scholarly journals Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 353
Author(s):  
Jesús Martín-Campos ◽  
Sheila Ruiz-Nogales ◽  
Daiana Ibarretxe ◽  
Emilio Ortega ◽  
Elisabet Sánchez-Pujol ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Characteristic Curve ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Single Nucleotide ◽  
Specificity And Sensitivity ◽  
Diagnostic Sensitivity And Specificity ◽  
And Control ◽  
Pathological Variant

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.

scholarly journals Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy

2021 ◽  
Author(s):  
Naoto Kuyama ◽  
Yu Kataoka ◽  
Misa Takegami ◽  
Kunihiro Nishimura ◽  
Mariko Harada‐Shiba ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Characteristic Curve ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Area Under The Curve ◽  
Density Lipoprotein ◽  
Multivariable Logistic Regression Analysis ◽  
Percent Reduction ◽  
Artery Disease ◽  
Study Participants

Background Statin‐mediated efficacy of lowering low‐density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine‐protease associated with LDL metabolism, which circulates as mature and furin‐cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin‐naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10‐ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [ P =0.03]), whereas furin‐cleaved level was not (per 10‐ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [ P =0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications

2019 ◽  
Vol 15 (3) ◽  
pp. 213-223 ◽  
Author(s):  
Rabia Nabi ◽  
Sahir Sultan Alvi ◽  
Mohd. Saeed ◽  
Saheem Ahmad ◽  
Mohammad Salman Khan
Keyword(s):  
Oxidized Ldl ◽  
Advanced Glycation Endproducts ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Therapeutic Effects ◽  
Hmg Coa Reductase ◽  
Toxicological Effects ◽  
Coa Reductase

Introduction: Diabetes Mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced Advanced Glycation Endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized Low-Density Lipoprotein (LDL) possessing greater atherogenicity and decreased the ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. Objective: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco-oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL-R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. Conclusion: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications.

scholarly journals Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

1986 ◽  
Vol 234 (1) ◽  
pp. 245-248 ◽  
Author(s):  
W Jessup ◽  
G Jurgens ◽  
J Lang ◽  
H Esterbauer ◽  
R T Dean
Keyword(s):  
Apolipoprotein B ◽  
Negative Charge ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Peroxidation Product ◽  
Modified Low Density Lipoproteins ◽  
Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

scholarly journals AB0644 EVALUATION OF MONOCYTE TO HIGH-DENSITY LIPOPROTEIN RATIO AND CAROTID INTIMA MEDIA THICKNESS IN GOUT PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1355.1-1355
Author(s):  
C. Kadiyoran ◽  
A. Kucuk ◽  
H. Aydemir ◽  
A. U. Uslu
Keyword(s):  
High Density Lipoprotein ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Density Lipoprotein ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Curve Analysis ◽  
High Density ◽  
Media Thickness ◽  
Operating Characteristic Curve

Background:The aim of this study is to investigate, evaluation of monocyte to high density liporotein ratio and carotid intima media thickness in gout patients.Objectives:Gout disease is an autoinflammatory disease caused by the accumulation of monosodium urate crystals (MSU) in tissues and organs due to hyperuricemia (1). It is a common cause of arthritis due to the changes in lifestyle and eating habits. The effects of the inflammatory process and hyperuricemia in gout are not limited to the joints, but are associated with increased atherosclerosis and cardiovascular disease (1,2) Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a systemic inflammatory marker and has recently been used quite widely for the evaluation of inflammation in cardiovascular disorders (3,4).Methods:Fourty eight patients who were evaluated in the rheumatology clinic with an arthritis attack and diagnosed with Gout, and 48 healthy individuals whose age, gender and body mass index were matched were included in our study. Basic laboratory and biochemical parameters of the period when gout patients were asymptomatic were examined. Carotid intima-media thickness (CIMT), which is a non-invasive procedure due to its widespread use, was used as a marker.Results:MHR and CIMT values were 18.22 ± 9.01 and 0.76 ± 0.11 mm in patients with gout. In the control group, it was 13.62 ± 4.48 and 0.65 ± 0.13 (p = 0.002, p <0.0001, respectively). When evaluated within the study group, it was found that there was a positive correlation between MHR and CIMT (r = 0.253, p = 0.013), and according to linear regression analysis, there was an independent relationship between MHR and CIMT (beta [β] = 0.293, p = 0.049). When assessing Gout patients in the study population, a cutoff value of 13.85 with sensitivity of 66 %, specificity of 53 %, and p = 0.011 (area under curve: 0.650, 95% confidence interval 0.540-0.760), was observed according to receiver-operating characteristic curve analysis (Figure 1).Figure 1.Receiver-operating characteristic curve analysis.Conclusion:This study showed us that MHR can be an inexpensive and easily accessible marker that can be used in the evaluation of atherosclerotic lesions. We think that studies with larger number of patients are needed on this subject.References:[1]Çukurova S, Pamuk ON, Unlu Ercument, Pamuk GE, Cakir NE. Subclinical atherosclerosis in gouty arthritis patients: a comparative study. Rheumatol Int. 2012 Jun; 3 2(6): 1769-73.[2]Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007 Aug 21; 116 (8): 894-900.[3]McAdams-DeMarco MA, Maynard JW, Coresh J, Baer AN.Anemia and the onset of gout in a population-based cohort of adults: Atherosclerosis Risk in Communities study. Arthritis Res Ther. 2012 Aug 20; 14(4): R193.[4]Enhos A, Cosansu K, Huyut MA, Turna F, Karacop E, Bakshaliyev N, Nadir A, Ozdemir R, Uluganyan M. Assessment of the Relationship between Monocyte to High-Density Lipoprotein Ratio and Myocardial Bridge. Arq Bras Cardiol. 2019 Jan;112(1):12-17.Disclosure of Interests:None declared.

