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1. 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, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

Published
2023
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2. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

Author

Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Capasso, Antonella, Pandzic, Tatjana, Weström, Simone, Foroughi-Asl, Hassan, Skaftason, Aron, Gellerbring, Anna, Lyander, Anna, Gandini, Francesca, Gaidano, Gianluca, Trentin, Livio, Bonello, Lisa, Reda, Gianluigi, Bödör, Csaba, Stavroyianni, Niki, Tam, Constantine S., Marasca, Roberto, Forconi, Francesco, Panayiotidis, Panayiotis, Ringshausen, Ingo, Jaksic, Ozren, Frustaci, Anna Maria, Iyengar, Sunil, Coscia, Marta, Mulligan, Stephen P., Ysebaert, Loïc, Strugov, Vladimir, Pavlovsky, Carolina, Walewska, Renata, Österborg, Anders, Cortese, Diego, Ranghetti, Pamela, Baliakas, Panagiotis, Stamatopoulos, Kostas, Scarfò, Lydia, Rosenquist, Richard, and Ghia, Paolo

Published
2023
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3. Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

Author

Lehtiö, Janne, Arslan, Taner, Siavelis, Ioannis, Pan, Yanbo, Socciarelli, Fabio, Berkovska, Olena, Umer, Husen M., Mermelekas, Georgios, Pirmoradian, Mohammad, Jönsson, Mats, Brunnström, Hans, Brustugun, Odd Terje, Purohit, Krishna Pinganksha, Cunningham, Richard, Foroughi Asl, Hassan, Isaksson, Sofi, Arbajian, Elsa, Aine, Mattias, Karlsson, Anna, Kotevska, Marija, Gram Hansen, Carsten, Drageset Haakensen, Vilde, Helland, Åslaug, Tamborero, David, Johansson, Henrik J., Branca, Rui M., Planck, Maria, Staaf, Johan, and Orre, Lukas M.

Published
2021
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4. 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, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

Published
2023
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5. Prediction of Causal Candidate Genes in Coronary Artery Disease Loci

Author

Brænne, Ingrid, Civelek, Mete, Vilne, Baiba, Di Narzo, Antonio, Johnson, Andrew D, Zhao, Yuqi, Reiz, Benedikt, Codoni, Veronica, Webb, Thomas R, Foroughi Asl, Hassan, Hamby, Stephen E, Zeng, Lingyao, Trégouët, David-Alexandre, Hao, Ke, Topol, Eric J, Schadt, Eric E, Yang, Xia, Samani, Nilesh J, Björkegren, Johan LM, Erdmann, Jeanette, Schunkert, Heribert, and Lusis, Aldons J

Subjects
Heart Disease, Cardiovascular, Atherosclerosis, Biotechnology, Heart Disease - Coronary Heart Disease, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Coronary Artery Disease, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, MicroRNAs, Polymorphism, Single Nucleotide, Predictive Value of Tests, Promoter Regions, Genetic, coronary artery disease, genome-wide association study, microRNAs, single-nucleotide polymorphism, systems biology, Leducq Consortium CAD Genomics‡, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

ObjectiveGenome-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 resultsAll 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.ConclusionsOur 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.

Published
2015

7. Sensitive Detection of Cell-Free Tumour DNA Using Optimised Targeted Sequencing Can Predict Prognosis in Gastro-Oesophageal Cancer

Author

Wallander, Karin, Haider, Zahra, Jeggari, Ashwini, Foroughi-Asl, Hassan, Gellerbring, Anna, Lyander, Anna, Chozhan, Athithyan, Gyllensten, Ollanta Cuba, Haegglund, Moa, Wirta, Valtteri, Nordenskjoeld, Magnus, Lindblad, Mats, Tham, Emma, Wallander, Karin, Haider, Zahra, Jeggari, Ashwini, Foroughi-Asl, Hassan, Gellerbring, Anna, Lyander, Anna, Chozhan, Athithyan, Gyllensten, Ollanta Cuba, Haegglund, Moa, Wirta, Valtteri, Nordenskjoeld, Magnus, Lindblad, Mats, and Tham, Emma

Abstract

Simple Summary Cancer in the stomach and oesophagus is deadly when discovered at a late stage. There are no good biomarkers for its detection or for making a prognostic prediction. In this study, we evaluate the analysis of cell-free DNA as a prognostic cancer biomarker. Cell-free DNA is DNA released from any tissue to a body fluid. When there is a tumour in the body, some of the cell-free DNA will come from that tumour, and it can be detected in a blood sample. We show that the detection of cell-free DNA from the cancer correlates to a worse prognosis than when no tumour DNA is detected. We also show that the method of analysis is important. Either a tissue biopsy must be included as a validation of the genetic variants detected or analysis of the blood cells or another blood sample after tumour resection needs to be analysed to improve detection. 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-sens, QC 20230321

Published
2023
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8. 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, Larry, Thorvaldsdottir, Birna, Sutton, Lesley Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, María José, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

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.

