22 results on '"H. Foroughi Asl"'
Search Results
2. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib.
- Author
-
Bonfiglio S, Sutton LA, Ljungström V, Capasso A, Pandzic T, Weström S, Foroughi-Asl H, Skaftason A, Gellerbring A, Lyander A, Gandini F, Gaidano G, Trentin L, Bonello L, Reda G, Bödör C, Stavroyianni N, Tam CS, Marasca R, Forconi F, Panayiotidis P, Ringshausen I, Jaksic O, Frustaci AM, Iyengar S, Coscia M, Mulligan SP, Ysebaert L, Strugov V, Pavlovsky C, Walewska R, Österborg A, Cortese D, Ranghetti P, Baliakas P, Stamatopoulos K, Scarfò L, Rosenquist R, and Ghia P
- Subjects
- Humans, Agammaglobulinaemia Tyrosine Kinase genetics, Drug Resistance, Neoplasm genetics, Piperidines, Recurrence, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
3. The BioLymph study - implementing precision medicine approaches in lymphoma diagnostics, treatment and follow-up: feasibility and first results.
- Author
-
Smedby KE, Wästerlid T, Tham E, Haider Z, Joelsson J, Thorvaldsdottir B, Krstic A, Wahlin BE, Foroughi-Asl H, Karlsson C, Eloranta S, Saft L, Palma M, Kwiecinska A, Hansson L, Österborg A, Wirta V, Rassidakis G, Sander B, Sonnevi K, and Rosenquist R
- Subjects
- Humans, Feasibility Studies, Precision Medicine methods, Lymphoma diagnosis, Lymphoma genetics, Lymphoma therapy
- Published
- 2023
- Full Text
- View/download PDF
4. Sensitive Detection of Cell-Free Tumour DNA Using Optimised Targeted Sequencing Can Predict Prognosis in Gastro-Oesophageal Cancer.
- Author
-
Wallander K, Haider Z, Jeggari A, Foroughi-Asl H, Gellerbring A, Lyander A, Chozhan A, Cuba Gyllensten O, Hägglund M, Wirta V, Nordenskjöld M, Lindblad M, and Tham E
- Abstract
In this longitudinal study, cell-free tumour DNA (a liquid biopsy) from plasma was explored as a prognostic biomarker for gastro-oesophageal cancer. Both tumour-informed and tumour-agnostic approaches for plasma variant filtering were evaluated in 47 participants. This was possible through sequencing of DNA from tissue biopsies from all participants and cell-free DNA from plasma sampled before and after surgery (n = 42), as well as DNA from white blood cells (n = 21) using a custom gene panel with and without unique molecular identifiers (UMIs). A subset of the plasma samples (n = 12) was also assayed with targeted droplet digital PCR (ddPCR). In 17/31 (55%) diagnostic plasma samples, tissue-verified cancer-associated variants could be detected by the gene panel. In the tumour-agnostic approach, 26 participants (59%) had cancer-associated variants, and UMIs were necessary to filter the true variants from the technical artefacts. Additionally, clonal haematopoietic variants could be excluded using the matched white blood cells or follow-up plasma samples. ddPCR detected its targets in 10/12 (83%) and provided an ultra-sensitive method for follow-up. Detectable cancer-associated variants in plasma correlated to a shorter overall survival and shorter time to progression, with a significant correlation for the tumour-informed approaches. In summary, liquid biopsy gene panel sequencing using a tumour-agnostic approach can be applied to all patients regardless of the presence of a tissue biopsy, although this requires UMIs and the exclusion of clonal haematopoietic variants. However, if sequencing data from tumour biopsies are available, a tumour-informed approach improves the value of cell-free tumour DNA as a negative prognostic biomarker in gastro-oesophageal cancer patients., Competing Interests: V.W. received speaker’s honoraria from Illumina and Roche, apart from that the authors declare no conflict of interest.
