Low-density Lipoprotein Phenotype Research Articles

Examination of a novel expression-based gene-SNP annotation strategy to identify tissue-specific contributions to heritability in multiple traits.

Complex traits show clear patterns of tissue-specific expression influenced by single nucleotide polymorphisms (SNPs), yet current strategies aggregate SNP effects to genes by employing simple physical proximity-based windows. Here, we examined whether incorporating SNPs with effects on tissue-specific cis-expression would improve our ability to detect trait-relevant tissues across 31 complex traits using stratified linkage disequilibrium score regression (S-LDSC). We found that a physical proximity annotation produced more significant tissue enrichments and larger S-LDSC regression coefficients, as compared to an expression-based annotation. Furthermore, we showed that our expression-based annotation did not outperform an annotation strategy in which an equal number of randomly chosen SNPs were annotated to genes within the same genomic window, suggesting extensive redundancy among SNP effect estimates due to linkage disequilibrium. That said, current sample sizes limit estimation of cis-genetic SNP effects; therefore, we recommend reexamination of the expression-based annotation when larger tissue-specific expression datasets become available. To examine the influence of sample size, we used a large whole blood eQTL reference panel (N = 31,684) applying a similar expression-based annotation strategy. We found that significant cis-expression QTLs in whole blood did not outperform the physical proximity annotation when estimating tissue-specific SNP heritability enrichment for either high- or low-density lipoprotein phenotypes but performed similarly for inflammatory bowel disease. Finally, we report new and updated tissue enrichment estimates across 31 complex traits, such as significant heritability enrichment of the frontal cortex for cognitive performance, educational attainment, and intelligence, providing further evidence of this structure's importance in higher cognitive function.

Effect of classic ketogenic diet treatment on lipoprotein subfractions in children and adolescents with refractory epilepsy

ObjectiveThe aim of this study was to evaluate the effects of the classic ketogenic diet (KD) on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions in children and adolescents with refractory epilepsy. MethodsThis prospective study recruited children and adolescents of either sex, whose epilepsy was refractory to treatment with multiple drugs. To be included, the patient had to have an indication for treatment with the KD and be treated as an outpatient. At baseline and after 3 and 6 mo of the KD, lipid profile (total cholesterol [TC], triacylglycerols [TG], LDL cholesterol [LDL-C], and HDL cholesterol [HDL-C]), apolipoproteins (apoA-I and apoB), 10 subfractions of HDL, 7 subfractions of LDL, LDL phenotype, and LDL size were analyzed using the Lipoprint system. ResultsThe lipid profile components (TC, TG, LDL-C, HDL-C, apoA-I, and apoB) increased during the 3-mo follow-up, and remained consistent after 6 mo of treatment. Similarly, non-HDL-C, TC/HDL-C, LDL-C/HDL-C, and apoB/apoA-I ratios, representing atherogenic particles, significantly increased. In contrast, qualitative lipoprotein characteristics progressively changed during the follow-up period. Small LDL subfractions increased, and this profile was related with reduced LDL size (27.3 nm to 26.7 nm). The LDL phenotype became worse; 52.1% of the patients had a non-A phenotype after 6 mo of the KD. Small HDL subfractions decreased only after 6 mo of the KD. ConclusionsKD treatment promotes negative changes in lipoprotein size and phenotype, contributing to atherogenic risk in these patients.

Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of ldl subfraction phenotype