scholarly journals Particles and corrected particles of LDL and non-HDL are stronger predicters of coronary lesion in postmenopausal women

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chuang Li ◽  
Jingxun Chen ◽  
Siyue Wei ◽  
Mei Zhang ◽  
Yushun Chu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Postmenopausal Women ◽  
Apolipoprotein B ◽  
Operating Characteristic ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Spearman Correlation ◽  
Coronary Lesion

Abstract Background The optimum lipid indexes, predicting the coronary lesion in postmenopausal women are not clear. Objective To evaluate the optimum lipid predicter for coronary lesion in routine and advanced lipid tests. Method 300 postmenopausal women were enrolled and assigned into coronary heart disease (CHD) Group (242), and non-CHD Group (58). Routine and advanced lipid indexes were measured with standard laboratory test and nuclear magnetic resonance (NMR) spectroscopy. The correlation and predictivities for CHD of routine and advanced lipid indexes were performed with Logistic regression, Spearman correlation analysis and receiver operating characteristic (ROC). Results Age (hazard ratio (HR) 2.58, 95% confidence interval (CI) 1.08–5.86, P = 0.03), apolipoprotein B (ApoB) (HR 1.35, 95% CI 1.15–1.59, P < 0.001), corrected particles of low-density lipoprotein (LDL-p-corr) (HR 1.05, 95% CI 1.03–1.06, P < 0.001) and corrected particles of non-high-density lipoprotein (non-HDL-p-corr) (HR 1.02, 95% CI 1.01–1.03, P < 0.001) were the risk factors of CHD. LDL cholesterol (LDL-C), LDL-p, LDL-p-corr, HDL cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), non-HDL-p and non-HDL-p-corr were in linear correlation with Gensini score. Advanced lipid indexes LDL-p (area under curve (AUC) = 0.750, P = 0.02), LDL-p-corr (AUC = 0.759, P = 0.02), non-HDL-p (AUC = 0.693, P = 0.03) and non-HDL-p-corr (AUC = 0.699, P = 0.03) were more predictive for CHD than the routine ones (LDL-C and non-HDL-C). Conclusion In postmenopausal women, age, ApoB, LDL-p-corr and non-HDL-p-corr were risk factors of CHD. Compared with traditional lipid items, LDL-p, LDL-p-corr, non-HDL-p and non-HDL-p-corr may be better lipid indexes for CHD in postmenopausal women.

scholarly journals Detection of the low-density-lipoprotein receptor with biotin-low-density lipoprotein. A rapid new method for ligand blotting

1985 ◽  
Vol 229 (3) ◽  
pp. 785-790 ◽  
Author(s):  
D P Wade ◽  
B L Knight ◽  
A K Soutar
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
High Sensitivity ◽  
Receptor Protein ◽  
Low Density ◽  
Very Low Density Lipoproteins ◽  
Cell Extracts ◽  
Density Lipoprotein Receptor ◽  
A New Technique

A new technique has been developed to identify low-density-lipoprotein (LDL) receptors on nitrocellulose membranes, after transfer from SDS/polyacrylamide gels, by ligand blotting with biotin-modified LDL. Modification with biotin hydrazide of periodate-oxidized lipoprotein sugar residues does not affect the ability of the lipoprotein to bind to the LDL receptor. Bound lipoprotein is detected with high sensitivity by a streptavidin-biotin-peroxidase complex, and thus this method eliminates the need for specific antibodies directed against the ligand. The density of the bands obtained is proportional to the amount of pure LDL receptor protein applied to the SDS/polyacrylamide gel, so that it is possible to quantify LDL receptor protein in cell extracts. Biotin can be attached to other lipoproteins, for example very-low-density lipoproteins with beta-mobility, and thus the method will be useful in the identification and isolation of other lipoprotein receptors.

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