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1.
Eur J Clin Invest ; : e14214, 2024 Apr 13.
Article in English | MEDLINE | ID: mdl-38613414

ABSTRACT

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

2.
Eur J Clin Invest ; 54(2): e14101, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37795744

ABSTRACT

BACKGROUND AND AIMS: We aimed to assess the associations of exposure to air pollutants and standard and advanced lipoprotein measures, in a nationwide sample representative of the adult population of Spain. METHODS: We included 4647 adults (>18 years), participants in the national, cross-sectional, population-based di@bet.es study, conducted in 2008-2010. Standard lipid measurements were analysed on an Architect C8000 Analyzer (Abbott Laboratories SA). Lipoprotein analysis was made by an advanced 1 H-NMR lipoprotein test (Liposcale®). Participants were assigned air pollution concentrations for particulate matter <10 µm (PM10 ), <2.5 µm (PM2.5 ) and nitrogen dioxide (NO2 ), corresponding to the health examination year, obtained by modelling combined with measurements taken at air quality stations (CHIMERE chemistry-transport model). RESULTS: In multivariate linear regression models, each IQR increase in PM10 , PM2.5 and NO2 was associated with 3.3%, 3.3% and 3% lower levels of HDL-c and 1.3%, 1.4% and 1.1% lower HDL particle (HDL-p) concentrations (p < .001 for all associations). In multivariate logistic regression, there was a significant association between PM10 , PM2.5 and NO2 concentrations and the odds of presenting low HDL-c (<40 mg/dL), low HDL-p (

Subject(s)
Air Pollutants , Air Pollution , Male , Adult , Humans , Nitrogen Dioxide/analysis , Spain/epidemiology , Cross-Sectional Studies , Air Pollution/adverse effects , Air Pollution/analysis , Air Pollutants/analysis , Particulate Matter/analysis , Lipids , Lipoproteins/analysis , Environmental Exposure/adverse effects
3.
Diabetes Res Clin Pract ; 202: 110772, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37301326

ABSTRACT

AIMS: The aim of this study was to combine nuclear magnetic resonance-based metabolomics and machine learning to find a glucose-independent molecular signature associated with future type 2 diabetes mellitus development in a subgroup of individuals from the Di@bet.es study. METHODS: The study group included 145 individuals developing type 2 diabetes mellitus during the 8-year follow-up, 145 individuals matched by age, sex and BMI who did not develop diabetes during the follow-up but had equal glucose concentrations to those who did and 145 controls matched by age and sex. A metabolomic analysis of serum was performed to obtain the lipoprotein and glycoprotein profiles and 15 low molecular weight metabolites. Several machine learning-based models were trained. RESULTS: Logistic regression performed the best classification between individuals developing type 2 diabetes during the follow-up and glucose-matched individuals. The area under the curve was 0.628, and its 95% confidence interval was 0.510-0.746. Glycoprotein-related variables, creatinine, creatine, small HDL particles and the Johnson-Neyman intervals of the interaction of Glyc A and Glyc B were statistically significant. CONCLUSIONS: The model highlighted a relevant contribution of inflammation (glycosylation pattern and HDL) and muscle (creatinine and creatine) in the development of type 2 diabetes as independent factors of hyperglycemia.


Subject(s)
Diabetes Mellitus, Type 2 , Humans , Glucose/metabolism , Creatinine , Creatine , Magnetic Resonance Spectroscopy , Metabolomics , Inflammation , Muscles/metabolism
4.
Int J Mol Sci ; 24(8)2023 Apr 18.
Article in English | MEDLINE | ID: mdl-37108578