BackgroundType 2 diabetes mellitus (T2D) is associated with higher cardiovascular risk partly related to an increase in inflammatory parameters. The aim of this study was to determine the association of inflammatory biomarkers with low-density lipoprotein (LDL) subfraction phenotype and glycemic control in subjects with T2D and poor glycemic control.MethodsA cross-sectional study was performed comparing 122 subjects with T2D (59 ± 11 years old, body mass index 30.2 ± 5.6 kg/m2) with 54 control subjects. Patients with T2D were classified according to their LDL subfraction phenotype and inflammatory biomarkers (C-reactive protein, Interleukin-6, Interleukin-8, Transforming growth factor β1, Monocyte chemotactic protein 1, Leptin, Adiponectin) were evaluated according to the degree of glycemic control, LDL phenotype and other clinical characteristics. Forty-two subjects with T2D were studied before and after 3 months of improving glycemic control by different strategies.ResultsPatients with T2D had higher C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP1) levels and lower adiponectin concentration, compared to controls. T2D subjects with body mass index ≥ 30 kg/m2 had higher CRP levels (5.2 ± 4.8 mg/l vs 3.7 ± 4.3 mg/l; p < 0.05). The presence of LDL phenotype B was related to higher levels of transforming growth factor-β1 (TGF-β1) (53.92 ± 52.82 ng/l vs 31.35 ± 33.74 ng/l; p < 0.05) and lower levels of adiponectin (3663 ± 3044 ng/l vs 2723 ± 1776 ng/l; p < 0.05). The reduction of HbA1c from 9.5 ± 1.8% at baseline to 7.4 ± 0.8% was associated with a significant reduction of TGF-β1 (41.86 ± 32.84 ng/l vs 26.64 ± 26.91 ng/l; p = 0.02).ConclusionsSubjects with T2D, especially those with LDL phenotype B and obesity, have higher levels of inflammatory biomarkers. Improvement of glycemic control reduces TGF-β1 levels, which may contribute partly to its renoprotective role.

Interrelated cathepsin S-lowering and LDL subclass profile improvements induced by atorvastatin in the plasma of stable angina patients.

We hypothesized that, in stable angina patients, atorvastatin therapy lowers the cathepsin S (CTSS) concentrations, as assessed non-invasively according to a plasma analysis. In addition, the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) size and subclasses in the plasma were analysed to establish the association between CTSS and lipoprotein metabolism and determine whether this association is atorvastatin-sensitive. A total of 43 patients with stable angina received atorvastatin therapy (20 mg/day, 10 weeks). The plasma CTSS mRNA levels, CTSS protein concentrations and CTSS activity, as well as LDL and HDL size and subclasses, were analysed before and after treatment. Atorvastatin treatment did not change the plasma CTSS mRNA levels, although it lowered the plasma CTSS concentrations and activity. An increased plasma CTSS concentration and activity were found to be associated with a more atherogenic LDL subclass profile (a decreased dominant LDL size and increased percentage of small, dense LDL particles). The atorvastatin-induced CTSS-loweringeffect was concomitant with an improvement in the LDL subclass profile, and the changes were found to be interrelated. Concomitant, interrelated changes in the CTSS levels and LDL subclass profiles were found in the LDL phenotype B patients only (a dominant LDL diameter of ≤ 25.5 nm at the start of the study). In this subgroup, lowering of the plasma CTSS mRNA level also correlated with lowering of the proportion of small, dense LDL particles. Atorvastatin-induced CTSS-lowering and LDL subclass profile improvements in the plasma of LDL phenotype B patients with stable angina are concomitant and interrelated.

LDL subclasses and lipoprotein-phospholipase A2 activity in suppressed HIV-infected patients switching to raltegravir: Spiral substudy