Published
2023

9. 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

Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute, Fundación la Caixa, American Association for Cancer Research, European Hematology Association, Lady Tata Memorial Trust, European Association for Cancer Research, Instituto de Salud Carlos III, Ministry of Innovation and Technology (Hungary), Università degli Studi di Ferrara, Associazione Italiana Contro le Leucemie - Linfomi e Mieloma, Danish Cancer Society Research Center, Cancer Research UK, Swedish Cancer Society, Swedish Research Council, Knut and Alice Wallenberg Foundation, Lions Cancerforskningsfond, Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana Eugenia, Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Mirás, Fátima, Martínez-López, Joaquín, Serna, Javier de la, De Las Rivas, Javier, Thornton, Patrick, Larráyoz, María José, Calasanz, Mª Jose, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E, Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón‐Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, María José, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U, Campo, Elías, Strefford, Jonathan C, Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute, Fundación la Caixa, American Association for Cancer Research, European Hematology Association, Lady Tata Memorial Trust, European Association for Cancer Research, Instituto de Salud Carlos III, Ministry of Innovation and Technology (Hungary), Università degli Studi di Ferrara, Associazione Italiana Contro le Leucemie - Linfomi e Mieloma, Danish Cancer Society Research Center, Cancer Research UK, Swedish Cancer Society, Swedish Research Council, Knut and Alice Wallenberg Foundation, Lions Cancerforskningsfond, Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana Eugenia, Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Mirás, Fátima, Martínez-López, Joaquín, Serna, Javier de la, De Las Rivas, Javier, Thornton, Patrick, Larráyoz, María José, Calasanz, Mª Jose, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E, Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch, Francesc, Tazón‐Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, María José, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U, Campo, Elías, Strefford, Jonathan C, Ghia, Paolo, Stamatopoulos, Kostas, and Rosenquist, Richard

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.

Published
2023

10. Sensitive Detection of Cell-Free Tumour DNA Using Optimised Targeted Sequencing Can Predict Prognosis in Gastro-Oesophageal Cancer

Author

Wallander, Karin, primary, Haider, Zahra, additional, Jeggari, Ashwini, additional, Foroughi-Asl, Hassan, additional, Gellerbring, Anna, additional, Lyander, Anna, additional, Chozhan, Athithyan, additional, Cuba Gyllensten, Ollanta, additional, Hägglund, Moa, additional, Wirta, Valtteri, additional, Nordenskjöld, Magnus, additional, Lindblad, Mats, additional, and Tham, Emma, additional

Published
2023
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11. Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases

Author

Franzén, Oscar, Ermel, Raili, Cohain, Ariella, Akers, Nicholas K., Di Narzo, Antonio, Talukdar, Husain A., Foroughi-Asl, Hassan, Giambartolomei, Claudia, Fullard, John F., Sukhavasi, Katyayani, Köks, Sulev, Gan, Li-Ming, Giannarelli, Chiara, Kovacic, Jason C., Betsholtz, Christer, Losic, Bojan, Michoel, Tom, Hao, Ke, Roussos, Panos, Skogsberg, Josefin, Ruusalepp, Arno, Schadt, Eric E., and Björkegren, Johan L. M.

Published
2016

12. 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, Larry, primary, Thorvaldsdottir, Birna, additional, Sutton, Lesley-Ann, additional, Karakatsoulis, Georgios, additional, Meggendorfer, Manja, additional, Parker, Helen, additional, Nadeu, Ferran, additional, Brieghel, Christian, additional, Laidou, Stamatia, additional, Moia, Riccardo, additional, Rossi, Davide, additional, Catherwood, Mark, additional, Kotaskova, Jana, additional, Delgado, Julio, additional, Rodríguez-Vicente, Ana E., additional, Benito, Rocío, additional, Rigolin, Gian Matteo, additional, Bonfiglio, Silvia, additional, Scarfo, Lydia, additional, Mattsson, Mattias, additional, Davis, Zadie, additional, Gogia, Ajay, additional, Rani, Lata, additional, Baliakas, Panagiotis, additional, Foroughi-Asl, Hassan, additional, Jylhä, Cecilia, additional, Skaftason, Aron, additional, Rapado, Inmaculada, additional, Miras, Fatima, additional, Martinez-Lopez, Joaquín, additional, de la Serna, Javier, additional, Rivas, Jesús María Hernández, additional, Thornton, Patrick, additional, Larráyoz, María José, additional, Calasanz, María José, additional, Fésüs, Viktória, additional, Mátrai, Zoltán, additional, Bödör, Csaba, additional, Smedby, Karin E., additional, Espinet, Blanca, additional, Puiggros, Anna, additional, Gupta, Ritu, additional, Bullinger, Lars, additional, Bosch, Francesc, additional, Tazón-Vega, Bárbara, additional, Baran-Marszak, Fanny, additional, Oscier, David, additional, Nguyen-Khac, Florence, additional, Zenz, Thorsten, additional, Terol, Maria Jose, additional, Cuneo, Antonio, additional, Hernández-Sánchez, María, additional, Pospisilova, Sarka, additional, Mills, Ken, additional, Gaidano, Gianluca, additional, Niemann, Carsten U., additional, Campo, Elias, additional, Strefford, Jonathan C., additional, Ghia, Paolo, additional, Stamatopoulos, Kostas, additional, and Rosenquist, Richard, additional

Published
2022
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13. Identification and Interpretation of Clinically Relevant Somatic Variants from Whole-Genome Sequencing Data

Author

Maqbool, Khurram, primary, Hassan Foroughi-Asl, Hassan, additional, Ashwini Jeggari, Ashwini, additional, Ivanchuk, Vadym, additional, Eisfeldt, Jesper, additional, Renevey, Annick, additional, Elhami, Keyvan, additional, Rasi, Chiara, additional, Nilsson, Daniel, additional, Heinäniemi, Merja, additional, Lohi, Olli, additional, and Wirta, Valtteri, additional

Published
2022
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16. Genomic profile – a possible diagnostic and prognostic marker in upper tract urothelial carcinoma.