- Published
- 2023
- Full Text
- View/download PDF
5. Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
- Author
-
Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
- Published
- 2023
- Full Text
- View/download PDF
6. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
- Author
-
Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, and Rosenquist R
- Subjects
- Humans, Prognosis, Myeloid Differentiation Factor 88 genetics, Mutation, Phenotype, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management., (© 2022. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
7. Genomic profile - a possible diagnostic and prognostic marker in upper tract urothelial carcinoma.
- Author
-
Grahn A, Eisfeldt J, Malm C, Foroughi Asl H, Jaremko G, Tham E, and Brehmer M
- Subjects
- Genomics methods, Humans, Kidney abnormalities, Nephroureterectomy, Prognosis, Urogenital Abnormalities, Carcinoma, Transitional Cell diagnosis, Carcinoma, Transitional Cell genetics, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Ureteral Neoplasms pathology, Urinary Bladder Neoplasms genetics
- Abstract
Objectives: To investigate gene alterations as diagnostic and prognostic markers in upper tract urothelial carcinoma (UTUC)., Patients and Methods: Patients with UTUC who underwent nephroureterectomy between 2005 and 2012 were followed until November 2020. DNA was extracted from paraffin-embedded tumour tissue. Next-generation sequencing using a 388-gene panel was performed. First a blinded analysis using principal component analysis and hierarchical clustering was used to search for patterns of mutations. Then a comparative analysis using analysis of variance (ANOVA) was used to search for mutations enriched in groups of various grades, stages, and survival. In addition, careful manual annotation was used to identify pathogenic mutations over-represented in tumours of high grade/stage and/or poor survival., Results: A total of 39 patients were included. All tumour stages and grades were represented in the cohort. The median follow-up was 10.6 years. In all, 11 patients died from UTUC during the follow-up. Tumour mutational burden showed a statistically significant correlation with stage, grade, and stage + grade. Grade 1, Grade 2, and Grade 3 tumours had different mutational patterns. Patients who died from UTUC had pathogenic mutations in specific genes e.g. tumour protein p53 (TP53) and HRas proto-oncogene, GTPase (HRAS). Patients with Ta Grade 1 tumours with a known pathogenic fibroblast growth factor receptor 3 (FGFR3) mutation did not die from UTUC., Conclusion: The genetic analysis was highly concordant with histopathological features and added prognostic information in some cases. Thus, results from genomic profiling may contribute to the choice of treatment and follow-up regimens in the future., (© 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)
- Published
- 2022
- Full Text
- View/download PDF
8. Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms.
- Author
-
Lehtiö J, Arslan T, Siavelis I, Pan Y, Socciarelli F, Berkovska O, Umer HM, Mermelekas G, Pirmoradian M, Jönsson M, Brunnström H, Brustugun OT, Purohit KP, Cunningham R, Foroughi Asl H, Isaksson S, Arbajian E, Aine M, Karlsson A, Kotevska M, Gram Hansen C, Drageset Haakensen V, Helland Å, Tamborero D, Johansson HJ, Branca RM, Planck M, Staaf J, and Orre LM
- Subjects
- Fibrinogen therapeutic use, Genomics methods, Humans, Immune Evasion genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, Proteogenomics
- Abstract
Despite major advancements in lung cancer treatment, long-term survival is still rare, and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune evasion mechanisms. Here we performed in-depth mass spectrometry (MS)-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints. Unexpectedly, high neoantigen burden was linked to global hypomethylation and complex neoantigens mapped to genomic regions, such as endogenous retroviral elements and introns, in immune-cold subtypes. Further, we linked immune evasion with LAG3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition MS-based NSCLC subtype classification method, validate it in an independent cohort of 208 NSCLC cases and demonstrate its clinical utility by analyzing an additional cohort of 84 late-stage NSCLC biopsy samples., Competing Interests: Competing interests J.L. has received grant funding from AstraZeneca, Roche and Novartis (not financing of the current manuscript). J.L. and L.M.O. are share holders of FenoMark Diagnostics. J.L., T.A., I.S., and L.M.O are co-inventors on a patent application related to this work. J.L. and D.T. are associate with Roche financed Cancer Core Europe clinical trial (not associated to current manuscript). Since completing his contribution to the current work, M.Pirmoradian has become an employee of AstraZeneca. All other authors declare no competing interests.
