Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

Dron, Jacqueline S.; Ho, Rosettia; Hegele, Robert A.

doi:10.1161/atvbaha.117.309934

Cited by 7 publications

(3 citation statements)

References 108 publications

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“…The most prevalent phenotype is hypertriglyceridemia (40.1%), followed by FH (28.3%). Briefly, patients with hypertriglyceridemia have elevated triglyceride levels (≥ 1.8 mmol/L) and can present with different clinical features depending on whether the patient has a mild-tomoderate (> 1.8 and < 10 mmol/L) or severe (≥ 10 mmol/ L) deviation [33,34]. These patients are referred to clinic to identify a possible genetic basis for their condition, and for recommendation of treatment options.…”

Section: Characterization Of Sequenced Samplesmentioning

confidence: 99%

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

et al. 2020

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Background: In 2013, our laboratory designed a targeted sequencing panel, "LipidSeq", to study the genetic determinants of dyslipidemia and metabolic disorders. Over the last 6 years, we have analyzed 3262 patient samples obtained from our own Lipid Genetics Clinic and international colleagues. Here, we highlight our findings and discuss research benefits and clinical implications of our panel. Methods: LipidSeq targets 69 genes and 185 single-nucleotide polymorphisms (SNPs) either causally related or associated with dyslipidemia and metabolic disorders. This design allows us to simultaneously evaluate monogenic-caused by rare single-nucleotide variants (SNVs) or copy-number variants (CNVs)-and polygenic forms of dyslipidemia. Polygenic determinants were assessed using three polygenic scores, one each for low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol. Results: Among 3262 patient samples evaluated, the majority had hypertriglyceridemia (40.1%) and familial hypercholesterolemia (28.3%). Across all samples, we identified 24,931 unique SNVs, including 2205 rare variants predicted disruptive to protein function, and 77 unique CNVs. Considering our own 1466 clinic patients, LipidSeq results have helped in diagnosis and improving treatment options. Conclusions: Our LipidSeq design based on ontology of lipid disorders has enabled robust detection of variants underlying monogenic and polygenic dyslipidemias. In more than 50 publications related to LipidSeq, we have described novel variants, the polygenic nature of many dyslipidemias-some previously thought to be primarily monogenic-and have uncovered novel mechanisms of disease. We further demonstrate several tangible clinical benefits of its use.

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Section: Characterization Of Sequenced Samplesmentioning

confidence: 99%

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

et al. 2020

Self Cite

View full text Add to dashboard Cite

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“…Thus, there is an urgent need to develop a more personalized medicine, and to enhance patient care through improved diagnostic sensitivity with more effective interventions in ATH prevention and treatment [4]. In this sense, years of research on the genomic basis of ATH have provided the biomedical community with a knowledge of gene‐related ATH risk factors, such as SNPs [5,6], genes and gene variants [7–9], alterations in DNA methylation [10,11], changes in gene expression [12,13], etc. Nevertheless, in the last years a new player has entered the game of disease‐associated genes: the highly heterogeneous group of non‐coding RNAs, which are progressively becoming important factors for atherosclerosis (and other diseases) research either as biomarkers of disease progression or as pathophysiological intermediates, while their operative interactions highlight the remarkable structural and functional complexity of the human genome.…”

Section: Background Atherosclerosis Progression and The Dark Transcrmentioning

confidence: 99%

Unveiling ncRNA regulatory axes in atherosclerosis progression

Navarro

Mallén

Cruzado

et al. 2020

Clinical & Translational Med

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Completion of the human genome sequencing project highlighted the richness of the cellular RNA world, and opened the door to the discovery of a plethora of short and long non‐coding RNAs (the dark transcriptome) with regulatory or structural potential, which shifted the balance of pathological gene alterations from coding to non‐coding RNAs. Thus, disease risk assessment currently has to also evaluate the expression of new RNAs such as small micro RNAs (miRNAs), long non‐coding RNAs (lncRNAs), circular RNAs (circRNAs), competing endogenous RNAs (ceRNAs), retrogressed elements, 3′UTRs of mRNAs, etc. We are interested in the pathogenic mechanisms of atherosclerosis (ATH) progression in patients suffering Chronic Kidney Disease, and in this review, we will focus in the role of the dark transcriptome (non‐coding RNAs) in ATH progression. We will focus in miRNAs and in the formation of regulatory axes or networks with their mRNA targets and with the lncRNAs that function as miRNA sponges or competitive inhibitors of miRNA activity. In this sense, we will pay special attention to retrogressed genomic elements, such as processed pseudogenes and Alu repeated elements, that have been recently seen to also function as miRNA sponges, as well as to the use or miRNA derivatives in gene silencing, anti‐ATH therapies. Along the review, we will discuss technical developments associated to research in lncRNAs, from sequencing technologies to databases, repositories and algorithms to predict miRNA targets, as well as new approaches to miRNA function, such as integrative or enrichment analysis and their potential to unveil RNA regulatory networks.

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“…There are numerous cellular and molecular mechanisms that contribute to the initiation and progression of vascular lesions in atherosclerosis including the infiltration of oxidized lipids into the sub-intima, transformation of macrophages from an anti-inflammatory into a pro-inflammatory phenotype, modification of the extracellular matrix due to imbalance between activities of matrix metalloproteinases and their inhibitors, the development of foam cells, over-production of inflammatory cytokines in the atherosclerotic plaque and within the sub-intima layer, expansion of the lipid core in the plaque and vascular tone dysregulation [7][8][9] . In turn, endothelial and vascular integrity are ensured by interaction of genetic and epigenetic programs that play a pivotal role in the maintenance of vascular homeostasis [10,11] .…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell-derived extracellular vesicles in atherosclerosis: the emerging value for diagnosis, risk stratification and prognostication

Berezin¹,

Berezin²

2020

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Endothelial cell-derived extracellular vesicles are produced by both activated and apoptotic endothelial cells, and play a pivotal role in various physiological conditions such as inflammation, repair, programmed cell death, and immune responses. There is a large body of evidence on the dysregulation of synthesis and secretion of several types of endothelial cell-derived extracellular vesicles, which can then trigger microvascular inflammation, atherosclerotic plaque formation, plaque rupture, thrombosis and endothelial dysfunction. The development of atherosclerosis and cardiovascular events is associated with an increased number of apoptotic, endothelial cellderived vesicles and a decrease in activated, endothelial cell-derived vesicles. This review depicts the role of endothelial cell-derived extracellular vesicles in the manifestation and progression of atherosclerosis. We also discuss the clinical use and benefits of altering the immune phenotypes of extracellular vesicles originating from endothelial cells, to function as predictive biomarkers in both asymptomatic and subclinical atherosclerosis.

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Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

Cited by 7 publications

References 108 publications

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

Unveiling ncRNA regulatory axes in atherosclerosis progression

Endothelial cell-derived extracellular vesicles in atherosclerosis: the emerging value for diagnosis, risk stratification and prognostication

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