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Search Results: 1 - 10 of 404709 matches for " Ronald M. Krauss "
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Levels of Cholesterol in Small LDL Particles Predict Atherosclerosis Progression and Incident CHD in the HDL-Atherosclerosis Treatment Study (HATS)
Paul T. Williams, Xue-Qiao Zhao, Santica M. Marcovina, B. Greg Brown, Ronald M. Krauss
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056782
Abstract: Objective Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. Methods Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. Results The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2–24.6 nm) and LDL-IVa (23.3–24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. Conclusions Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. Trial Registration ClinicalTrials.gov NCT00000553
Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes
Maxwell A. Ruby, Daniel K. Nomura, Carolyn S. S. Hudak, Anne Barber, John E. Casida, Ronald M. Krauss
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026415
Abstract: Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes.
RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin
Marisa W. Medina ,Elizabeth Theusch,Devesh Naidoo,Frederick Bauzon,Kristen Stevens,Lara M. Mangravite,Yu-Lin Kuang,Ronald M. Krauss
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003058
Abstract: Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the changes in plasma total cholesterol, LDL-cholesterol, and APOB induced by simvastatin treatment (40 mg/d for 6 wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of rs11716445, a SNP located in a novel cryptic RHOA exon, dramatically increased inclusion of the exon in RHOA transcripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participants from the CAP and Pravastatin Inflamation and CRP Evaluation (PRINCE; pravastatin 40 mg/d) statin clinical trials. Thus, an unbiased filter approach based on transcriptome-wide profiling identified RHOA as a gene contributing to variation in LDL-cholesterol response to statin, illustrating the power of this approach for identifying candidate genes involved in drug response phenotypes.
Coordinately Regulated Alternative Splicing of Genes Involved in Cholesterol Biosynthesis and Uptake
Marisa Wong Medina,Feng Gao,Devesh Naidoo,Lawrence L. Rudel,Ryan E. Temel,Allison L. McDaniel,Stephanie M. Marshall,Ronald M. Krauss
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019420
Abstract: Genes involved in cholesterol biosynthesis and uptake are transcriptionally regulated in response to cellular sterol content in a coordinated manner. A number of these genes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR), undergo alternative splicing, resulting in reductions of enzyme or protein activity. Here we demonstrate that cellular sterol depletion suppresses, and sterol loading induces, alternative splicing of multiple genes involved in the maintenance of cholesterol homeostasis including HMGCR and LDLR, the key regulators of cellular cholesterol biosynthesis and uptake, respectively. These changes were observed in both in vitro studies of the HepG2 human hepatoma derived cell line, as well as in vivo studies of St. Kitts vervets, also known as African green monkeys, a commonly used primate model for investigating cholesterol metabolism. These effects are mediated in part by sterol regulation of polypyrimidine tract binding protein 1 (PTBP1), since knock-down of PTBP1 eliminates sterol induced changes in alternative splicing of several of these genes. Single nucleotide polymorphisms (SNPs) that influence HMGCR and LDLR alternative splicing (rs3846662 and rs688, respectively), have been associated with variation in plasma LDL-cholesterol levels. Sterol-induced changes in alternative splicing are blunted in carriers of the minor alleles for each of these SNPs, indicating an interaction between genetic and non-genetic regulation of this process. Our results implicate alternative splicing as a novel mechanism of enhancing the robust transcriptional response to conditions of cellular cholesterol depletion or accumulation. Thus coordinated regulation of alternative splicing may contribute to cellular cholesterol homeostasis as well as plasma LDL levels.