- Published
- 2021
- Full Text
- View/download PDF
9. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques.
- Author
-
van der Laan SW, Siemelink MA, Haitjema S, Foroughi Asl H, Perisic L, Mokry M, van Setten J, Malik R, Dichgans M, Worrall BB, Samani NJ, Schunkert H, Erdmann J, Hedin U, Paulsson-Berne G, Björkegrenn JLM, de Borst GJ, Asselbergs FW, den Ruijter FW, de Bakker PIW, and Pasterkamp G
- Subjects
- Adaptor Proteins, Vesicular Transport genetics, Aged, Alleles, Carotid Artery Diseases genetics, Female, Gene Expression Regulation, Genotype, High Mobility Group Proteins genetics, Humans, Male, Middle Aged, Plaque, Atherosclerotic genetics, Repressor Proteins genetics, Atherosclerosis genetics, Cardiovascular Diseases genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms., Methods: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression., Results: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10
-6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood., Conclusions: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.- Published
- 2018
- Full Text
- View/download PDF
10. Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.
- Author
-
Siemelink MA, van der Laan SW, Haitjema S, van Koeverden ID, Schaap J, Wesseling M, de Jager SCA, Mokry M, van Iterson M, Dekkers KF, Luijk R, Foroughi Asl H, Michoel T, Björkegren JLM, Aavik E, Ylä-Herttuala S, de Borst GJ, Asselbergs FW, El Azzouzi H, den Ruijter HM, Heijmans BT, and Pasterkamp G
- Subjects
- Aged, Atherosclerosis etiology, Carotid Artery Diseases etiology, CpG Islands genetics, Endarterectomy, Carotid methods, Endarterectomy, Carotid statistics & numerical data, Epigenesis, Genetic, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Plaque, Atherosclerotic etiology, Plaque, Atherosclerotic genetics, Atherosclerosis genetics, Carotid Artery Diseases genetics, DNA Methylation, Epigenomics methods, Genome-Wide Association Study methods, Smoking adverse effects
- Abstract
Background: Tobacco smoking is a major risk factor for atherosclerotic disease and has been associated with DNA methylation (DNAm) changes in blood cells. However, whether smoking influences DNAm in the diseased vascular wall is unknown but may prove crucial in understanding the pathophysiology of atherosclerosis. In this study, we associated current tobacco smoking to epigenome-wide DNAm in atherosclerotic plaques from patients undergoing carotid endarterectomy., Methods: DNAm at commonly methylated sites (cytosine-guanine nucleotide pairs separated by a phospho-group [CpGs]) was assessed in atherosclerotic plaque samples and peripheral blood samples from 485 carotid endarterectomy patients. We tested the association of current tobacco smoking with DNAm corrected for age and sex. To control for bias and inflation because of cellular heterogeneity, we applied a Bayesian method to estimate an empirical null distribution as implemented by the R package bacon. Replication of the smoking-associated methylated CpGs in atherosclerotic plaques was executed in the second sample of 190 carotid endarterectomy patients, and results were meta-analyzed using a fixed-effects model., Results: Tobacco smoking was significantly associated to differential DNAm in atherosclerotic lesions of 4 CpGs (false discovery rate <0.05) mapped to 2 different genes ( AHRR, ITPK1) and 17 CpGs mapped to 8 genes and RNAs in blood. The strongest associations were found for CpGs mapped to the gene AHRR, a repressor of the aryl hydrocarbon receptor transcription factor involved in xenobiotic detoxification. One of these methylated CpGs were found to be regulated by local genetic variation., Conclusions: The risk factor tobacco smoking associates with DNAm at multiple loci in carotid atherosclerotic lesions. These observations support further investigation of the relationship between risk factors and epigenetic regulation in atherosclerotic disease.