ObjectiveTo analyze the effect of switching the ritonavir-boosted protease inhibitor (PI/r) in a stable combined antiretroviral therapy (cART) regimen to raltegravir on low-density lipoprotein (LDL) particles, and lipoprotein-associated phospholipase A2 (Lp-PLA2). DesignSubstudy of a multicenter randomized trial that compared the efficacy of switching a PI/r to raltegravir-based cART in stable HIV-infected patients. MethodsLDL size and phenotype (by gel-gradient electrophoresis), Lp-PLA2 (by 2-thio-PAF [Cayman]), proprotein convertase subtilisin/kexin type 9 (PCSK9) (by ELISA), and standard lipid parameters were measured at baseline and week 48. ResultsEighty-one (PI/r n = 41 and raltegravir n = 40) patients were evaluated. No differences in baseline demographic and metabolic variables between arms were found except in apolipoprotein (Apo) B (p = 0.042). At week 48, total cholesterol (TC) (p < 0.001), LDL-c (p = 0.023), non-high density lipoprotein cholesterol non-high-density lipoprotein cholesterol (non-HDL-c) (p < 0.001), TC/HDL (p = 0.026), triglyceride (p < 0.001), Apo B (p < 0.001), Apo A-I (p = 0.004) and Lp (a) (p = 0.005) decreased in raltegravir arm compared to PI/r arm. At week 48, a shift from LDL phenotype B to the less atherogenic phenotype A was observed only in raltegravir arm (p < 0.001). LDL size increased (PI/r 2.1 nm, p = 0.019; raltegravir 3.8 nm, p = 0.001) and cholesterol content in small and dense LDL subfractions (LDL 4,5,6) decreased (PI/r p = 0.007, raltegravir p = 0.006) at week 48 in both arms. Total Lp-PLA2 activity (PI/r p = 0.037 and raltegravir p = 0.051) and PCSK9 plasma concentration decreased in both arms (PI/r p = 0.034 and raltegravir p < 0.001). ConclusionsSwitching a PI/r to a raltegravir-based cART in virologically suppressed HIV-infected patients was associated with an overall improvement in lipid profile, including a shift to a less atherogenic LDL phenotype.

Higher levels of serum triglyceride and dietary carbohydrate intake are associated with smaller LDL particle size in healthy Korean women

The aim of this study was to investigate the influencing factors that characterize low density lipoprotein (LDL) phenotype and the levels of LDL particle size in healthy Korean women. In 57 healthy Korean women (mean age, 57.4 ± 13.1 yrs), anthropometric and biochemical parameters such as lipid profiles and LDL particle size were measured. Dietary intake was estimated by a developed semi-quantitative food frequency questionnaire. The study subjects were divided into two groups: LDL phenotype A (mean size: 269.7Å, n = 44) and LDL phenotype B (mean size: 248.2Å, n = 13). Basic characteristics were not significantly different between the two groups. The phenotype B group had a higher body mass index, higher serum levels of triglyceride, total-cholesterol, LDL-cholesterol, apolipoprotein (apo)B, and apoCIII but lower levels of high density lipoprotein (HDL)-cholesterol and LDL particle size than those of the phenotype A group. LDL particle size was negatively correlated with serum levels of triglyceride (r = -0.732, P < 0.001), total-cholesterol, apoB, and apoCIII, as well as carbohydrate intake (%En) and positively correlated with serum levels of HDL-cholesterol and ApoA1 and fat intake (%En). A stepwise multiple linear regression analysis revealed that carbohydrate intake (%En) and serum triglyceride levels were the primary factors influencing LDL particle size (P < 0.001, R2 = 0.577). This result confirmed that LDL particle size was closely correlated with circulating triglycerides and demonstrated that particle size is significantly associated with dietary carbohydrate in Korean women.

Prevalence of LDL atherogenic phenotype in patients with systemic lupus erythematosus.

Background:Patients with systemic lupus erythematosus (SLE) are 5–8 times more likely to develop coronary heart disease than the general population. The aim of this study was to find out the prevalence of the small dense low-density lipoprotein (LDL) cholesterol particle in patients with SLE.Methods:We recruited 50 consecutive patients with SLE who had no evidence of hypertension or renal failure. Fifty age- and gender-matched healthy controls were also recruited. We measured serum lipid levels and LDL particle diameters by gradient gel electrophoresis in both patients and controls.Results:Patients with SLE had significant dyslipidemia, characterized by elevated plasma triglycerides, LDL cholesterol, Apoprotein B, triglyceride:high-density (HDL) lipoprotein cholesterol ratio, and decreased plasma concentrations of HDL cholesterol. The LDL particle size in SLE (24.8 ± 1.23 nm) was significantly (P < 0.01) smaller than that in controls (26.1 ± 1.31 nm). The prevalence of the LDL phenotype B (the atherogenic phenotype) was 52% in SLE but only 20% in healthy controls.Conclusion:We conclude that the high prevalence of small dense LDL in SLE may contribute to the high incidence of coronary heart disease seen in this disorder.