Author

Grahn, Alexandra, Eisfeldt, Jesper, Malm, Camilla, Foroughi Asl, Hassan, Jaremko, Georg, Tham, Emma, and Brehmer, Marianne

Subjects
TRANSITIONAL cell carcinoma, FIBROBLAST growth factor receptors, PROGNOSIS, HIERARCHICAL clustering (Cluster analysis), PRINCIPAL components analysis
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. [ABSTRACT FROM AUTHOR]

Published
2022
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17. Genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques

Author

van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B, Samani, Nilesh J, Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M, de Borst, Gert J., Asselbergs, Folkert W, den Ruijter, Folkert W, de Bakker, Paul I.W, Pasterkamp, Gerard, Ford, Ian, Sattar, Naveed, and Stott, David J.

Subjects
R1
Abstract

Background:\ud 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.\ud \ud Methods:\ud 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.\ud \ud Results:\ud 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.\ud \ud Conclusions:\ud Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.

Published
2018

18. Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions

Author

Siemelink, MA, van der Laan, S.W., Haitjema, S, van Koeverden, ID, Schaap, J, Wesseling, M, de Jager, SCA, Mokry, M, Van Iterson, Maarten, Dekkers, Koen F, Luijk, René, Foroughi Asl, Hassan, Björkegren, Johan L M, Aavik, Einari, Ylä-Herttuala, Seppo, de Borst, GJ, Asselbergs, FW, el Azzouzi, H, den Ruijter, HM, Heijmans, Bastiaan T., Pasterkamp, G, Siemelink, MA, van der Laan, S.W., Haitjema, S, van Koeverden, ID, Schaap, J, Wesseling, M, de Jager, SCA, Mokry, M, Van Iterson, Maarten, Dekkers, Koen F, Luijk, René, Foroughi Asl, Hassan, Björkegren, Johan L M, Aavik, Einari, Ylä-Herttuala, Seppo, de Borst, GJ, Asselbergs, FW, el Azzouzi, H, den Ruijter, HM, Heijmans, Bastiaan T., and Pasterkamp, G

Published
2018

19. Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Author

Lempiäinen, Harri, Brænne, Ingrid, Michoel, Tom, Tragante, Vinicius, Vilne, Baiba, Webb, Tom R., Kyriakou, Theodosios, Eichner, Johannes, Zeng, Lingyao, Willenborg, Christina, Franzen, Oscar, Ruusalepp, Arno, Goel, Anuj, Van Der Laan, Sander W., Biegert, Claudia, Hamby, Stephen, Talukdar, Husain A., Foroughi Asl, Hassan, Dichgans, Martin, Dreker, Tobias, Graettinger, Mira, Gribbon, Philip, Kessler, Thorsten, Malik, Rainer, Prestel, Matthias, Stiller, Barbara, Schofield, Christine, Pasterkamp, Gerard, Watkins, Hugh, Samani, Nilesh J., Wittenberger, Timo, Erdmann, Jeanette, Schunkert, Heribert, Asselbergs, Folkert W., Björkegren, Johan L.M., Lempiäinen, Harri, Brænne, Ingrid, Michoel, Tom, Tragante, Vinicius, Vilne, Baiba, Webb, Tom R., Kyriakou, Theodosios, Eichner, Johannes, Zeng, Lingyao, Willenborg, Christina, Franzen, Oscar, Ruusalepp, Arno, Goel, Anuj, Van Der Laan, Sander W., Biegert, Claudia, Hamby, Stephen, Talukdar, Husain A., Foroughi Asl, Hassan, Dichgans, Martin, Dreker, Tobias, Graettinger, Mira, Gribbon, Philip, Kessler, Thorsten, Malik, Rainer, Prestel, Matthias, Stiller, Barbara, Schofield, Christine, Pasterkamp, Gerard, Watkins, Hugh, Samani, Nilesh J., Wittenberger, Timo, Erdmann, Jeanette, Schunkert, Heribert, Asselbergs, Folkert W., and Björkegren, Johan L.M.