- Published
- 2018
- Full Text
- View/download PDF
11. Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets.
- Author
-
Lempiäinen H, Brænne I, Michoel T, Tragante V, Vilne B, Webb TR, Kyriakou T, Eichner J, Zeng L, Willenborg C, Franzen O, Ruusalepp A, Goel A, van der Laan SW, Biegert C, Hamby S, Talukdar HA, Foroughi Asl H, Pasterkamp G, Watkins H, Samani NJ, Wittenberger T, Erdmann J, Schunkert H, Asselbergs FW, and Björkegren JLM
- Subjects
- Coronary Artery Disease drug therapy, Drug Discovery, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Molecular Targeted Therapy, Polymorphism, Single Nucleotide drug effects, Quantitative Trait Loci drug effects, Coronary Artery Disease genetics, Gene Regulatory Networks drug effects
- Abstract
Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci.
- Published
- 2018
- Full Text
- View/download PDF
12. Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation.
- Author
-
Vilne B, Skogsberg J, Foroughi Asl H, Talukdar HA, Kessler T, Björkegren JLM, and Schunkert H
- Subjects
- Animals, Antioxidants metabolism, Aorta, Thoracic metabolism, Binding Sites, Carrier Proteins metabolism, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Genome-Wide Association Study, Humans, Mice, Mitochondria metabolism, Nuclear Proteins metabolism, Oligonucleotide Array Sequence Analysis, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Polymorphism, Single Nucleotide, RNA-Binding Proteins, Reactive Oxygen Species metabolism, Receptors, Estrogen metabolism, Risk Factors, Systems Biology, Transcription Factors metabolism, Transcriptome, ERRalpha Estrogen-Related Receptor, Atherosclerosis metabolism, Coronary Artery Disease metabolism, Gene Expression Regulation, Genes, Mitochondrial, Hypercholesterolemia metabolism
- Abstract
Background and Aims: Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation., Methods: To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach., Results: During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses., Conclusions: Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
13. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization.
- Author
-
Haitjema S, Meddens CA, van der Laan SW, Kofink D, Harakalova M, Tragante V, Foroughi Asl H, van Setten J, Brandt MM, Bis JC, O'Donnell C, Cheng C, Hoefer IE, Waltenberger J, Biessen E, Jukema JW, Doevendans PA, Nieuwenhuis EE, Erdmann J, Björkegren JL, Pasterkamp G, Asselbergs FW, den Ruijter HM, and Mokry M
- Subjects
- Atherosclerosis metabolism, Atherosclerosis pathology, Cell Line, Chromatin metabolism, Endothelial Cells metabolism, Female, Genome-Wide Association Study, Humans, Male, Monocytes metabolism, Atherosclerosis genetics, Chromatin genetics, Genetic Loci, Genetic Predisposition to Disease, Molecular Sequence Annotation
- Abstract
Background: As genome-wide association efforts, such as CARDIoGRAM and METASTROKE, are ongoing to reveal susceptibility loci for their underlying disease-atherosclerotic disease-identification of candidate genes explaining the associations of these loci has proven the main challenge. Many disease susceptibility loci colocalize with DNA regulatory elements, which influence gene expression through chromatin interactions. Therefore, the target genes of these regulatory elements can be considered candidate genes. Applying these biological principles, we used an alternative approach to annotate susceptibility loci and identify candidate genes for human atherosclerotic disease based on circular chromosome conformation capture followed by sequencing., Methods and Results: In human monocytes and coronary endothelial cells, we generated 63 chromatin interaction data sets for 37 active DNA regulatory elements that colocalize with known susceptibility loci for coronary artery disease (CARDIoGRAMplusC4D) and large artery stroke (METASTROKE). By circular chromosome conformation capture followed by sequencing, we identified a physical 3-dimensional interaction with 326 candidate genes expressed in at least 1 of these cell types, of which 294 have not been reported before. We highlight 16 genes based on expression quantitative trait loci., Conclusions: Our findings provide additional candidate-gene annotation for 37 disease susceptibility loci for human atherosclerotic disease that are of potential interest to better understand the complex pathophysiology of cardiovascular diseases., (© 2017 American Heart Association, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
14. Poliovirus Receptor-Related 2: A Cholesterol-Responsive Gene Affecting Atherosclerosis Development by Modulating Leukocyte Migration.