Estimation of the low-density lipoprotein (LDL) subclass phenotype using a direct, automated assay of small dense LDL-cholesterol without sample pretreatment

A new method (sLDL-EX "SEIKEN") is commercially available for the direct quantification of small dense LDL-cholesterol (sd-LDL) on automated chemistry analyzers, without manual sample pretreatment. We evaluated the performance of this direct assay to estimate the small dense LDL subclass phenotype ("non-A"), defined by polyacrylamide gel tube electrophoresis. Fasting serum samples from 189 healthy subjects (age 18-75y, 96 females) were collected. The direct sd-LDL assay (from Randox Laboratories) was applied on a Roche Modular P analyzer. The Quantimetrix Lipoprint(TM) LDL System was used to define LDL subclass phenotypes (A and non-A). ROC curve analysis was performed for sd-LDL and other lipids and apolipoproteins (apo) with respect to phenotype non-A. sd-LDL concentrations (40.4+/-18.6mg/dl) in the total group correlated (P<0.0001) with apoB (r=0.831), apoB/A-I ratio (r=0.757), non-HDL-cholesterol (r=0.821), triglycerides (r=0.439), and LDL-cholesterol (r=0.641). Higher sd-LDL concentrations (P<0.0001) were measured in subjects with LDL phenotype non-A (53.6+/-17.0mg/dl, n=92) than in those with phenotype A (27.9+/-8.9mg/dl, n=97). In logistic regression analysis, sd-LDL and apoA-I were independently associated with LDL subclass phenotype non-A. Highest areas under ROC curves were obtained for sd-LDL (0.943), triglycerides (0.833), triglyceride/HDL-cholesterol (0.838) and apoB/A-I ratio (0.826) to predict phenotype non-A. The sd-LDL cut-off point for optimal sensitivity (87.9%) and specificity (92.8%) was >38.5mg/dl. The direct, homogeneous sd-LDL method is easily applicable on an automated chemistry analyzer and shows acceptable performance to estimate the electrophoretic LDL subclass phenotype.

Use of Wrapper Algorithms Coupled with a Random Forests Classifier for Variable Selection in Large-Scale Genomic Association Studies

Modern large-scale genetic association studies generate increasingly high-dimensional datasets. Therefore, some variable selection procedure should be performed before the application of traditional data analysis methods, for reasons of both computational efficiency and problems related to overfitting. We describe here a "wrapper" strategy (SIZEFIT) for variable selection that uses a Random Forests classifier, coupled with various local search/optimization algorithms. We apply it to a large dataset consisting of 2,425 African-American and non-Hispanic white individuals genotyped for 4,869 single-nucleotide polymorphisms (SNPs) in a coronary heart disease (CHD) case-cohort association study (Atherosclerosis Risk in Communities), using incident CHD and plasma low-density lipoprotein (LDL) cholesterol levels as the dependent variables. We show that most SNPs can be safely removed from the dataset without compromising the predictive (classification) accuracy, with only a small number of SNPs (sometimes less than 100) containing any predictive signal. A statistical (SUMSTAT) approach is also applied to the dataset for comparison purposes. We describe a novel method for refining the subset of signal-containing SNPs (FIXFIT), based on an Extremal Optimization algorithm. Finally, we compare the top SNP rankings obtained by different methods and devise practical guidelines for researchers trying to generate a compact subset of predictive SNPs from genome-wide association datasets. Interestingly, there is a significant amount of overlap between seemingly very heterogeneous rankings. We conclude by constructing compact optimal predictive SNP subsets for CHD (less than 150 SNPs) and LDL (less than 300 SNPs) phenotypes, and by comparing various rankings for two well-known positive control SNPs for LDL in the apolipoprotein E gene.

