-visible spectrophotometer (UV–vis) were used to characterize and analyze the morphology, grain size, material phase, and photocatalytic performance of the samples, respectively. Furthermore, the mechanism derived for the APO/CPO/TIO/Si catalyst in the photocatalytic degradation revealed that superoxide radical (•O2-), singlet oxygen (1O2), and hydroxyl radical (•OH) are the major active substances during the photocatalytic process, the enhanced photocatalytic activity contributing to a heterojunction electron transfer pathway. This work provides a promising approach for waste solar panels management as well as a high-performance photocatalyst for environmental decontamination.