- Author
-
Rossignoli A, Shang MM, Gladh H, Moessinger C, Foroughi Asl H, Talukdar HA, Franzén O, Mueller S, Björkegren JL, Folestad E, and Skogsberg J
- Subjects
- Animals, Aorta, Thoracic pathology, Aortic Diseases genetics, Aortic Diseases pathology, Apolipoprotein B-100, Apolipoproteins B deficiency, Apolipoproteins B genetics, Atherosclerosis genetics, Atherosclerosis pathology, Cell Adhesion, Cell Adhesion Molecules deficiency, Cell Adhesion Molecules genetics, Cell Line, Tumor, Coculture Techniques, Disease Models, Animal, Disease Progression, Endothelium, Vascular pathology, Genetic Predisposition to Disease, Human Umbilical Vein Endothelial Cells metabolism, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Nectins, Phenotype, RNA Interference, Receptors, LDL deficiency, Receptors, LDL genetics, Signal Transduction, Time Factors, Transfection, Aorta, Thoracic metabolism, Aortic Diseases metabolism, Atherosclerosis metabolism, Cell Adhesion Molecules metabolism, Cholesterol blood, Endothelium, Vascular metabolism, Leukocytes metabolism, Transendothelial and Transepithelial Migration
- Abstract
Objective: Recently, poliovirus receptor-related 2 ( Pvrl2 ) emerged as a top gene in a global gene expression study aiming to detect plasma cholesterol-responsive genes causally related to atherosclerosis regression in hypercholesterolemic mice. PVRL2 is an adherens junction protein implied to play a role in transendothelial migration of leukocytes, a key feature in atherosclerosis development. In this study, we investigated the effect of Pvrl2 deficiency on atherosclerosis development and transendothelial migration of leukocytes activity. APPROACH AND RESULTS: Pvrl2 -deficient mice bred onto an atherosclerosis-prone background ( Pvrl2
-/- Ldlr-/- Apob100/100 ) had less atherosclerotic lesions and more stable plaques compared with littermate controls ( Pvrl2+/+ Ldlr-/- Apob100/100 ). Pvrl2-/- Ldlr-/- Apob100/100 mice also showed a 49% decrease in transendothelial migration of leukocytes activity observed using the in vivo air pouch model. In accordance, augmented arterial wall expression of Pvrl2 during atherosclerosis progression coincided with an increased gene expression of migrating leukocytes into the vessel wall. Both in human and mice, gene and protein expression of PVRL2 was predominantly observed in the vascular endothelium according to the immunohistochemical and gene expression data. In addition, the cholesterol responsiveness of PVRL2 was also observed in humans., Conclusions: PVRL2 is a plasma cholesterol-responsive gene acting at endothelial sites of vascular inflammation that could potentially be a new therapeutic target for atherosclerosis prevention through its suggested transendothelial migration of leukocytes modulating activity., (© 2017 American Heart Association, Inc.)- Published
- 2017
- Full Text
- View/download PDF
15. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.