Comparison between single-marker analysis using Merlin and multi-marker analysis using LASSO for Framingham simulated data

We compared family-based single-marker association analysis using Merlin and multi-marker analysis using LASSO (least absolute shrinkage and selection operator) for the low-density lipoprotein phenotype at the first visit for all 200 replicates of the Genetic Analysis Workshop 16 Framingham simulated data sets. Using "answers," we selected single-nucleotide polymorphisms (SNPs) on chromosome 22 for comparison of results between single-marker and multi-marker analyses. For the major causal SNP rs2294207 on chromosome 22, both single-marker and multi-marker analyses provided similar results, indicating the importance of this SNP. For the 12 polygenic SNPs on the same chromosome, both single-marker and multi-marker analyses failed to provide statistically significant associations, indicating that their effects were too weak to be detected by either method. The main difference between the two methods was that for the 14 SNPs near the causal SNPs, p-values from Merlin were the next smallest, whereas LASSO often excluded these non-causal neighboring SNPs entirely from the first 10,000 models.

Advanced Lipoprotein Testing and Subfractionation Are Not (Yet) Ready for Routine Clinical Use

Standard lipid tests measure the cholesterol or triglyceride content of lipoproteins, expressed as mg/dL (or mmol/L) of cholesterol or triglyceride. A standard lipid panel includes total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These lipids are carried within lipoprotein particles that are heterogeneous in size, density, charge, core lipid composition, specific apolipoproteins, and function.1 A variety of lipoprotein assays have been developed that subfractionate lipoprotein particles according to some of these properties such as size, density, or charge.2 These lipoprotein assays have been proposed for improving assessment of risk of cardiovascular disease (CVD) and for guiding lipid-lowering therapies. They are mostly used today in specialized lipid clinics or research studies, and their general utility for clinical practice is not well delineated.3 In this review, I first provide a summary of current guideline statements that address this topic. Then I give a brief overview of the different laboratory methods available for clinical use and discuss the literature evaluating these methods. Finally, I discuss current limitations to the widespread clinical application of these methods. Response by Superko on p 2404 The Third Adult Treatment Panel of the National Cholesterol Education Program4 and the American Heart Association5 recommend measuring a standard lipid panel in adults and targeting lipid-lowering therapy on the basis of levels of LDL cholesterol, and non-HDL cholesterol in subjects with hypertriglyceridemia. European and Canadian guidelines recommend measuring standard lipids while also emphasizing the total/HDL cholesterol ratio in risk assessment.6,7 Current guidelines do not recommend routine use of advanced lipoprotein tests, mainly because it is unclear how much incremental prognostic information is provided by these tests beyond that available from a standard lipid panel.4,6,7 Recently, an international panel proposed that cardiovascular risk may be more closely related to atherogenic lipoprotein …

Multistage analysis strategies for genome‐wide association studies: summary of group 3 contributions to Genetic Analysis Workshop 16

This contribution summarizes the work done by six independent teams of investigators to identify the genetic and non-genetic variants that work together or independently to predispose to disease. The theme addressed in these studies is multistage strategies in the context of genome-wide association studies (GWAS). The work performed comes from Group 3 of the Genetic Analysis Workshop 16 held in St. Louis, Missouri in September 2008. These six studies represent a diversity of multistage methods of which five are applied to the North American Rheumatoid Arthritis Consortium rheumatoid arthritis case-control data, and one method is applied to the low-density lipoprotein phenotype in the Framingham Heart Study simulated data. In the first stage of analyses, the majority of studies used a variety of screening techniques to reduce the noise of single-nucleotide polymorphisms purportedly not involved in the phenotype of interest. Three studies analyzed the data using penalized regression models, either LASSO or the elastic net. The main result was a reconfirmation of the involvement of variants in the HLA region on chromosome 6 with rheumatoid arthritis. The hope is that the intense computational methods highlighted in this group of papers will become useful tools in future GWAS.