Published
2018

20. Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions

Author

Experimentele Afd. Cardiologie 1, Circulatory Health, Divisie Biomedische Genetica, Onderzoek Vrouw Hart & Vaatziekten, Team Medisch, Cardiologie, MDL onderzoek 1, Child Health, Brain, Zorgeenheid Vaatchirurgie Medisch, CDL Staf Research, Experimentele Afd. Cardiologie 2, Cardiovasculaire Immunologie, Infection & Immunity, Onderzoek Cardiovasculair Reg. Med., Siemelink, MA, van der Laan, S.W., Haitjema, S, van Koeverden, ID, Schaap, J, Wesseling, M, de Jager, SCA, Mokry, M, Van Iterson, Maarten, Dekkers, Koen F, Luijk, René, Foroughi Asl, Hassan, Björkegren, Johan L M, Aavik, Einari, Ylä-Herttuala, Seppo, de Borst, GJ, Asselbergs, FW, el Azzouzi, H, den Ruijter, HM, Heijmans, Bastiaan T., Pasterkamp, G, Experimentele Afd. Cardiologie 1, Circulatory Health, Divisie Biomedische Genetica, Onderzoek Vrouw Hart & Vaatziekten, Team Medisch, Cardiologie, MDL onderzoek 1, Child Health, Brain, Zorgeenheid Vaatchirurgie Medisch, CDL Staf Research, Experimentele Afd. Cardiologie 2, Cardiovasculaire Immunologie, Infection & Immunity, Onderzoek Cardiovasculair Reg. Med., Siemelink, MA, van der Laan, S.W., Haitjema, S, van Koeverden, ID, Schaap, J, Wesseling, M, de Jager, SCA, Mokry, M, Van Iterson, Maarten, Dekkers, Koen F, Luijk, René, Foroughi Asl, Hassan, Björkegren, Johan L M, Aavik, Einari, Ylä-Herttuala, Seppo, de Borst, GJ, Asselbergs, FW, el Azzouzi, H, den Ruijter, HM, Heijmans, Bastiaan T., and Pasterkamp, G

Published
2018

21. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques

Author

Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Arcadia, MDL onderzoek 1, Onderzoek, Child Health, Device, Onderzoek Precision medicine, Gipskamer Chirurgie, Zorgeenheid Vaatchirurgie Medisch, Brain, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Divisie Biomedische Genetica, CDL Onderzoek Pasterkamp, Divisie LAB, van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B., Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M., de Borst, Gert J., Asselbergs, Folkert W., den Ruijter, Folkert W., de Bakker, Paul I.W., Pasterkamp, Gerard, METASTROKE Collaboration of the International Stroke Genetics Consortium, Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Arcadia, MDL onderzoek 1, Onderzoek, Child Health, Device, Onderzoek Precision medicine, Gipskamer Chirurgie, Zorgeenheid Vaatchirurgie Medisch, Brain, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Divisie Biomedische Genetica, CDL Onderzoek Pasterkamp, Divisie LAB, van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B., Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M., de Borst, Gert J., Asselbergs, Folkert W., den Ruijter, Folkert W., de Bakker, Paul I.W., Pasterkamp, Gerard, and METASTROKE Collaboration of the International Stroke Genetics Consortium

Published
2018

22. Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Author

Planningssecretariaat HCK, Onderzoek Precision medicine, Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Cluster Onderzoek en Onderwijs, Team Medisch, Lempiäinen, Harri, Brænne, Ingrid, Michoel, Tom, Tragante, Vinicius, Vilne, Baiba, Webb, Tom R., Kyriakou, Theodosios, Eichner, Johannes, Zeng, Lingyao, Willenborg, Christina, Franzen, Oscar, Ruusalepp, Arno, Goel, Anuj, Van Der Laan, Sander W., Biegert, Claudia, Hamby, Stephen, Talukdar, Husain A., Foroughi Asl, Hassan, Dichgans, Martin, Dreker, Tobias, Graettinger, Mira, Gribbon, Philip, Kessler, Thorsten, Malik, Rainer, Prestel, Matthias, Stiller, Barbara, Schofield, Christine, Pasterkamp, Gerard, Watkins, Hugh, Samani, Nilesh J., Wittenberger, Timo, Erdmann, Jeanette, Schunkert, Heribert, Asselbergs, Folkert W., Björkegren, Johan L.M., Planningssecretariaat HCK, Onderzoek Precision medicine, Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Cluster Onderzoek en Onderwijs, Team Medisch, Lempiäinen, Harri, Brænne, Ingrid, Michoel, Tom, Tragante, Vinicius, Vilne, Baiba, Webb, Tom R., Kyriakou, Theodosios, Eichner, Johannes, Zeng, Lingyao, Willenborg, Christina, Franzen, Oscar, Ruusalepp, Arno, Goel, Anuj, Van Der Laan, Sander W., Biegert, Claudia, Hamby, Stephen, Talukdar, Husain A., Foroughi Asl, Hassan, Dichgans, Martin, Dreker, Tobias, Graettinger, Mira, Gribbon, Philip, Kessler, Thorsten, Malik, Rainer, Prestel, Matthias, Stiller, Barbara, Schofield, Christine, Pasterkamp, Gerard, Watkins, Hugh, Samani, Nilesh J., Wittenberger, Timo, Erdmann, Jeanette, Schunkert, Heribert, Asselbergs, Folkert W., and Björkegren, Johan L.M.