Metabolomics Reveals Amino Acids Contribute to Variation in Response to Simvastatin Treatment
Miles Trupp, Hongjie Zhu, William R. Wikoff, Rebecca A. Baillie, Zhao-Bang Zeng, Peter D. Karp, Oliver Fiehn, Ronald M. Krauss, Rima Kaddurah-Daouk
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038386
Abstract: Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution (“good” and “poor” responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. Trial Registration ClinicalTrials.gov NCT00451828
Harnessing Expression Data to Identify Novel Candidate Genes in Polycystic Ovary Syndrome
Michelle R. Jones,Angela Chua,Yii-Der I. Chen,Xiaohui Li,Ronald M. Krauss,Jerome I. Rotter,Richard S. Legro,Ricardo Azziz,Mark O. Goodarzi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020120
Abstract: Novel pathways in polycystic ovary syndrome (PCOS) are being identified in gene expression studies in PCOS tissues; such pathways may contain key genes in disease etiology. Previous expression studies identified both dickkopf homolog 1 (DKK1) and DnaJ (Hsp40) homolog, subfamily B, member 1 (DNAJB1) as differentially expressed in PCOS tissue, implicating them as candidates for PCOS susceptibility. To test this, we genotyped a discovery cohort of 335 PCOS cases and 198 healthy controls for three DKK1 single nucleotide polymorphisms (SNPs) and four DNAJB1 SNPs and a replication cohort of 396 PCOS cases and 306 healthy controls for 1 DKK1 SNP and 1 DNAJB1 SNP. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. We found that no single nucleotide polymorphisms were associated with PCOS risk; however, the major allele of rs1569198 from DKK1 was associated with increased total testosterone (discovery cohort P = 0.0035) and dehydroepiandrosterone sulfate (replication cohort P = 0.05). Minor allele carriers at rs3962158 from DNAJB1 had increased fasting insulin (discovery cohort P = 0.003), increased HOMA-IR (discovery cohort P = 0.006; replication cohort P = 0.036), and increased HOMA-%B (discovery cohort P = 0.004). Carriers of haplotype 2 at DNAJB1 also had increased fasting insulin, HOMA-IR, and HOMA-%B. These findings suggest that genetic variation in DKK1 and DNAJB1 may have a role in the hyperandrogenic and metabolic dysfunction of PCOS, respectively. Our results also demonstrate the utility of gene expression data as a source of novel candidate genes in PCOS, a complex and still incompletely defined disease, for which alternative methods of gene identification are needed.
CNR1 Genotype Influences HDL-Cholesterol Response to Change in Dietary Fat Intake
Heidi J. Silver, Kevin D. Niswender, Charles D. Keil, Lan Jiang, Qiping Feng, Sally Chiu, Ronald M. Krauss, Russell A. Wilke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036166
Abstract: Background Success in further reducing the burden of cardiovascular disease (CVD) is threatened by the increasing prevalence of obesity-related atherogenic dyslipidemia. HDL-cholesterol (HDL-C) level is inversely correlated with CVD risk; each 1 mg/dl decrease in HDL-C is associated with a 6% reduction in risk. We previously showed that a common CNR1 haplotype, H3 (frequency 20%), is protective against the reduction in HDL-C that typically accompanies weight gain. In the present study, we extend that observation by reporting the effect of CNR1 haplotype on HDL-C response to modification of dietary fat intake in weight maintenance and weight loss. Methods Six haplotype tagging SNPs that cover the CNR1 gene locus were genotyped in 590 adults of varying body mass index (cohort 1 is 411 males with BMI 18.5–30.0 kg/m2; cohort 2 is 71 females with BMI18.5–30.0 kg/m2; and cohort 3 is 108 females with BMI 30–39.9 kg/m2). Dietary intakes were modified so that fat intake in the “high fat” condition was 15–20% greater than in the “low fat” condition, and lipid profiles were compared between carriers versus noncarriers for each of the five commonly observed CNR1 haplotypes (H1–H5). Results In normal to overweight subjects on eucaloric diets, the H3 haplotype was significantly associated with short-term high fat diet induced changes in HDL-C level in females (carriers 5.9 mg/dl>noncarriers, p = 0.007). The H3 haplotype was also significantly associated with HDL-C level after 16 weeks on high fat calorie restricted diet in obese females (carriers 6.8 mg/dl>noncarriers, p = 0.009). Conclusion Variability within the CNR1 gene locus contributes to gender-related differences in the HDL-cholesterol response to change in dietary fat intake. Functional characterization of this relationship in vitro may offer insights that potentially yield therapeutic guidance targeting dietary macronutrient composition, a direction much needed in the current epidemic of obesity.
Tracing Sub-Structure in the European American Population with PCA-Informative Markers
Peristera Paschou equal contributor ,Petros Drineas equal contributor,Jamey Lewis,Caroline M. Nievergelt,Deborah A. Nickerson,Joshua D. Smith,Paul M. Ridker,Daniel I. Chasman,Ronald M. Krauss,Elad Ziv
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000114
Abstract: Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals–307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150–200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs.
Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment
Rima Kaddurah-Daouk, Rebecca A. Baillie, Hongjie Zhu, Zhao-Bang Zeng, Michelle M. Wiest, Uyen Thao Nguyen, Katie Wojnoonski, Steven M. Watkins, Miles Trupp, Ronald M. Krauss
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025482
Abstract: Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.
Dark Matter Candidates: What Cold, ..and What's Not
Krauss, Lawrence M.
High Energy Physics - Phenomenology , 2007,
Abstract: In this brief review of recent theoretical developments associated with the search for dark matter I describe the following: why baryons are now ruled out as dark matter candidates; SUSY WIMPS and signatures in the MSSM and NMSSM why claimed indirect signatures are probably not WIMP related, why axions may be of new interest, how WIMP detection might tell us about the galactic halo, and how theorists are preparing to avoid the next generation of experimental constraints.
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