Inter-relationship between low-density lipoprotein phenotype and carotid intima-media thickness in North Indian type 2 diabetic subjects

Aims Diabetic dyslipidemia is characterized by a preponderance of small dense LDL which is highly atherogenic. The aim of this study was to examine the interrelationship between LDL Phenotype and atherosclerosis; to determine the factors determining LDL phenotype; and evaluate LDLc:apo-B ratio as a surrogate for the assessment of LDL phenotype in a group of North Indian Type 2 diabetic subjects. Methods 285 diabetic subjects attending the outpatient Endocrine Clinic were subjected to detailed anthropometry and fasting serum lipid and apo-B was measured. The carotid intima-media thickness (IMT) was determined using a high resolution B-mode Ultrasonography. LDLc:apo-B ratio was taken as a surrogate index for LDL size. Results 29.5% patients with normal triglyceride levels and 52.1% patients with normal LDLc levels showed the presence of small dense LDL or Phenotype B as estimated by the LDL cholesterol/apo-B ratio. The mean IMT in Phenotype B group was higher (0.88 mm vs. 0.68 mm). Triglycerides was the most important predictor variable predicting carotid IMT ( R 2 = 0.15, β = 0.376) as well as LDL phenotype B ( R 2 = 0.28, β = 0.561). Conclusions Triglycerides and HDLc contribute independently to the variability in LDL particle size, and LDL particle size was associated with preclinical atherosclerosis as determined by carotid IMT in North Indian Type 2 diabetic subjects. LDL cholesterol/apo-B ratio serves as an easy clinical tool to determine the elevated small dense LDL.

Abdominal obesity and the metabolic syndrome: A surgeon's perspective

Over the past decade, a major shift in the clinical risk factors in the population undergoing a cardiac surgery has been observed. In the general population, an increasing prevalence of obesity has largely contributed to the development of cardiovascular disorders. Obesity is a heterogeneous condition in which body fat distribution largely determines metabolic perturbations. Consequently, individuals characterized by increased abdominal fat deposition and the so-called metabolic syndrome (MetS) have a higher risk of developing coronary artery disease. Recent studies have also emphasized that visceral obesity is a strong risk factor for the development of heart valve diseases. In fact, individuals characterized by visceral obesity and its metabolic consequences, such as the small dense low-density lipoprotein phenotype, have a faster progression rate of aortic stenosis, which is related to increased valvular inflammation. Furthermore, the degenerative process of implanted bioprostheses is increased in subjects with the MetS and/or diabetes, suggesting that a process akin to atherosclerosis could be involved in the failure of bioprostheses. In addition to being an important risk factor for the development of cardiovascular disorders, the MetS is increasing the operative mortality risk following coronary artery bypass graft surgery. Thus, recent evidence supports visceral obesity as a global risk factor that is affecting the development of many heart disorders, and that is also impacting negatively on the results of patients undergoing surgical treatment for cardiovascular diseases. In the present paper, recent concepts surrounding the MetS and its implications in various cardiovascular disorders are reviewed along with the clinical implications.

Lipoprotein separation in a novel iodixanol density gradient, for composition, density, and phenotype analysis

Separation of lipoproteins by traditional sequential salt density floatation is a prolonged process ( approximately 72 h) with variable recovery, whereas iodixanol-based, self-generating density gradients provide a rapid ( approximately 4 h) alternative. A novel, three-layered iodixanol gradient was evaluated for its ability to separate lipoprotein fractions in 63 subjects with varying degrees of dyslipidemia. Lipoprotein cholesterol, triglycerides, and apolipoproteins were measured in 21 successive iodixanol density fractions. Iodixanol fractionation was compared with sequential floatation ultracentrifugation. Iodixanol gradient formation showed a coefficient of variation of 0.29% and total lipid recovery from the gradient of 95.4% for cholesterol and 84.7% for triglyceride. Recoveries for VLDL-, LDL-, and HDL-cholesterol, triglycerides, and apolipoproteins were approximately 10% higher with iodixanol compared with sequential floatation. The iodixanol gradient effectively discriminated classic lipoproteins and their subfractions, and there was evidence for improved resolution of lipoproteins with the iodixanol gradient. LDL particles subfractionated by the gradient showed good correlation between density and particle size with small, dense LDL (<25.5 nm) separated in fractions with density >1.028 g/dl. The new iodixanol density gradient enabled rapid separation with improved resolution and recovery of all lipoproteins and their subfractions, providing important information with regard to LDL phenotype from a single centrifugation step with minimal in-vitro modification of lipoproteins.