Published
2018

23. Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions

Author

Siemelink, Marten A., primary, van der Laan, Sander W., additional, Haitjema, Saskia, additional, van Koeverden, Ian D., additional, Schaap, Jacco, additional, Wesseling, Marian, additional, de Jager, Saskia C.A., additional, Mokry, Michal, additional, van Iterson, Maarten, additional, Dekkers, Koen F., additional, Luijk, René, additional, Foroughi Asl, Hassan, additional, Michoel, Tom, additional, Björkegren, Johan L.M., additional, Aavik, Einari, additional, Ylä-Herttuala, Seppo, additional, de Borst, Gert J., additional, Asselbergs, Folkert W., additional, el Azzouzi, Hamid, additional, den Ruijter, Hester M., additional, Heijmans, Bas T., additional, and Pasterkamp, Gerard, additional

Published
2018
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24. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., Mokry, Michal, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., and Mokry, Michal

Published
2017

25. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Experimentele Afd. Cardiologie 1, MDL onderzoek 3, Child Health, Circulatory Health, Onderzoek Precision medicine, Planningssecretariaat HCK, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, CDL Staf Research, CDL Arcadia, Team Medisch, Pathologie Groep Brosens, Zorg en O&O, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., Mokry, Michal, Experimentele Afd. Cardiologie 1, MDL onderzoek 3, Child Health, Circulatory Health, Onderzoek Precision medicine, Planningssecretariaat HCK, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, CDL Staf Research, CDL Arcadia, Team Medisch, Pathologie Groep Brosens, Zorg en O&O, Infection & Immunity, CDL Cluster Onderzoek en Onderwijs, Haitjema, Saskia, Meddens, Claartje A., Van Der Laan, Sander W., Kofink, Daniel, Harakalova, Magdalena, Tragante, Vinicius, Foroughi Asl, Hassan, Van Setten, Jessica, Brandt, Maarten M., Bis, Joshua C., O'Donnell, Christopher, Cheng, Caroline, Hoefer, Imo E., Waltenberger, Johannes, Biessen, Erik A L, Jukema, J. Wouter, Doevendans, Pieter A.F.M., Nieuwenhuis, Edward E.S., Erdmann, Jeanette, Björkegren, Johan L M, Pasterkamp, Gerard, Asselbergs, Folkert W., Den Ruijter, Hester M., and Mokry, Michal

Published
2017

26. Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease

Author

Talukdar, Husain A., Foroughi Asl, Hassan, Jain, Rajeev K., Ermel, Raili, Ruusalepp, Arno, Franzén, Oscar, Kidd, Brian A., Readhead, Ben, Giannarelli, Chiara, Kovacic, Jason C., Ivert, Torbjörn, Dudley, Joel T., Civelek, Mete, Lusis, Aldons J., Schadt, Eric E., Skogsberg, Josefin, Michoel, Tom, and Björkegren, Johan L.M.

Subjects
Histology, cardiovascular diseases, Cell Biology, Pathology and Forensic Medicine
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. Well-established atherosclerosis risk factors and pathways are shown to operate through regulatory gene networks, active both within and across vascular and metabolic tissues, to cause coronary artery disease (CAD). Within these CAD-causal networks, the hierarchical order and connectivity patterns of both established and new genes in CAD, including so-called key disease driver genes, advance not only our global understanding of the molecular landscape in CAD but also reveal new candidate genes that may serve as suitable drug targets.

Published
2016

27. Additional Candidate Genes for Human Atherosclerotic Disease Identified Through Annotation Based on Chromatin Organization

Author

Haitjema, Saskia, primary, Meddens, Claartje A., additional, van der Laan, Sander W., additional, Kofink, Daniel, additional, Harakalova, Magdalena, additional, Tragante, Vinicius, additional, Foroughi Asl, Hassan, additional, van Setten, Jessica, additional, Brandt, Maarten M., additional, Bis, Joshua C., additional, O’Donnell, Christopher, additional, Cheng, Caroline, additional, Hoefer, Imo E., additional, Waltenberger, Johannes, additional, Biessen, Erik, additional, Jukema, J. Wouter, additional, Doevendans, Pieter A.F.M., additional, Nieuwenhuis, Edward E.S., additional, Erdmann, Jeanette, additional, Björkegren, Johan L.M., additional, Pasterkamp, Gerard, additional, Asselbergs, Folkert W., additional, den Ruijter, Hester M., additional, and Mokry, Michal, additional

Published
2017
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28. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

Meddens, Claartje A., primary, Harakalova, Magdalena, additional, van den Dungen, Noortje A. M., additional, Foroughi Asl, Hassan, additional, Hijma, Hemme J., additional, Cuppen, Edwin P. J. G., additional, Björkegren, Johan L. M., additional, Asselbergs, Folkert W., additional, Nieuwenhuis, Edward E. S., additional, and Mokry, Michal, additional

Published
2016
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30. Genomic Determinants of Therapy Response in ETV6::RUNX1Leukemia

Author

Oksa, Laura, Moisio, Sanni, Maqbool, Khurram, Foroughi-Asl, Hassan, Kramer, Roger, Nikkilä, Atte, Vepsäläinen, Kaisa, Duque-Afonso, Jesus, Hauer, Julia, Nordlund, Jessica, Wirta, Valtteri, Lohi, Olli, and Heinäniemi, Merja

Abstract

ETV6::RUNX1leukemia is the second most common childhood B-cell acute lymphoblastic leukemia subtype. Although it has a low overall relapse risk, a significant proportion of relapses occur within this subtype due to its relatively high incidence. No consistent genomic biomarkers have been identified that predict therapy response beyond early therapy response as measured by minimal residual disease at the end of induction.

