scholarly journals Atherosclerosis in Different Vascular Locations Unbiasedly Approached with Mouse Genetics

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1427
Author(s):  
Yukako Kayashima ◽  
Nobuyo Maeda-Smithies
Keyword(s):  
Progenitor Cells ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Strain Differences ◽  
Mouse Genetics ◽  
Genome Wide Association Studies ◽  
Vascular Integrity ◽  
Plaque Development ◽  
Inflammatory Stimuli ◽  
Clinical Consequences

Atherosclerosis in different vascular locations leads to distinct clinical consequences, such as ischemic stroke and myocardial infarction. Genome-wide association studies in humans revealed that genetic loci responsible for carotid plaque and coronary artery disease were not overlapping, suggesting that distinct genetic pathways might be involved for each location. While elevated plasma cholesterol is a common risk factor, plaque development in different vascular beds is influenced by hemodynamics and intrinsic vascular integrity. Despite the limitation of species differences, mouse models provide platforms for unbiased genetic approaches. Mouse strain differences also indicate that susceptibility to atherosclerosis varies, depending on vascular locations, and that the location specificity is genetically controlled. Quantitative trait loci analyses in mice suggested candidate genes, including Mertk and Stab2, although how each gene affects the location-specific atherosclerosis needs further elucidation. Another unbiased approach of single-cell transcriptome analyses revealed the presence of a small subpopulation of vascular smooth muscle cells (VSMCs), which are “hyper-responsive” to inflammatory stimuli. These cells are likely the previously-reported Sca1+ progenitor cells, which can differentiate into multiple lineages in plaques. Further spatiotemporal analyses of the progenitor cells are necessary, since their distribution pattern might be associated with the location-dependent plaque development.

scholarly journals In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

2020 ◽  
Vol 21 (6) ◽  
pp. 2097 ◽  
Author(s):  
Anastasia V. Poznyak ◽  
Andrey V. Grechko ◽  
Reinhard Wetzker ◽  
Alexander N. Orekhov
Keyword(s):  
Animal Models ◽  
Current Knowledge ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Genetically Modified ◽  
Moderate Increase ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
Gene Search ◽  
Atherosclerosis Development

Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr−/−), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE−/−) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr−/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies For The Treatment Of Obesity, Do Agonists = Antagonists?

2019 ◽  
Author(s):  
Elizabeth A Killion ◽  
Shu-Chen Lu ◽  
Madeline Fort ◽  
Yuichiro Yamada ◽  
Murielle M Véniant ◽  
...  
Keyword(s):  
Weight Gain ◽  
Association Studies ◽  
Mouse Genetics ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Genome Wide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

Abstract Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is associated with obesity in human genome-wide association studies (GWAS). Similarly, mouse genetic studies indicate that loss of function alleles and GIP overexpression both protect from high-fat diet (HFD)-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when co-dosed or molecularly combined with glucagon-like peptide-1 (GLP-1) analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the two approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?

2019 ◽  
Vol 41 (1) ◽  
pp. 1-21 ◽  
Author(s):  
Elizabeth A Killion ◽  
Shu-Chen Lu ◽  
Madeline Fort ◽  
Yuichiro Yamada ◽  
Murielle M Véniant ◽  
...  
Keyword(s):  
Weight Gain ◽  
Association Studies ◽  
Mouse Genetics ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Studies ◽  
Genome Wide ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Treatment Of Obesity

Abstract Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet–induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the 2 approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity, and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

Abstract 5: Sortilin Regulates Hepatic VLDL Secretion and LDL Uptake in a Lysosome-Dependent Manner

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Alanna Strong ◽  
Qiurong Ding ◽  
Andrew Edmondson ◽  
Sumeet Khetarpal ◽  
Carlos Morales ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Ldl Receptor ◽  
Genome Wide Association Studies ◽  
Dependent Manner ◽  
Ldl Particles ◽  
Vldl Secretion ◽  
Ldl Uptake

Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of sortilin on both VLDL secretion and LDL turnover is dependent on the ability of sortilin to traffic to the lysosome, as sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between sortilin and the apoB in LDL particles at physiological pH with a K d of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic sortilin overexpression in humans with reduced plasma cholesterol.