PAI‐1 activity, but not fibrinogen or von Willebrand factor, is inversely related to LDL particle size in type 2 diabetes

Levels of fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) have been associated with small low-density lipoprotein (LDL) particles. However, it is not clear whether these associations are independent of visceral adiposity or other components of the metabolic syndrome such as triglycerides or insulin resistance. Visceral adipose tissue (VAT; CT-scan), fibrinogen, von Willebrand factor antigen (vWF:Ag), PAI-1 activity and different metabolic parameters such as total cholesterol (chol), HDL-chol, triglycerides, insulin resistance (homeostasis model assessment; HOMA-IR) were determined in 41 women and 78 men with type 2 diabetes. LDL particle size was assessed by polyacrylamide gradient gel electrophoresis. PAI-1 activity was inversely related to LDL particle size after adjustment for age and body mass index (BMI) (r=-0.28; p=0.006) or age and VAT (r=-0.26; p=0.01), but not after adjustment for age and HOMA-IR (r=-0.15; p=0.148) or age and triglycerides (r=-0.04; p=0.679). In multiple regression analysis, LDL particle size did not independently determine PAI-1 activity levels. Fibrinogen and vWF:Ag did not seem to be related to LDL size. PAI-1 activity levels, in contrast to fibrinogen and vWF:Ag, seem to be related to the small LDL phenotype in patients with type 2 diabetes. However, this relationship was not independent of insulin resistance or triglycerides.

Atherogenic lipid phenotype in a general group of subjects.

Abstract Context.—The atherogenic lipid phenotype is a major cardiovascular risk factor, but normal values do not exist derived from 1 analysis in a general study group. Objective.—To determine normal values of all of the atherogenic lipid phenotype parameters using subjects from a general study group. Design.—One hundred two general subjects were used to determine their atherogenic lipid phenotype using polyacrylamide gradient gels. Results.—Low-density lipoprotein (LDL) size revealed 24% of subjects express LDL phenotype B, defined as average LDL peak particle size 258 A or less; however, among the Chinese subjects, the expression of the B phenotype was higher at 44% (P = .02). For the total group, mean LDL size was 265 ± 11 A (1 SD); however, histograms were bimodal in both men and women. After excluding subjects expressing LDL phenotype B, because they are at increased cardiovascular risk and thus are not completely healthy, LDL histograms were unimodal and the mean LDL size was 270 ± 7 A. A small, de...

Atherogenic Lipid Phenotype in a General Group of Subjects

The atherogenic lipid phenotype is a major cardiovascular risk factor, but normal values do not exist derived from 1 analysis in a general study group. To determine normal values of all of the atherogenic lipid phenotype parameters using subjects from a general study group. One hundred two general subjects were used to determine their atherogenic lipid phenotype using polyacrylamide gradient gels. Low-density lipoprotein (LDL) size revealed 24% of subjects express LDL phenotype B, defined as average LDL peak particle size 258 A or less; however, among the Chinese subjects, the expression of the B phenotype was higher at 44% (P = .02). For the total group, mean LDL size was 265 +/- 11 A (1 SD); however, histograms were bimodal in both men and women. After excluding subjects expressing LDL phenotype B, because they are at increased cardiovascular risk and thus are not completely healthy, LDL histograms were unimodal and the mean LDL size was 270 +/- 7 A. A small, dense LDL concentration histogram (total group) revealed skewing; thus, phenotype B subjects were excluded, for the rationale described previously, and the mean value was 13 +/- 9 mg/dL (0.33 +/- 0.23 mmol/L). High-density lipoprotein (HDL) cholesterol histograms were bimodal in both sexes. After removing subjects as described previously or if HDL cholesterol levels were less than 45 mg/dL, histograms were unimodal and revealed a mean HDL cholesterol value of 61 +/- 12 mg/dL (1.56 +/- 0.31 mmol/L). HDL 2, HDL 2a, and HDL 2b were similarly evaluated. Approximate normal values for the atherogenic lipid phenotype, similar to those derived from cardiovascular endpoint trials, can be determined if those high proportions of subjects with dyslipidemic cardiovascular risk are excluded.