Published
2023
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31. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, Mokry, Michal, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, and Mokry, Michal

Published
2016

32. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

Author

MDL onderzoek 3, Child Health, Cardiologie Arts-onderzoekers, CMM, Circulatory Health, Cancer, Brain, Cardiologie, Zorg en O&O, Regenerative Medicine and Stem Cells, Infection & Immunity, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, Mokry, Michal, MDL onderzoek 3, Child Health, Cardiologie Arts-onderzoekers, CMM, Circulatory Health, Cancer, Brain, Cardiologie, Zorg en O&O, Regenerative Medicine and Stem Cells, Infection & Immunity, Meddens, Claartje A, Harakalova, Magdalena, van den Dungen, Noortje A M, Foroughi Asl, Hassan, Hijma, Hemme J, Cuppen, Edwin P J G, Björkegren, Johan L M, Asselbergs, Folkert W, Nieuwenhuis, Edward E S, and Mokry, Michal

Published
2016

33. eQTL mapping and inherited risk enrichment analysis : a systems biology approach for coronary artery disease

Author

Foroughi Asl, Hassan and Foroughi Asl, Hassan

Abstract

Despite extensive research during the last decades, coronary artery disease (CAD) remains the number one cause of death, responsible for near 50% of global mortal- ity. A main reason for this is that CAD has a complex inheritance and etiology that unlike rare single gene disorders cannot fully be understood from studies of of genes one-by-one.In parallel, studies that simultaneously assess multiple, function- ally associated genes are warranted. For this reason we undertook the Stockholm Atherosclerosis Gene Expression (STAGE) study that besides careful clinical charac- terization and genome-wide DNA genotyping also assessed the global gene expression profiles from seven CAD-relevant vascular and metabolic tissues. In paper I, we used STAGE to develop a bioinformatics tool for efficient eQTL mapping called kruX based on Kruskal-Wallis statistics test. kruX excels in de- tecting a higher proportion of nonlinear expression quantitative expression traits loci (eQTLs) compared to other established methods. This tool was developed for Python, MATLAB, and R and is available online. In paper II, we applied kruX to detect eQTLs across the seven tissues in STAGE and assessed their tissue speci- ficity. A tool for analyzing inherited risk enrichment was also developed assessing CAD association (i.e., risk enrichment) of STAGE eQTLs according to genome-wide association studies (GWAS) of CAD. We found that eQTLs active across multiple vascular and metabolic tissues are more enriched in inherited risk for CAD than tissue-specific eQTLs. In paper III, we integrate the analysis of STAGE data with data from GWAS of CAD to identify 30 regulatory-gene networks causal for CAD. In paper IV, we again used kruX to investigate STAGE eQTLs for three established candidate genes in CAD and atherosclerosis (ALOX5, ALOX5AP, and LTA4H). In addition, we used the Athero-Express dataset of genotype and atherosclerotic carotid plaque characteristics to further elucidate the role of these genes in a

Published
2016

34. Human Validation of Genes Associated With a Murine Atherosclerotic Phenotype

Author

Pasterkamp, Gerard, primary, van der Laan, Sander W., additional, Haitjema, Saskia, additional, Foroughi Asl, Hassan, additional, Siemelink, Marten A., additional, Bezemer, Tim, additional, van Setten, Jessica, additional, Dichgans, Martin, additional, Malik, Rainer, additional, Worrall, Bradford B., additional, Schunkert, Heribert, additional, Samani, Nilesh J., additional, de Kleijn, Dominique P.V., additional, Markus, Hugh S., additional, Hoefer, Imo E., additional, Michoel, Tom, additional, de Jager, Saskia C.A., additional, Björkegren, Johan L.M., additional, den Ruijter, Hester M., additional, and Asselbergs, Folkert W., additional

Published
2016
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35. Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease

Author

Talukdar, Husain A., primary, Foroughi Asl, Hassan, additional, Jain, Rajeev K., additional, Ermel, Raili, additional, Ruusalepp, Arno, additional, Franzén, Oscar, additional, Kidd, Brian A., additional, Readhead, Ben, additional, Giannarelli, Chiara, additional, Kovacic, Jason C., additional, Ivert, Torbjörn, additional, Dudley, Joel T., additional, Civelek, Mete, additional, Lusis, Aldons J., additional, Schadt, Eric E., additional, Skogsberg, Josefin, additional, Michoel, Tom, additional, and Björkegren, Johan L.M., additional

Published
2016
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36. Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes : The Athero-Express Genomics Study

Author

Van Der Laan, Sander W., Foroughi Asl, Hassan, van den Borne, Pleunie, van Setten, Jessica, van der Perk, M. E Madeleine, van de Weg, Sander M., Schoneveld, Arjan H., de Kleijn, Dominique P V, Michoel, Tom, Björkegren, Johan L M, den Ruijter, Hester M., Asselbergs, Folkert W., de Bakker, Paul I W, Pasterkamp, Gerard, Van Der Laan, Sander W., Foroughi Asl, Hassan, van den Borne, Pleunie, van Setten, Jessica, van der Perk, M. E Madeleine, van de Weg, Sander M., Schoneveld, Arjan H., de Kleijn, Dominique P V, Michoel, Tom, Björkegren, Johan L M, den Ruijter, Hester M., Asselbergs, Folkert W., de Bakker, Paul I W, and Pasterkamp, Gerard

