An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis

Marchetti, Giovanna; Girelli, Domenico; Zerbinati, Carlotta; Lunghi, Barbara; Friso, Simonetta; Meneghetti, Silvia; Coen, Matteo; Gagliano, Teresa; Guastella, Giuseppe; Bochaton‐Piallat, Marie‐Luce; Pizzolo, Francesca; Mascoli, Francesco; Malerba, Giovanni; Bovolenta, Matteo; Ferracin, Manuela; Olivieri, Oliviero; Bernardi, Francesco; Martinelli, Nicola

doi:10.1160/th14-05-0466

Cited by 14 publications

(11 citation statements)

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“…There is also a weaker but significant correlation in the liver in the opposite direction (r = -0.27, p = 0.007) ( Fig 11C , S6 Table ). This gene encodes a protein that is part of the adherens junctions [ 63 ], and PVRL2 mRNA and protein were shown to be elevated in the vessel wall of diseased human carotid arteries [ 64 ] and lesioned mouse aortas [ 65 ]. In addition to genes identified by GWAS approaches, the data from the Ath-HMDP should be useful to identify rare variants affecting atherosclerosis.…”

Section: Resultsmentioning

confidence: 99%

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

et al. 2015

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Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression showed that the combined variations in plasma metabolites, including LDL/VLDL-cholesterol, trimethylamine N-oxide (TMAO), arginine, glucose and insulin, account for approximately 30 to 40% of the variation in atherosclerotic lesion area. Overall, our data provide a rich resource for studies of complex interactions underlying atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

et al. 2015

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“…Although ERCC1 methylation has been previously reported in lung and breast cancer3132, DNAm of BCL3 , SLC1A5 and PPP1R15A were first linked to health-related outcomes in our study. In light of the known gene functions of BCL3 (pathogenesis of CVD and solid tumours)333435, SLC1A5 (a glutamine transporter in various types of cancer development, progression and response to therapy)36 and PPP1R15A (neurological and CVD pathophysiology, as well as obesity and insulin resistance in animal models)373839, it appears plausible that DNAm may play regulating roles in the development or progression of the respective diseases, which requires elucidation in future studies. This also applies to most of the other genes known to be related to specific diseases whose relationship to methylation-relevant outcomes were first disclosed in our study, such as DNAm of SARS , VCAM1 , KCNQ1OT1 , MIR19A , SEMA7A , BCL3 , PPP1R15A and PDE9A for CVD, DNAm of SQLE , MIR19A , MIR10A , SOCS3 , CALR , BCL3 and SLC1A5 for lung cancer, and DNAm of ATL3 , SHANK2 and PPP1R15A for neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation signatures in peripheral blood strongly predict all-cause mortality

et al. 2017

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DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10–4.24), 3.42 (1.81–6.46) and 7.36 (3.69–14.68), respectively, for participants with scores of 1, 2–5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the ‘epigenetic clock'. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification.

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“…Microarray raw-data were obtained with Feature Extraction software v.10.7 (Agilent Technologies) and analyzed by using the GeneSpring GX v.14 software (Agilent Technologies) as previously described (Coen et al 2013a ; Marchetti et al 2015 ).…”

Section: Methodsmentioning

confidence: 99%

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis

Marchetti

Ziliotto

Meneghetti

et al. 2018

Mol Med

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BackgroundMultiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels.MethodsWe studied a group of MS patients (n = 19), screened by echo-color Doppler and magnetic resonance venography, who underwent surgical reconstruction of IJV for chronic cerebrospinal venous insufficiency (CCSVI). Microarray-based transcriptome analysis was conducted on specimens of IJV wall from MS patients and from subjects undergoing carotid endarterectomy, as controls. Protein levels were determined by multiplex assay in: i) jugular and peripheral plasma from 17 MS/CCSVI patients; ii) peripheral plasma from 60 progressive MS patients, after repeated sampling and iii) healthy individuals.ResultsOf the differentially expressed genes (≥ 2 fold-change, multiple testing correction, P < 0.05), the immune-related CD86 (8.5 fold-change, P = 0.002) emerged among the up regulated genes (N = 409). Several genes encoding HOX transcription factors and histones potentially regulated by blood flow, were overexpressed. Smooth muscle contraction and cell adhesion processes emerged among down regulated genes (N = 515), including the neuronal cell adhesion L1CAM as top scorer (5 fold-change, P = 5 × 10− 4).Repeated measurements in jugular/peripheral plasma and overtime in peripheral plasma showed conserved individual plasma patterns for immune-inflammatory (CCL13, CCL18) and adhesion (NCAM1, VAP1, SELL) proteins, despite significant variations overtime (SELL P < 0.0001). Both age and MS disease phenotypes were determinants of VAP1 plasma levels.Data supported cerebral related-mechanisms regulating ANGPT1 levels, which were remarkably lower in jugular plasma and correlated in repeated assays but not between jugular/peripheral compartments.ConclusionsThis study provides for the first time expression patterns of the IJV wall, suggesting signatures of altered vascular mRNA profiles in MS disease also independently from CCSVI. The combined transcriptome-protein analysis provides intriguing links between IJV wall transcript alteration and plasma protein expression, thus highlighting proteins of interest for MS pathophysiology.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0043-4) contains supplementary material, which is available to authorized users.

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An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis

Cited by 14 publications

References 50 publications

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains

DNA methylation signatures in peripheral blood strongly predict all-cause mortality

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis

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