Tu-P10:446 Relationship between C-reactive proteine and cerebrovascular stenosis

The fasting atherogenic dyslipidemia of visceral obesity, which includes the presence of small, dense low-density lipoprotein (LDL) particles, is predictive of an increased risk of coronary heart disease (CHD). It has also been suggested that progression of atherosclerosis may be accelerated in the presence of postprandial hyperlipidemia independently from the fasting dyslipidemic state. Studies have shown that the best predictor of postprandial hyperlipidemia and of the small, dense LDL phenotype is fasting triglyceride (TG) concentration. In the present study, we evaluated the impact of postprandial hypertriglyceridemia on the variation in LDL particle size. Fasting (0 hour) and postprandial changes (2, 4, 6, and 8 hours) in LDL particle size were measured by nondenaturing 2% to 16% polyacrylamide gel electrophoresis in a sample of 49 men (mean age ± SD: 46.6 ± 9.2 years) who underwent a standardized breakfast with a high-fat (64% calories as fat) content. The postprandial increase in TG levels was associated with a transient reduction in LDL particle size, the most substantial reduction being observed 4 hours (−1.0 ± 2.4 Å) after the oral fat load. Although there were strong correlations between TG-rich lipoprotein (TRL)-TG levels and LDL particle size in the fasting state (r = −0.71, P < .0001) as well as 4 hours after the oral fat load (r = −0.70, P < .0001), changes in TRL-TG concentrations during the postprandial state (from time 0 to 4 hours) were not associated with changes in LDL particle size during this period (r = −0.04, not significant [NS]). However, among subgroups of men matched for similar fasting TRL-TG levels (n = 12), subjects with the highest total area under the curve (AUC) of TRL-TG after the fat load were characterized by smaller LDL particle size at 6 and 8 hours compared with men with the lowest AUC TRL-TG (P < .02). Men displaying the highest postprandial AUC TRL-TG were also characterized by the greatest accumulation of visceral adipose tissue (AT) (P < .05). These results indicate that the hypertriglyceridemic (hyperTG) state induced by a high-fat meal is associated with a transient reduction in LDL peak particle diameter, which is not proportionate, however, to the level of TG achieved in the postprandial state. Furthermore, despite similar TG levels at baseline, viscerally obese men with an impaired postprandial lipemia had smaller LDL particles at the end of the oral fat load than obese men with a lower accumulation of visceral AT.

Dietary and Genetic Probes of Atherogenic Dyslipidemia

A goal of dietary management of cardiovascular disease risk in patients with obesity and metabolic syndrome is improvement in the atherogenic dyslipidemia comprising elevated triglyceride, reduced high-density lipoprotein (HDL) cholesterol, and increased numbers of small, dense low-density lipoprotein (LDL) particles. Individuals with a genetically influenced trait characterized by a high proportion of small, dense LDL (phenotype B) respond to a low-fat, high-carbohydrate diet with greater reduction of LDL cholesterol, apoprotein B, and mid-sized LDL2 particles than unaffected subjects (phenotype A). In contrast, in phenotype A subjects there is a reciprocal shift from large LDL1 to small LDL3 such that a high proportion convert to phenotype B. There is evidence for heritable effects on these diet-induced subclass changes and for the involvement of specific genes. For example, a haplotype of the APOA5 gene associated with increased plasma triglyceride and small, dense LDL predicts greater diet-induced reduction of LDL2, a haplotype-specific effect that is strongly correlated with both increased VLDL precursors and LDL4 products. Understanding of such diet-genotype interactions may help to elucidate mechanisms that are responsible for phenotype B and for its differential dietary responsiveness. This information may also ultimately help in identifying those individuals who are most likely to achieve cardiovascular risk benefit from specific dietary interventions.