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Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

ABSTRACT: The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n?=?8-13/strain) and two progenitor strains SHR-Lx (n?=?13) and BXH2/Cub (n?=?18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains.

SUBMITTER: Hodulova M

PROVIDER: S-EPMC4190321 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

Hodúlová Miloslava M Šedová Lucie L Křenová Drahomíra D Liška František F Krupková Michaela M Kazdová Ludmila L Tremblay Johanne J Hamet Pavel P Křen Vladimír V Šeda Ondřej O

PloS one 20141008 10

The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate togethe ...[more]

PMID: 25296178

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Project description:BackgroundElevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease.ObjectivesThe purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD).MethodsIn a prospective case-cohort study within the Women's Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.ResultsThe risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HRQ4: 2.58 [95% CI: 1.18 to 5.63]; ptrend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71 [95% CI: 1.59 to 8.63]; ptrend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl).ConclusionsTRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women's Health Study; NCT00000479).

Project description:BackgroundThe coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can lead to serious complications such as respiratory failure, requiring mechanical ventilation or ICU care, and can even result in death, especially in older patients with comorbidities. The ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), a biomarker of atherosclerotic dyslipidemia and insulin resistance, is related to cardiovascular mortality and morbidity. We aimed to evaluate the link between serious complications of COVID-19 and TG/HDL in the general population.MethodsWe conducted a comprehensive analysis of 3,933 COVID-19 patients from a nationwide cohort in Korea spanning from January 1 to June 4, 2020. TG/HDL ratio was calculated from the national health screening examination data underwent before the COVID-19 infection. Serious complications of COVID-19 were defined as a composite of high-flow oxygen therapy, mechanical ventilation, admission to the intensive care unit (ICU), and mortality. We employed logistic regression analysis to investigate the relationship between the TG/HDL ratio and the likelihood of developing severe complications within 2 months of the diagnosis. To visualize this association, we used a smoothing spline plot based on the generalized additive regression model. Multivariate analysis was performed with adjustment for age, gender, body mass index, lifestyle measures, and comorbidities.ResultsAmong the 3,933 COVID-19 patients, the proportion of serious complications was 7.53%. Regarding individual outcomes, the number of patients who received high-flow oxygen therapy, mechanical ventilation, ICU care, and died was 84 (2.14%), 122 (3.10%), 173 (4.40%), and 118 (3.00%), respectively. In the multivariable logistic regression, a positive association was found between TG/HDL ratio and serious complications of COVID-19 (adjusted OR, 1.09; 95% CI [1.03-1.15], p = 0.004).ConclusionOur study revealed a significant positive association between TG/HDL ratio and the risk of developing severe complications in COVID-19-infected patients. While this finding provides valuable insight into the potential prognostic role of TG/HDL ratio in COVID-19, further studies are needed to fully elucidate the underlying mechanisms behind this relationship.

Project description:ImportanceLow-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited.ObjectiveTo compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations.Design, setting, and participantsThis cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021.Main outcomes and measuresAccuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression.ResultsA total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (<40, 40-69, 70-99, 100-129, 130-159, 160-189, and ≥190), estimation of LDL-C by the extended Martin/Hopkins equation was most accurate (62.1%) compared with the Friedewald (19.3%) and Sampson (40.4%) equations. In classifying LDL-C levels less than 70 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (67.3%) compared with Friedewald (5.1%) and Sampson (26.4%) equations. In addition, for classifying LDL-C levels less than 40 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (57.2%) compared with the Friedewald (4.3%) and Sampson (14.4%) equations. However, considerable underclassification of LDL-C occurred. The magnitude of error between the Martin/Hopkins equation estimation and dLDL-C was also smaller: at LDL-C levels less than 40 mg/dL, 2.7% of patients had 30 mg/dL or greater differences between dLDL-C and estimated LDL-C using the Martin/Hopkins equation compared with the Friedewald (92.5%) and Sampson (38.7%) equations.Conclusions and relevanceIn this cross-sectional study, the extended Martin/Hopkins equation offered greater LDL-C accuracy compared with the Friedewald and Sampson equations in patients with triglyceride levels of 400 to 799 mg/dL. However, regardless of method used, caution is advised with LDL-C estimation in this triglyceride range.

Dataset Information

Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

Publications

Genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the rat.

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