Published
2015

37. Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: The Athero-Express Genomics Study

Author

Experimentele Afd. Cardiologie 1, Cardiologie, Onderzoek Vrouw Hart & Vaatziekten, Circulatory Health, Analisten, JC onderzoeksprogramma Methodologie, Cancer, CDL Cluster Onderzoek en Onderwijs, Van Der Laan, Sander W., Foroughi Asl, Hassan, van den Borne, Pleunie, van Setten, Jessica, van der Perk, M. E Madeleine, van de Weg, Sander M., Schoneveld, Arjan H., de Kleijn, Dominique P V, Michoel, Tom, Björkegren, Johan L M, den Ruijter, Hester M., Asselbergs, Folkert W., de Bakker, Paul I W, Pasterkamp, Gerard, Experimentele Afd. Cardiologie 1, Cardiologie, Onderzoek Vrouw Hart & Vaatziekten, Circulatory Health, Analisten, JC onderzoeksprogramma Methodologie, Cancer, CDL Cluster Onderzoek en Onderwijs, Van Der Laan, Sander W., Foroughi Asl, Hassan, van den Borne, Pleunie, van Setten, Jessica, van der Perk, M. E Madeleine, van de Weg, Sander M., Schoneveld, Arjan H., de Kleijn, Dominique P V, Michoel, Tom, Björkegren, Johan L M, den Ruijter, Hester M., Asselbergs, Folkert W., de Bakker, Paul I W, and Pasterkamp, Gerard

Published
2015

38. Inherited Risk Enrichment Analysis ofgene sets using Genome-wide AssociationStudies for Coronary Artery Disease

Author

FOROUGHI ASL, HASSAN

Subjects
Biomedicinsk laboratorievetenskap/teknologi, Biomedical Laboratory Science/Technology
Abstract

Genome-wide association studies (GWAS) has been in the heartof medical research for the last 5 years. These studies seek forcommon variants in the genome that are linked to risk for commoncomplex diseases (CCDs). Although GWAS has defined a numberof interesting genetic loci for a range of CCDs, the current GWASanalysis has limitation such as investigating the DNA variantsone-by-one focusing on the most significant DNA variants. As aconsequence, most risk variants for CCDs are, in my belief, stillhidden in the GWAS data. Herein, I use a method of GWASanalysis that considers risk-enrichment for groups of functionallyassociated genes defined by for example gene networks, believedto play a role in CCDs.In this method, a set of expression SNP (single nucleotidepolymorphism) was selected from genes which are known to berelated to coronary artery disease (CAD) in a way that a singleeSNP was chosen for each gene. Then using the data availablefrom the International HapMap Project and a GWAS data available,it is possible to find SNPs which are in strong linkage withthe initial set, which we call it expanded set. Depending on theassociation of the initial set to the CAD, expanded set can showan enrichment score greater or smaller compared to the null distributionset of SNPs with same properties of the expanded set.In conclusions, CCDs are not a consequence of isolated geneticvariants/genes in isolated pathways but instead sets of geneticvariants/genes acting in conjunction, cause CAD. Genetic riskenrichment analysis is a fairly simple and straightforward methodto determine to what extent a group of functionally associatedgenetic variants/genes are enriched for a given CCD. In addition,this analysis can perhaps help to decipher some of the 90-85% ofrisk variation in populations that remains unaccounted.

Published
2013

39. Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: The Athero-Express Genomics Study

Author

van der Laan, Sander W., primary, Foroughi Asl, Hassan, additional, van den Borne, Pleunie, additional, van Setten, Jessica, additional, van der Perk, M.E. Madeleine, additional, van de Weg, Sander M., additional, Schoneveld, Arjan H., additional, de Kleijn, Dominique P.V., additional, Michoel, Tom, additional, Björkegren, Johan L.M., additional, den Ruijter, Hester M., additional, Asselbergs, Folkert W., additional, de Bakker, Paul I.W., additional, and Pasterkamp, Gerard, additional

Published
2015
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40. Expression Quantitative Trait Loci Acting Across Multiple Tissues Are Enriched in Inherited Risk for Coronary Artery Disease

Author

Foroughi Asl, Hassan, primary, Talukdar, Husain A., additional, Kindt, Alida S.D., additional, Jain, Rajeev K., additional, Ermel, Raili, additional, Ruusalepp, Arno, additional, Nguyen, Khanh-Dung H., additional, Dobrin, Radu, additional, Reilly, Dermot F., additional, Schunkert, Heribert, additional, Samani, Nilesh J., additional, Braenne, Ingrid, additional, Erdmann, Jeanette, additional, Melander, Olle, additional, Qi, Jianlong, additional, Ivert, Torbjörn, additional, Skogsberg, Josefin, additional, Schadt, Eric E., additional, Michoel, Tom, additional, and Björkegren, Johan L.M., additional

Published
2015
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41. Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.

