• ABCA1
• Analphalipoproteinemia
• Familial high-density lipoprotein deficiency 1
• High-density lipoprotein cholesterol
• Histiocytosis
• Primary hypoalphalipoproteinemia 4
• Tangier Disease

• Atherosclerosis
• genes
• hemodynamics
• inflammation
• lipid metabolism
• non-coding RNAs.
• regulation

• Humans
• Atherosclerosis/genetics
• Atherosclerosis/metabolism
• Inflammation

• HDL
• LDL
• VLDL
• apolipoproteins
• ceramides
• genetic architecture
• genomics
• lipoproteins/metabolism

• Female
• Humans
• Mice
• Animals
• Collaborative Cross Mice
• Genome-Wide Association Study
• Lipoproteins/genetics
• Quantitative Trait Loci/genetics
• Phenotype
• Lipoproteins, VLDL

• T32 HL007936 NHLBI NIH HHS
• R01 DK101573 NIDDK NIH HHS
• R01 DK102948 NIDDK NIH HHS
• RC2 DK125961 NIDDK NIH HHS
• R01 DK130296 NIDDK NIH HHS
• R01 DK122001 NIDDK NIH HHS
• MR/S003703/1 Medical Research Council
• T32 DK091317 NIDDK NIH HHS

• atherosclerosis
• epigenetics
• genes
• inflammation
• lipid mediators
• lncRNAs
• microRNA
• polymorphism

• Atherosclerosis/metabolism
• Cholesterol/genetics
• Cholesterol/metabolism
• Epigenesis, Genetic
• Humans
• Inflammation/genetics
• Lipid Metabolism
• Lipoxygenases/genetics

• CRISPR/Cas9
• Syrian golden hamster
• atherosclerosis
• cardiovascular disease
• mouse

• National Natural Science Foundation of China
• Peking University

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis.

Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels.

• ATP-binding cassette transporter
• cholesterol efflux
• hematopoietic stem and progenitor cells
• leukemia biology
• somatic mutations
• ten-eleven translocation 2

• Beta-2 adrenoceptor agonists
• Cystic fibrosis transmembrane conductance regulator
• Glucocorticoids
• Multi-drug resistance protein-4
• Phosphodiesterase-4

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function.

• ABCA1
• NBD1
• in silico
• molecular dynamics simulations
• nsSNPs
• polymorphism

• bioinformatic analysis
• diagnostic tools
• dyslipidemias
• genetic testing
• human genetics
• lipoprotein lipase
• next-generation sequencing
• triglycerides

• Clustered phenotypes
• Generalized estimating equations
• Pathway analysis
• Rare variants

• Cluster Analysis
• Computational Biology/methods
• Genetic Variation
• Phenotype
• Exome Sequencing

• chitosan
• cholesterol
• macrophage
• microRNA
• nanoparticle

• ATP Binding Cassette Transporter 1/genetics
• ATP Binding Cassette Transporter 1/metabolism
• Animals
• Cells, Cultured
• Chitosan/analogs & derivatives
• Cholesterol/blood
• Cholesterol/metabolism
• Gene Transfer Techniques
• Liver/metabolism
• Macrophages, Peritoneal/metabolism
• Mice
• Mice, Inbred C57BL
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Nanoparticles/chemistry
• RNAi Therapeutics/methods

Brain-specific angiogenesis inhibitors (BAIs) 1, 2, and 3 are members of the adhesion G protein-coupled receptors, subfamily B, which share a conserved seven-transmembrane structure and an N-terminal extracellular domain. In cell- and animal-based studies, these receptors have been shown to play diverse roles under physiological and pathological conditions. BAI1 is an engulfment receptor and performs major functions in apoptotic-cell clearance and interacts (as a pattern recognition receptor) with pathogen components. BAI1 and -3 also participate in myoblast fusion. Furthermore, BAI1–3 have been linked to tumor progression and neurological diseases. In this review, we summarize the current understanding of the functions of BAI1–3 in pathological and physiological conditions and discuss future directions in terms of the importance of BAIs as pharmacological targets in diseases.

• apoptotic cell clearance
• brain-specific angiogenesis inhibitor
• engulfment
• tumorigenesis

• GWAS
• Hi-C
• Mendelian
• body mass index
• common disease
• complex traits
• monogenic
• polygenic
• statistical genetics

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV^® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.