- Author
-
Meddens CA, Harakalova M, van den Dungen NA, Foroughi Asl H, Hijma HJ, Cuppen EP, Björkegren JL, Asselbergs FW, Nieuwenhuis EE, and Mokry M
- Subjects
- Autophagy-Related Proteins genetics, Autophagy-Related Proteins metabolism, Gene Expression, Gene Expression Regulation, Hepatocyte Nuclear Factor 4 metabolism, Humans, Inflammatory Bowel Diseases metabolism, Interleukin-10 Receptor alpha Subunit genetics, Interleukin-10 Receptor alpha Subunit metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Organ Specificity genetics, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Reproducibility of Results, Signal Transduction, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, Chromatin genetics, Epistasis, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Inflammatory Bowel Diseases genetics, Quantitative Trait Loci
- Abstract
Background: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DREs are to be considered as candidate genes. This study uses circular chromosome conformation capture-sequencing (4C-seq) to systematically analyze chromatin-interactions at IBD susceptibility loci that localize to regulatory DNA., Results: Using 4C-seq, we identify genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell-type specific, 4C-seq was performed in monocytes, lymphocytes, and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These include genes specific for IBD-subtypes and many noteworthy genes including ATG9A and IL10RA. We show that expression of many novel candidate genes is genotype-dependent and that these genes are upregulated during intestinal inflammation in IBD. Furthermore, we identify HNF4α as a potential key upstream regulator of IBD candidate genes., Conclusions: We reveal many novel and relevant IBD candidate genes, pathways, and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.
- Published
- 2016
- Full Text
- View/download PDF
16. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases.
- Author
-
Franzén O, Ermel R, Cohain A, Akers NK, Di Narzo A, Talukdar HA, Foroughi-Asl H, Giambartolomei C, Fullard JF, Sukhavasi K, Köks S, Gan LM, Giannarelli C, Kovacic JC, Betsholtz C, Losic B, Michoel T, Hao K, Roussos P, Skogsberg J, Ruusalepp A, Schadt EE, and Björkegren JL
- Subjects
- Abdominal Fat metabolism, Alzheimer Disease genetics, Cholesterol, LDL blood, Cholesterol, LDL genetics, Coronary Artery Disease epidemiology, Female, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Liver metabolism, Male, Muscle, Skeletal metabolism, Organ Specificity genetics, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases genetics, Quantitative Trait Loci, Risk, Serine Endopeptidases genetics, Coronary Artery Disease genetics, Gene Expression Regulation
- Abstract
Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
- Full Text
- View/download PDF
17. Human Validation of Genes Associated With a Murine Atherosclerotic Phenotype.
- Author
-
Pasterkamp G, van der Laan SW, Haitjema S, Foroughi Asl H, Siemelink MA, Bezemer T, van Setten J, Dichgans M, Malik R, Worrall BB, Schunkert H, Samani NJ, de Kleijn DP, Markus HS, Hoefer IE, Michoel T, de Jager SC, Björkegren JL, den Ruijter HM, and Asselbergs FW
- Subjects
- Animals, Computational Biology, Coronary Artery Disease pathology, Databases, Genetic, Disease Models, Animal, Gene Expression Regulation, Gene Regulatory Networks, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracranial Arteriosclerosis pathology, Mice, Phenotype, Plaque, Atherosclerotic, Quantitative Trait Loci, Reproducibility of Results, Risk Assessment, Risk Factors, Species Specificity, Stroke pathology, Coronary Artery Disease genetics, Gene Expression Profiling methods, Intracranial Arteriosclerosis genetics, Polymorphism, Single Nucleotide, Stroke genetics
- Abstract
Objective: The genetically modified mouse is the most commonly used animal model for studying the pathogenesis of atherosclerotic disease. We aimed to assess if mice atherosclerosis-related genes could be validated in human disease through examination of results from genome-wide association studies., Approach and Results: We performed a systematic review to identify atherosclerosis-causing genes in mice and carried out gene-based association tests of their human orthologs for an association with human coronary artery disease and human large artery ischemic stroke. Moreover, we investigated the association of these genes with human atherosclerotic plaque characteristics. In addition, we assessed the presence of tissue-specific cis-acting expression quantitative trait loci for these genes in humans. Finally, using pathway analyses we show that the putative atherosclerosis-causing genes revealed few associations with human coronary artery disease, large artery ischemic stroke, or atherosclerotic plaque characteristics, despite the fact that the majority of these genes have cis-acting expression quantitative trait loci., Conclusions: A role for genes that has been observed in mice for atherosclerotic lesion development could scarcely be confirmed by studying associations of disease development with common human genetic variants. The value of murine atherosclerotic models for selection of therapeutic targets in human disease remains unclear., (© 2016 American Heart Association, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
18. Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease.