scholarly journals The Complex Cardiac Atherosclerotic Disorder: The Elusive Role of Genetics and the New Consensus of Systems Biology Approach

2017 ◽  
Vol 2 ◽  
Author(s):  
George Louridas ◽  
Katerina Lourida
Keyword(s):  
Systems Biology ◽  
Association Studies ◽  
Methodological Approach ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Therapeutic Procedures ◽  
Clinical Consequences ◽  
Artery Disease ◽  
Atherosclerotic Process

<p>The present technological status of genetics and genomics or the genome-wide association studies (GWAS) are insufficient to explain complex diseases like atherosclerosis and coronary artery disease (CAD). It appears that the genetic risk variants of atherosclerosis are activated concurrently with functionally active specific environmental risk factors. With the systems biology methodological approach the atherosclerotic process and CAD are better explained and studied as a unified entity with significant clinical consequences.</p><p>Systems biology is an alternative approach for the study of atherosclerosis and CAD. With the systems biology approach the follow-up of the atherosclerotic process requires four conceptual areas of study: 1) the two potential directions, the bottom-up direction (functional composition from genes to phenotypes) and the top-down direction (functional decomposition from phenotypes to genes); 2) the four disciplines or levels of complexity: the genomic, the cellular, the modular and the model (clinical phenotype) level; 3) the concept of network construction; 4) the atherosclerotic plaque development and progression across all levels of complexity.</p><p>The systems biology methodology is holistic in conception. The proposed systems patterns are able to follow up the progressive nature of atherosclerosis and to explain the appearance of the clinical cardiovascular phenotypes. The phenotypes of CAD are integrated clinical wholes that determine through constrains and therapeutic procedures the behavior of the biological parts in the lower levels of complexity. This way of thinking is leading from genomics, through networks, to the mainstay of clinical cardiology. </p>

Abstract 204: Prioritizing Genome-Wide Association Study Lipid Loci With Global Gene Networks

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jennifer Nguyen ◽  
Brian W Parks
Keyword(s):  
Gene Networks ◽  
Genome Wide Association Study ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Cholesterol Biosynthesis ◽  
Dietary Cholesterol ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

Large genome-wide association studies (GWAS) conducted in humans by the Global Lipids Genetics Consortium (GLGC) have identified more than 150 genome-wide significant loci that are associated with variation in plasma lipid levels (cholesterol, LDL/HDL-cholesterol, and triglycerides). Some loci contain genes with well-described roles in lipid metabolism, such as CETP , LDLR , and APOB ; however, for many genome-wide significant loci, there is no clear causal gene. To test the hypothesis that lipid genes in the liver are co-regulated, we constructed global co-expression gene networks from genome-wide gene expression data obtained from the livers of multiple independent mouse genetic crosses. All together, we constructed global gene networks from eight distinct studies, representing more than 800 unique mice of diverse genetic backgrounds. For all studies analyzed, we identified a module (or sub-network) of genes that is significantly enriched (p<1x10 -15 ) functionally for cholesterol biosynthesis and metabolism genes. This module ranges in size from 70 to 824 genes across the eight studies and contains all genes involved in the cholesterol biosynthesis pathway ( Acat2, Hmgcs2, Hmgcr, Lss, Sc5d, etc. ). This module also contains many genes involved in the regulation of cholesterol metabolism, such as Ldlr , Pcsk9 , and Insig1 . Because of the significant enrichment of cholesterol genes in this module, we have begun to cross-reference all genes in the module against the GLGC lipid GWAS data. Through this analysis, we have identified genes of unknown function that are clearly located within genome-wide significant lipid loci as well as sub-threshold (suggestive significant) lipid loci. Among the genes we identified was Sestrin1 , which was located within a clear sub-threshold locus associated with plasma cholesterol (rs12206606; p=1.4 x 10 -5 ). In conclusion, our studies provide a framework to identify causal genes within reported lipid GWAS loci as well as to identify novel sub-threshold loci associated with variations in lipids among humans. We illustrate the approach by identifying Sestrin1 within a sub-threshold locus associated with plasma cholesterol levels and show that Sestrin1 is transcriptionally regulated in the liver by dietary cholesterol.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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