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic alterations such as abnormal insulin and lipid metabolism and have some common genetic factors such as APOE genotype. Taking this into account, we hypothesized that we could identify common genetic factors involved in the development of diabetes and cardiovascular diseases. METHODOLOGY: We first genotyped 48 single nucleotide polymorphisms (SNPs) previously associated with AD in a cohort composed of 330 patients with cognitive impairment (CI) to assess their association with plasma lipids. Second, we conducted pleiotropy-informed conjunctional false discovery rate (FDR) analysis designed to identify shared variants between AD and plasma lipid levels. Finally, we used the SNPs to be found associated with lipid parameters and AD to search for associations with lipoprotein parameters in 281 patients with cardiometabolic risk. RESULTS: Five SNPs were significantly associated with lower levels of cholesterol transported in remnant lipoprotein particles (RLPc) in subjects with CI; among these SNPs was the rs73572039 variant in PVRL2. Stratified QQ-plots were conducted on GWAS designed for AD and triglycerides (TG). The cross-trait analysis resulted in a total of 22 independent genomic loci associated with both AD and TG levels with a conjFDR < 0.05. Among these loci, two pleiotropic variants were located in PVRL2 (rs12978931 and rs11667640). The three SNPs in PVRL2 were significantly associated with RLPc, TG, and number of circulating VLDL and HDL particles in subjects with cardiometabolic risk. CONCLUSIONS: We have identified three variants in PVRL2 that predispose individuals to AD that also influence the lipid profile that confers cardiovascular risk in T2DM subjects. PVRL2 is a potential new modulating factor of atherogenic dyslipidemia.


Subject(s)
Alzheimer Disease , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Dyslipidemias , Metabolic Syndrome , Humans , Alzheimer Disease/genetics , Alzheimer Disease/complications , Cardiovascular Diseases/genetics , Cholesterol , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Dyslipidemias/genetics , Dyslipidemias/complications , Genome-Wide Association Study , Metabolic Syndrome/genetics , Metabolic Syndrome/complications , Polymorphism, Single Nucleotide , Triglycerides
5.
Int J Mol Sci ; 24(3)2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36768645

ABSTRACT

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.


Subject(s)
Cardiovascular Diseases , Proprotein Convertase 9 , Humans , Proprotein Convertase 9/metabolism , PCSK9 Inhibitors , Apolipoprotein C-III , Cardiovascular Diseases/etiology , C-Reactive Protein , Proton Magnetic Resonance Spectroscopy , Risk Factors , Cholesterol , Cholesterol, LDL , Triglycerides , Magnetic Resonance Spectroscopy/adverse effects , Lipoproteins , Inflammation/drug therapy , Inflammation/complications , Anti-Inflammatory Agents , Glycoproteins , Heart Disease Risk Factors
6.
Clín. investig. arterioscler. (Ed. impr.) ; 34(1): 27-32, ene.-feb. 2022. tab
Article in Spanish | IBECS | ID: ibc-203138

ABSTRACT

ANTECEDENTES:Las quilomicronemias generalmente se diagnostican genéticamente mediante secuenciación genómica o cribado de mutaciones en genes causales con un gran efecto fenotípico. Esta estrategia ha permitido mejorar la caracterización de estos pacientes, pero aún tenemos un 30% de ellos sin un diagnóstico genético concluyente. Es por esto que hipotetizamos que añadiendo el componente epigenético podemos mejorar el diagnóstico genético y para ello hemos explorado el grado de metilación en el ADN de pacientes hipertrigliceridémicos. METODOLOGÍA: El ADN de células sanguíneas fue obtenido de 16 pacientes hipertrigliceridémicos y de 16 sujetos control emparejados por edad y sexo. El grado de metilación en el ADN de todo el genoma fue determinado mediante el Illumina® Infinium MethylationEPIC Array Analysis. RESULTADOS: Identificamos 31 citosinas diferencialmente metiladas al comparar los patrones de metilación que presentaban los pacientes hipertrigliceridémicos vs. los sujetos control. La cg03636183 en el gen F2RL3 estaba un 10% hipometilada en los pacientes hipertrigliceridémicos, y ha sido previamente asociada a un mayor riesgo cardiovascular. La cg13824500 está un 10% hipometilada en pacientes hipertrigliceridémicos y se localiza en VTI1A, que es un gen limitante en el tránsito de los quilomicrones en el enterocito a través del retículo endoplásmico y el aparato de Golgi. La cg26468118 en el gen RAB20 (13% hipometilada) y la cg21560722 en el gen SBF2 (33% hipermetilada) están implicadas en la regulación de vesículas del aparato de Golgi. CONCLUSIONES: Nuestros resultados evidencian que existen regiones diferencialmente metiladas relacionadas con la formación de los quilomicrones en pacientes hipertrigliceridémicos.


BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.


Subject(s)
Humans , Health Sciences , DNA Methylation , Epigenesis, Genetic , Mutation/genetics , rab GTP-Binding Proteins/genetics
7.
J Proteomics ; 251: 104398, 2022 01 16.
Article in English | MEDLINE | ID: mdl-34688878

ABSTRACT

Glycosylation of ApoC-III modulates its function in TG metabolism, with some variants being associated with a more atherogenic lipid profile. These associations have been studied in whole plasma but rarely in individual lipoprotein fractions. In this study, we aimed to measure the relative content of ApoC-III glycoforms in each lipoprotein fraction as a potential biomarker for TG metabolism and cardiovascular risk. Lipoprotein fractions were separated by differential ultracentrifugation of plasma samples from healthy subjects. Relative concentrations of seven ApoC-III variants were measured by MSIA. ApoC-III1, ApoC-III0b and ApoC-III2 were the most abundant glycoforms. There was high interindividual variability in the distribution of glycoforms across the study population but a uniform proportion in all lipoprotein fractions of each given subject. Two ApoC-III variants, ApoC-III0b and ApoC-III1d, negatively correlated with plasma and VLDL triglycerides irrespectively of VLDL size and were associated with increased LDL size when transported in LDL particles. ApoC-III0b also showed a negative correlation with lipoprotein-insulin resistance score. We have been able to measure seven ApoC-III glycoforms in each lipoprotein fraction, setting the basis for future studies exploring their role on cardiovascular risk. Some glycoforms suggest a less proatherogenic role on TG and lipoprotein metabolism. SIGNIFICANCE: Apo CIII has an important role on plasma TG metabolism through different mechanisms and it is also involved in type 1 and type 2 Diabetes Mellitus. Different glycosylated forms of Apo CIII exist and they show different roles. For this reason, this protein has gained interest in the las years and the relationship between ApoC-III glycoforms and lipids, lipoproteins and metabolic disorders has been increasingly studied in the last years. Apo CIII glycoforms have been previously analysed in plasma, and the function of the main four glycoforms has been assessed in a variety of cohorts; but in the present study, ApoC-III glycoforms are measured in each lipoprotein fraction, which may be of clinical interest.


Subject(s)
Diabetes Mellitus, Type 2 , Apolipoprotein C-III , Healthy Volunteers , Humans , Lipoproteins/metabolism , Lipoproteins, LDL , Lipoproteins, VLDL , Triglycerides
8.
Clin Investig Arterioscler ; 34(1): 27-32, 2022.
Article in English, Spanish | MEDLINE | ID: mdl-34879978

ABSTRACT

BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.


Subject(s)
DNA Methylation , Epigenesis, Genetic , Humans , Mutation , rab GTP-Binding Proteins/genetics
9.
Comput Struct Biotechnol J ; 19: 6169-6178, 2021.
Article in English | MEDLINE | ID: mdl-34900130