- Author
-
Talukdar HA, Foroughi Asl H, Jain RK, Ermel R, Ruusalepp A, Franzén O, Kidd BA, Readhead B, Giannarelli C, Kovacic JC, Ivert T, Dudley JT, Civelek M, Lusis AJ, Schadt EE, Skogsberg J, Michoel T, and Björkegren JL
- Subjects
- Animals, Carrier Proteins, Coronary Artery Disease, DNA-Binding Proteins, Genome-Wide Association Study, Humans, Mice, Nuclear Proteins, Repressor Proteins, Gene Regulatory Networks
- Abstract
Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
19. Prediction of Causal Candidate Genes in Coronary Artery Disease Loci.
- Author
-
Brænne I, Civelek M, Vilne B, Di Narzo A, Johnson AD, Zhao Y, Reiz B, Codoni V, Webb TR, Foroughi Asl H, Hamby SE, Zeng L, Trégouët DA, Hao K, Topol EJ, Schadt EE, Yang X, Samani NJ, Björkegren JL, Erdmann J, Schunkert H, and Lusis AJ
- Subjects
- Coronary Artery Disease physiopathology, Female, Genetic Loci, Genetic Variation, Humans, Male, MicroRNAs genetics, Predictive Value of Tests, Promoter Regions, Genetic genetics, Coronary Artery Disease genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide
- Abstract
Objective: Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes., Approach and Results: All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously., Conclusions: Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses., (© 2015 American Heart Association, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
20. Expression quantitative trait Loci acting across multiple tissues are enriched in inherited risk for coronary artery disease.
- Author
-
Foroughi Asl H, Talukdar HA, Kindt AS, Jain RK, Ermel R, Ruusalepp A, Nguyen KD, Dobrin R, Reilly DF, Schunkert H, Samani NJ, Braenne I, Erdmann J, Melander O, Qi J, Ivert T, Skogsberg J, Schadt EE, Michoel T, and Björkegren JL
- Subjects
- Female, Genome-Wide Association Study, Humans, Male, Organ Specificity genetics, Coronary Artery Disease genetics, Coronary Artery Disease metabolism, Databases, Genetic, Gene Expression Regulation, Muscle Proteins biosynthesis, Muscle Proteins genetics, Quantitative Trait Loci
- Abstract
Background: Despite recent discoveries of new genetic risk factors, the majority of risk for coronary artery disease (CAD) remains elusive. As the most proximal sensor of DNA variation, RNA abundance can help identify subpopulations of genetic variants active in and across tissues mediating CAD risk through gene expression., Methods and Results: By generating new genomic data on DNA and RNA samples from the Stockholm Atherosclerosis Gene Expression (STAGE) study, 8156 cis-acting expression quantitative trait loci (eQTLs) for 6450 genes across 7 CAD-relevant tissues were detected. The inherited risk enrichments of tissue-defined sets of these eQTLs were assessed using 2 independent genome-wide association data sets. eQTLs acting across increasing numbers of tissues were found increasingly enriched for CAD risk and resided at regulatory hot spots. The risk enrichment of 42 eQTLs acting across 5 to 6 tissues was particularly high (≤7.3-fold) and confirmed in the combined genome-wide association data from Coronary Artery Disease Genome Wide Replication And Meta-Analysis Consortium. Sixteen of the 42 eQTLs associated with 19 master regulatory genes and 29 downstream gene sets (n>30) were further risk enriched comparable to that of the 153 genome-wide association risk single-nucleotide polymorphisms established for CAD (8.4-fold versus 10-fold). Three gene sets, governed by the master regulators FLYWCH1, PSORSIC3, and G3BP1, segregated the STAGE patients according to extent of CAD, and small interfering RNA targeting of these master regulators affected cholesterol-ester accumulation in foam cells of the THP1 monocytic cell line., Conclusions: eQTLs acting across multiple tissues are significant carriers of inherited risk for CAD. FLYWCH1, PSORSIC3, and G3BP1 are novel master regulatory genes in CAD that may be suitable targets., (© 2015 American Heart Association, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
21. Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: the Athero-Express Genomics Study.
