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- Franceschini, N., et al.
(author)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Journal article (peer-reviewed)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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- Benavente, ED, et al.
(author)
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Female gene networks are expressed in myofibroblast-like smooth muscle cells in vulnerable atherosclerotic plaques
- 2023
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In: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Women presenting with coronary artery disease (CAD) more often present with fibrous atherosclerotic plaques, which are currently understudied. Phenotypically modulated smooth muscle cells (SMCs) contribute to atherosclerosis in women. How these phenotypically modulated SMCs shape female versus male plaques is unknown. Here, we show sex-stratified gene regulatory networks (GRNs) from human carotid atherosclerotic tissue. Prioritization of these networks identified two main SMC GRNs in late-stage atherosclerosis. Single-cell RNA-sequencing mapped these GRNs to two SMC phenotypes: a phenotypically modulated myofibroblast-like SMC network and a contractile SMC network. The myofibroblast-like GRN was mostly expressed in plaques that were vulnerable in females. Finally, mice orthologs of the female myofibroblast-like genes showed retained expression in advanced plaques from female mice but were downregulated in male mice during atherosclerosis progression. Female atherosclerosis is driven by GRNs that promote a fibrous vulnerable plaque rich in myofibroblast-like SMCs.
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- Dusart, Philip, et al.
(author)
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A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein
- 2018
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein.
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- Olin, JW, et al.
(author)
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A plasma proteogenomic signature for fibromuscular dysplasia
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:1, s. 63-77
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Journal article (peer-reviewed)abstract
- AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
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- Jha, Abhishek, et al.
(author)
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High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma
- 2021
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In: Clinical Cancer Research. - : American Association For Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 27:11, s. 2989-2995
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Journal article (peer-reviewed)abstract
- Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.
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