ABSTRACT

Aging is a major risk factor for metabolic impairment that may lead to age-related diseases such as cardiovascular disease. Different mechanisms that may explain the interplay between aging and lipoproteins, and between aging and low-molecular-weight metabolites (LMWMs), in the metabolic dysregulation associated with age-related diseases have been described separately. Here, we statistically evaluated the possible mediation effects of LMWMs on the relationships between chronological age and lipoprotein concentrations in healthy men ranging from 19 to 75 years of age. Relative and absolute concentrations of LMWMs and lipoproteins, respectively, were assessed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate linear regression and mediation analysis were conducted to explore the associations between age, lipoproteins and LMWMs. The statistical significance of the identified mediation effects was evaluated using the bootstrapping technique, and the identified mediation effects were validated on a publicly available dataset. Chronological age was statistically associated with five lipoprotein classes and subclasses. The mediation analysis showed that serine mediated 24.1% (95% CI: 22.9 - 24.7) of the effect of age on LDL-P, and glutamate mediated 17.9% (95% CI: 17.6 - 18.5) of the effect of age on large LDL-P. In the publicly available data, glutamate mediated the relationship between age and an NMR-derived surrogate of cholesterol. Our results suggest that the age-related increase in LDL particles may be mediated by a decrease in the nonessential amino acid glutamate. Future studies may contribute to a better understanding of the potential biological role of glutamate and LDL particles in aging mechanisms and age-related diseases.

10.
Article in English, Spanish | MEDLINE | ID: mdl-34716123

ABSTRACT

INTRODUCTION AND OBJECTIVES: Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. METHODS: This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. RESULTS: The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9µmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6µmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. CONCLUSIONS: Patients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference.

12.
Biomolecules ; 12(1)2021 12 29.
Article in English | MEDLINE | ID: mdl-35053195

ABSTRACT

Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be transported by lipoproteins. Since humans are much more sensitive to LPS than other mammals, and very low amounts of LPS can elicit an immune response, the aim of this study is to characterize the distribution of LPS and its immunogenic portion (3OHFAs) among lipoprotein types of healthy men. We separated lipoprotein fractions by ultracentrifugation and the amount of each 3OHFA was measured by MS in each lipoprotein fraction to calculate LPS concentration. Lipoprotein particle concentration was measured by NMR. LDL and HDL fractions transported the highest concentration of LPS (35.7% and 31.5%, respectively), but VLDL particles carried more LPS molecules per particle (0.55 molecules/particle) than LDL or HDL (p < 0.01). The distribution of LPS and all 3OHFAs among lipoprotein fractions showed high interindividual variability, suggesting that they may be studied as a potential biomarker. This may help understand the role of LPS in atherosclerosis in those cases where the disease cannot be explained by traditional risk factors.


Subject(s)
Atherosclerosis , Lipopolysaccharides , Animals , Humans , Lipoproteins , Lipoproteins, LDL , Lipoproteins, VLDL , Male , Mammals , Ultracentrifugation
13.
Rheumatology (Oxford) ; 60(2): 866-871, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32844232

ABSTRACT

OBJECTIVES: SLE patients have an enhanced risk of atherosclerosis and cardiovascular disease. However, the increased prevalence of cardiovascular disease is not fully explained by traditional Framingham cardiovascular risk factors. Specific features of low-density lipoprotein (LDL) particles, other than plasma concentration, may induce accelerated atherosclerosis at early stages in these patients. Thus, we aimed to explore the impact of LDL from both active and inactive SLE patients on human aortic endothelial cells. METHODS: Human aortic endothelial cells were stimulated with the same concentration of LDL particles isolated from pooled serum that was collected from 13 SLE patients during both active and inactive states. Gene expression and cell migration assays were performed. RESULTS: Circulating LDL particles obtained from healthy volunteers and SLE patients in both remission and flare states were comparable in terms of number, cholesterol and triglyceride content, and net electric charge. Stimulation of cells with LDL from active SLE patients induced the expression of vascular cell adhesion molecule 1 (∼2.0-fold, P < 0.05), monocyte chemoattractant protein 1 (∼2.0-fold, P < 0.05) and matrix metallopeptidase 2 (∼1.6-fold, P < 0.01) compared with cells stimulated with LDL from inactive SLE patients. Additionally, LDL extracted from active patients increased cell migration in a wound-healing assay (1.4-fold, P < 0.05). CONCLUSION: Our data show that, at the same LDL concentration, LDL from active SLE patients had increased proatherogenic effects on endothelial cells compared with LDL from the same patients when in an inactive or remission state.