- Author
-
van der Laan SW, Foroughi Asl H, van den Borne P, van Setten J, van der Perk ME, van de Weg SM, Schoneveld AH, de Kleijn DP, Michoel T, Björkegren JL, den Ruijter HM, Asselbergs FW, de Bakker PI, and Pasterkamp G
- Subjects
- Aged, Atherosclerosis diagnosis, Atherosclerosis enzymology, Biological Specimen Banks, Carotid Artery Diseases diagnosis, Carotid Artery Diseases enzymology, Coronary Artery Disease diagnosis, Coronary Artery Disease enzymology, Female, Femoral Artery pathology, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Netherlands, Phenotype, Quantitative Trait Loci, Sweden, 5-Lipoxygenase-Activating Proteins genetics, Arachidonate 5-Lipoxygenase genetics, Atherosclerosis genetics, Carotid Artery Diseases genetics, Coronary Artery Disease genetics, Epoxide Hydrolases genetics, Femoral Artery enzymology, Genomics methods, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide
- Abstract
Background: The eicosanoid genes ALOX5, ALOX5AP and LTA4H have been implicated in atherosclerosis. We assessed the impact of common variants in these genes on gene expression, circulating protein levels, and atherosclerotic plaque phenotypes., Methods: We included patients from the Stockholm Atherosclerosis Gene Expression study (STAGE, N = 109), and the Athero-Express Biobank Study (AE, N = 1443). We tested 1453 single-nucleotide variants (SNVs) in ALOX5, ALOX5AP and LTA4H for association with gene expression in STAGE. We also tested these SNVs for association with seven histologically defined plaque phenotypes in the AE (which included calcification, collagen, cellular content, atheroma size, and intraplaque vessel density and hemorrhage)., Results: We replicate a known cis-eQTL (rs6538697, p = 1.96 × 10(-6)) for LTA4H expression in whole blood of patients from STAGE. We found no significant association for any of the SNVs tested with serum levels of ALOX5 or ALOX5AP (p > 5.79 × 10(-4)). For atherosclerotic plaque phenotypes the strongest associations were found for intraplaque vessel density and smooth muscle cells in the ALOX5AP locus (p > 1.67 × 10(-4))., Conclusions: We replicate a known eQTL for LTA4H expression in whole blood using STAGE data. We found no associations of variants in and around ALOX5, ALOX5AP and LTA4H with serum ALOX5 or ALOX5AP levels, or plaque phenotypes. On the supposition that these genes play a causal role in atherosclerosis, these results suggest that common variants in these loci play a limited role (if any) in influencing advanced atherosclerotic plaque morphology to the extent that it impacts atherosclerotic disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
22. Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
- Author
-
Björkegren JL, Hägg S, Talukdar HA, Foroughi Asl H, Jain RK, Cedergren C, Shang MM, Rossignoli A, Takolander R, Melander O, Hamsten A, Michoel T, and Skogsberg J
- Subjects
- Animals, Aorta drug effects, Apolipoproteins B genetics, Atherosclerosis drug therapy, Atherosclerosis pathology, Gene Expression Regulation drug effects, Histone-Lysine N-Methyltransferase biosynthesis, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage, Mice, Mice, Transgenic, Nuclear Proteins biosynthesis, Ribonucleoproteins biosynthesis, Serine-Arginine Splicing Factors, Aorta metabolism, Atherosclerosis blood, Cholesterol blood, Receptors, LDL genetics
- Abstract
Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.