• ATP-binding cassette subfamily A member 1
• bioinformatic analysis
• copy-number variation
• diagnostic tools
• dyslipidemia
• genetic testing
• high density lipoprotein cholesterol
• next-generation sequencing

• hdl biogenesis
• hdl phenotypes
• apolipoprotein a-i mutations
• apolipoprotein e
• apolipoprotein a-iv
• atp- binding cassette transporter a1 (abca1)

• Tangier
• demyelinating
• hypoalphalipoproteinemia
• neuropathy

• HDL heterogeneity
• Inhibitors of ABCA1-mediated cholesterol efflux
• Mechanism of HDL formation
• Reconstituted HDL
• Tangier disease mutations

• Computational Biology/methods
• Computer Simulation
• Databases, Factual
• Exome
• Genetic Variation
• High-Throughput Nucleotide Sequencing
• Humans
• Liver/enzymology
• Oligonucleotide Array Sequence Analysis
• Phenotype

• U01 DK085501 NIDDK NIH HHS
• U01 DK085524 NIDDK NIH HHS
• U01 DK085545 NIDDK NIH HHS
• U01 DK085526 NIDDK NIH HHS
• U01 DK085584 NIDDK NIH HHS
• P30 DK020595 NIDDK NIH HHS

This meta-analysis investigated the correlation of ABCA1 R219K and CRP +1059G/C gene polymorphisms with susceptibility to coronary heart disease (CHD).

We searched PubMed, Springer link, Wiley, EBSCO, Ovid, Wanfang database, VIP database, and China National Knowledge Infrastructure (CNKI) databases to retrieve published studies by keyword. Searches were filtered using our stringent inclusion and exclusion criteria. Resultant high-quality data collected from the final selected studies were analyzed using Comprehensive Meta-analysis 2.0 software. Eleven case-control studies involving 3053 CHD patients and 3403 healthy controls met our inclusion criteria. Seven studies were conducted in Asian populations, 3 studies were done in Caucasian populations, and 1 was in an African population.

Our major finding was that ABCA1 R219K polymorphism increased susceptibility to CHD in allele model (OR=0.729, 95% CI=0.559~0.949, P=0.019) and dominant model (OR=0.698, 95% CI=0.507~0.961, P=0.027). By contrast, we were unable to find any significant association between the CRP +1059G/C polymorphism and susceptibility to CHD (allele model: OR=1.170, 95% CI=0.782~1.751, P=0.444; dominant model: OR=1.175, 95% CI=0.768~1.797, P=0.457).

This meta-analysis provides convincing evidence that polymorphism of ABCA1 R219K is associated with susceptibility to CHD while the CRP +1059G/C polymorphism appears to have no correlation with susceptibility to CHD.

• Förster resonance energy transfer (FRET)
• apolipoprotein A-I (apoA-I)
• electron microscopy (EM)
• electron paramagnetic spectroscopy (EPR)
• high density lipoprotein (HDL)
• hydrogen–deuterium exchange mass spectrometry (HDX-MS)
• molecular dynamics (MD) simulation
• small angle neutron scattering (SANS) with contrast variation

• HDL cholesterol
• Metabolic syndrome X
• Obesity
• Triglycerides

• ATP Binding Cassette Transporter 1/biosynthesis
• ATP Binding Cassette Transporter 1/deficiency
• ATP Binding Cassette Transporter 1/genetics
• Adaptor Proteins, Signal Transducing/deficiency
• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Angiogenic Proteins/genetics
• Angiogenic Proteins/metabolism
• Animals
• Apoptosis/physiology
• Cell Membrane/metabolism
• Cholesterol/metabolism
• Female
• Humans
• Jurkat Cells
• Lipid Metabolism
• Liver X Receptors
• Macrophages/cytology
• Macrophages/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neuropeptides/deficiency
• Neuropeptides/genetics
• Neuropeptides/metabolism
• Orphan Nuclear Receptors/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Signal Transduction
• Up-Regulation
• rac1 GTP-Binding Protein/deficiency
• rac1 GTP-Binding Protein/genetics
• rac1 GTP-Binding Protein/metabolism

• T32 GM007267 NIGMS NIH HHS
• HL120840 NHLBI NIH HHS
• P01 HL120840 NHLBI NIH HHS
• T32 AI007496 NIAID NIH HHS
• P30 CA044579 NCI NIH HHS
• GM064709 NIGMS NIH HHS
• R01 GM064709 NIGMS NIH HHS