Subject(s)
Atherosclerosis/metabolism , Chemokine CCL2/metabolism , Lipoproteins, LDL , Lupus Erythematosus, Systemic , Matrix Metalloproteinase 2/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Aorta/pathology , Cell Migration Assays/methods , Cells, Cultured , Correlation of Data , Disease Progression , Endothelial Cells/metabolism , Female , Heart Disease Risk Factors , Humans , Lipoproteins, LDL/blood , Lipoproteins, LDL/metabolism , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/metabolism , Patient Acuity
15.
Int J Rheum Dis ; 22(3): 480-487, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30450745

ABSTRACT

AIMS: Patients with systemic lupus erythematosus (SLE) suffer from accelerated atherosclerosis. Their most common cause of death is a cardiovascular disease (CVD), in spite of the presence of moderate lipid alterations and normal cardiovascular risk scores. However, cholesterol still accumulates in the arteries of SLE patients, so we aim to identify additional factors that may help explain the residual risk that exists in these patients. We focus on investigating whether the net charge contributes significantly to both the development and the progression of atherosclerosis in patients with SLE. METHODS: The lipoproteins from 78 patients with SLE and 32 controls were isolated via sequential ultracentrifugation. Lipoprotein subclasses distributions were analyzed via nuclear magnetic resonance spectroscopy and the net charges of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured using a Zetasizer Nano-ZS. The degree of atherosclerosis (carotid intima-media thickness [cIMT]) was determined in all the participants. RESULTS: Each lipoprotein class exhibited a negative net charge. IDL and LDL net charge correlated negatively with cIMT (r = -0.274, P = 0.034; r = -0.288; P = 0.033, respectively) in patients with SLE. This effect was independent of age, body mass index (BMI), gender, tobacco consumption, high-sensitivity C-reactive protein (hsCRP), lipid concentration and lipoprotein particle number. LDL net charge explained 4% of the cIMT variability among these patients; this contribution was also independent of age, BMI, gender, tobacco consumption, lipids levels, apolipoproteins and hsCRP. CONCLUSIONS: Low-density lipoprotein net charge may be considered a new independent contributor to subclinical atherosclerosis in SLE patients. The observed relationship was independent of lipid concentrations and extends the prominent role that IDL and LDL play in cardiovascular risk.


Subject(s)
Carotid Artery Diseases/blood , Lipoproteins, LDL/blood , Lupus Erythematosus, Systemic/blood , Adult , Asymptomatic Diseases , Biomarkers/blood , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/etiology , Carotid Intima-Media Thickness , Case-Control Studies , Disease Progression , Female , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Magnetic Resonance Spectroscopy , Male , Middle Aged , Plaque, Atherosclerotic , Risk Factors , Surface Properties
16.
Curr Atheroscler Rep ; 19(7): 30, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28500476

ABSTRACT

PURPOSE OF REVIEW: This review is intended to summarize the genetic studies published during the last 3 years that help us understand the physiology of apoAV and its clinical implications. RECENT FINDINGS: APOA5 is probably the gene with the strongest effect on triglyceride (TG) metabolism. APOA5 is almost exclusively expressed in the liver, and its product apoAV has a very low circulating concentration. New physiological roles of apoAV have been recently elucidated, such as control of chylomicron production in the intestine and TG accumulation in adipose tissue. The key role of APOA5 in TG metabolism has been largely shown through genetic studies in association with either severe or moderate hypertriglyceridemia. Studies suggest that APOA5 variants affect not only total TG concentrations but also the entire lipoprotein subclass distribution, shifting them toward atherogenic dyslipidemia in high-risk subjects. Environmental interactions and epigenetic factors are also crucial in regulating these processes. Delineation of the mechanisms involved in the transcriptional control of the gene, combined with determination of biological significance of the SNPs in the APOA5 locus, would help to fully understand the effect of APOA5 on TGs. In summary, APOA5 variants cause hypertriglyceridemia. In high cardiovascular risk patients (e.g., patients with metabolic syndrome or type 2 diabetes), APOA5 variants elevate TG levels and shift the entire lipoprotein subclass distribution toward atherogenic dyslipidemia. At a physiological level, apoAV seems to encompass more roles than those initially suggested after its discovery.


Subject(s)
Apolipoprotein A-V/genetics , Hypertriglyceridemia , Atherosclerosis/etiology , Atherosclerosis/prevention & control , Humans , Hypertriglyceridemia/complications , Hypertriglyceridemia/genetics , Polymorphism, Single Nucleotide , Triglycerides/metabolism
17.
Clin Sci (Lond) ; 130(22): 2053-2059, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27613158

ABSTRACT

Apolipoprotein A5 gene (APOA5) variability explains part of the individual's predisposition to hypertriacylglycerolaemia (HTG). Such predisposition has an inherited component (polymorphisms) and an acquired component regulated by the environment (epigenetic modifications). We hypothesize that the integrated analysis of both components will improve our capacity to estimate APOA5 contribution to HTG. We followed a recruit-by-genotype strategy to study a population composed of 44 individuals with high cardiovascular disease risk selected as being carriers of at least one APOA5 SNP (-1131T>C and/or, S19W and/or 724C>G) compared against 34 individuals wild-type (WT) for these SNPs. DNA methylation patterns of three APOA5 regions [promoter, exon 2 and CpG island (CGI) in exon 3] were evaluated using pyrosequencing technology. Carriers of APOA5 SNPs had an average of 57.5% higher circulating triacylglycerol (TG) levels (P=0.039). APOA5 promoter and exon 3 were hypermethylated whereas exon 2 was hypomethylated. Exon 3 methylation positively correlated with TG concentration (r=0.359, P=0.003) and with a lipoprotein profile associated with atherogenic dyslipidaemia. The highest TG concentrations were found in carriers of at least one SNP and with a methylation percentage in exon 3 ≥82% (P=0.009). In conclusion, CGI methylation in exon 3 of APOA5 acts, in combination with -1131T>C, S19W and 724C>G polymorphisms, in the individual's predisposition to high circulating TG levels. This serves as an example that combined analysis of SNPs and methylation applied to a larger set of genes would improve our understanding of predisposition to HTG.


Subject(s)
Apolipoprotein A-V/genetics , Hypertriglyceridemia/genetics , Triglycerides/blood , Adult , Aged , CpG Islands , DNA Methylation , Epigenomics , Female , Genetic Predisposition to Disease , Genotype , Humans , Hypertriglyceridemia/blood , Male , Middle Aged , Polymorphism, Single Nucleotide
20.
Clín. investig. arterioscler. (Ed. impr.) ; 28(2): 102-119, mar.-abr. 2016. ilus, tab, graf
Article in Spanish | IBECS | ID: ibc-151739

ABSTRACT

Los estudios de asociación basados en genes candidato llevados a cabo durante décadas han servido para visualizar la influencia del componente genético en enfermedades complejas como la arteriosclerosis y también para evidenciar la interacción entre diferentes genes y, especialmente, la de estos con factores ambientales. Incluso con el conocimiento acumulado, aún queda camino por recorrer para descifrar la predisposición individual a la enfermedad y, si tenemos en cuenta la gran influencia que los factores ambientales juegan en el desarrollo y la progresión de la arteriosclerosis, la epigenética se nos presenta como un elemento clave para ampliar nuestro conocimiento de la predisposición individual a la arteriosclerosis. La epigenética se puede describir como la disciplina que estudia los mecanismos de regulación transcripcional independientes de la secuencia del ADN, mayoritariamente inducidos por factores ambientales. Esta revisión pretende describir qué es la epigenética y de qué manera los mecanismos epigenéticos participan en la arteriosclerosis


The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis


Subject(s)
Humans , Epigenesis, Genetic , Arteriosclerosis/genetics , Genome-Wide Association Study , DNA Methylation/genetics , Histones/genetics , MicroRNAs/genetics
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