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis. Macrophage generation of oxysterol activators of liver X receptors (LXRs), via sterol 27-hydroxylase, is regulated by the rate of flux of cholesterol to the inner mitochondrial membrane, via a complex of cholesterol trafficking proteins. Oxysterols are key signalling molecules, regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production, key features influencing the impact of these cells within atherosclerotic lesions. The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate, but may include steroidogenic acute regulatory protein and translocator protein. There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters (ABCA1, ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages. Thus, molecules which can sustain or improve mitochondrial structure, the function of the electron transport chain, or increase the activity of components of the protein complex involved in cholesterol transfer, may therefore have utility in limiting or regressing atheroma development, reducing the incidence of coronary heart disease and myocardial infarction.

• Atherosclerosis
• Macrophage
• Cholesterol
• High density lipoproteins
• Apolipoproteins
• ATP binding cassette transporters
• Scavenger receptor B1
• Mitochondria (dys)function
• Sterol 27-hydroxylase
• Liver X receptors

• Niemann–Pick disease type C
• Smith–Lemli–Opitz syndrome
• Tangier disease
• cholesterol
• sphingolipids

The CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Sequencing Project is a national, collaborative effort from 3 studies: Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), and Atherosclerosis Risk in Communities (ARIC). It uses a case-cohort design, whereby a random sample of study participants is enriched with participants in extremes of traits. Although statistical methods are available to investigate the role of rare variants, few have evaluated their performance in a case-cohort design.

We evaluate several methods, including the sequence kernel association test (SKAT), Score-Seq, and weighted (Madsen and Browning) and unweighted burden tests. Using genotypes from the CHARGE targeted-sequencing project for FHS (n = 1096), we simulate phenotypes in a large population for 11 correlated traits and then sample individuals to mimic the CHARGE Sequencing study design. We evaluate type I error and power for 77 targeted regions.

We provide some guidelines on the performance of these aggregate-based tests to detect associations with rare variants when applied to case-cohort study designs, using CHARGE targeted sequencing data. Type I error is conservative when we consider variants with minor allele frequency (MAF) < 1%. Power is generally low, although it is relatively larger for Score-Seq. Greater numbers of causal variants and a greater proportion of variance improve the power, but it tends to be lower in the presence of bi-directionality of effects of causal genotypes, especially for Score-Seq.

The online version of this article (doi:10.1186/s12863-014-0104-9) contains supplementary material, which is available to authorized users.

• Carotid intima media thickness
• Cholesterol efflux
• Endothelium
• HDL subclasses
• High density lipoprotein
• Inherited HDL disorder

• Dyslipidemias/etiology
• Humans
• Leg
• Male
• Middle Aged
• Muscle Weakness/etiology
• Tangier Disease/complications
• Tangier Disease/diagnosis

• Animals
• Atherosclerosis/drug therapy
• Atherosclerosis/epidemiology
• Atherosclerosis/genetics
• Drug Discovery
• Fibric Acids/therapeutic use
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Pharmacogenetics

• Lipoproteins
• Macrophage cholesterol efflux
• Metabolic syndrome
• Obesity
• Weight loss

• Adult
• Apolipoprotein A-I/blood
• Apolipoproteins B/blood
• Blood Pressure
• Cholesterol/metabolism
• Cholesterol, HDL/metabolism
• Diet
• Dyslipidemias/metabolism
• Dyslipidemias/pathology
• Female
• Humans
• Insulin Resistance
• Macrophages/metabolism
• Male
• Metabolic Syndrome/blood
• Metabolic Syndrome/pathology
• Middle Aged
• Weight Loss

• R01 HL030914 NHLBI NIH HHS
• T32 HL007812 NHLBI NIH HHS
• R01 HL129767 NHLBI NIH HHS
• R01 HL056865 NHLBI NIH HHS
• HL030914 NHLBI NIH HHS

• ATP-binding cassette transporter A1 (ABCA1)
• Gene polymorphism
• Ischemic stroke
• Meta analysis
• R219K
• The Chinese population

• Genetic Heterogeneity
• Genome-Wide Association Study
• Humans
• Linkage Disequilibrium
• Parents