Author

Björkegren, Johan L M, Hägg, Sara, Talukdar, Husain A, Foroughi Asl, Hassan, Jain, Rajeev K, Cedergren, Cecilia, Shang, Ming-Mei, Rossignoli, Aránzazu, Takolander, Rabbe, Melander, Olle, Hamsten, Anders, Michoel, Tom, Skogsberg, Josefin, Björkegren, Johan L M, Hägg, Sara, Talukdar, Husain A, Foroughi Asl, Hassan, Jain, Rajeev K, Cedergren, Cecilia, Shang, Ming-Mei, Rossignoli, Aránzazu, Takolander, Rabbe, Melander, Olle, Hamsten, Anders, Michoel, Tom, and Skogsberg, Josefin

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

42. Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

Author

Björkegren, Johan L. M., primary, Hägg, Sara, additional, Talukdar, Husain A., additional, Foroughi Asl, Hassan, additional, Jain, Rajeev K., additional, Cedergren, Cecilia, additional, Shang, Ming-Mei, additional, Rossignoli, Aránzazu, additional, Takolander, Rabbe, additional, Melander, Olle, additional, Hamsten, Anders, additional, Michoel, Tom, additional, and Skogsberg, Josefin, additional

Published
2014
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44. BTKand PLCG2remain unmutated in one third of patients with CLL relapsing on ibrutinib

Author

Bonfiglio, Silvia, Sutton, Lesley-Ann, Ljungström, Viktor, Capasso, Antonella, Pandzic, Tatjana, Weström, Simone, Foroughi-Asl, Hassan, Skaftason, Aron, Gellerbring, Anna, Lyander, Anna, Gandini, Francesca, Gaidano, Gianluca, Trentin, Livio, Bonello, Lisa, Reda, Gianluigi, Bödör, Csaba, Stavroyianni, Niki, Tam, Constantine S., Marasca, Roberto, Forconi, Francesco, Panayiotidis, Panayiotis, Ringshausen, Ingo, Jaksic, Ozren, Frustaci, Anna Maria, Iyengar, Sunil, Coscia, Marta, Mulligan, Stephen P., Ysebaert, Loïc, Strugov, Vladimir, Pavlovsky, Carolina, Walewska, Renata, Österborg, Anders, Cortese, Diego, Ranghetti, Pamela, Baliakas, Panagiotis, Stamatopoulos, Kostas, Scarfò, Lydia, Rosenquist, Richard, and Ghia, Paolo

Abstract

•One third of patients with CLL relapsing on ibrutinib do not carry BTK/PLCG2mutations, even with a 0.1% sensitivity.•Additional mechanisms, such as del(8p), EGR2and NF-κB pathway mutations, may be cooperating in determining progression on ibrutinib.

Published
2023
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45. 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, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, M.J, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch José, Francesc Xavier, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Mansouri L, Thorvaldsdottir B, Sutton LA] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. [Karakatsoulis G] Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece. Department of Mathematics, University of Ioannina, Ioannina, Greece. [Meggendorfer M] MLL Munich Leukemia Laboratory, Munich, Germany. [Parker H] Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. [Bosch F, Tazón-Vega B] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Karolinska Institutet [Stockholm], Institute of Applied Biosciences [Thessaloniki, Greece] (IAB), University of Ioannina, Munich Leukemia Laboratory [Munich, Germany] (M2L), University of Southampton, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Copenhagen University Hospital, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Oncology Institute of Southern Switzerland (IOSI), Institute Of Oncology Research [Bellinzona, Switzerland] (IOL), Queen's University [Belfast] (QUB), University Hospital Brno, Masaryk University [Brno] (MUNI), Clinic Barcelona Hospital Universitari, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Università degli Studi di Ferrara = University of Ferrara (UniFE), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Uppsala University, University Hospitals Dorset NHS Foundation Trust [Bournemouth, UK] (UHD), All India Institute of Medical Sciences [New Delhi], Hospital Universitario 12 de Octubre [Madrid], Spanish National Cancer Research Center (CNIO), Hôpital de Beaumont [Dublin, Ireland] (HB), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Semmelweis University [Budapest], South-Pest Hospital Centre [Budapest, Hungary] (SPHC), IMIM-Hospital del Mar, Generalitat de Catalunya, Humboldt University Of Berlin, Universitat Autònoma de Barcelona (UAB), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Hôpital Avicenne HUPSSD - Service d'Hématologie Biologique, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Universitat de València (UV), Centre for Research and Technology Hellas (CERTH), Karolinska University Hospital [Stockholm], and Baran-Marszak, Fanny

Subjects
Cancer Research, Otros calificadores::Otros calificadores::/genética [Otros calificadores], [SDV]Life Sciences [q-bio], Leucèmia limfocítica crònica - Aspectes genètics, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Hematology, [SDV] Life Sciences [q-bio], Anomalies cromosòmiques, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Oncology, Genetics research, Other subheadings::Other subheadings::/genetics [Other subheadings], Cancer genetics, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES]
Abstract

Cancer genetics; Genetics research Genètica del càncer; Recerca genètica Genética del cáncer; Investigación genética 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. The European Research Initiative on CLL (ERIC) is a partner in the HARMONY Alliance, the EHA Scientific Working group on CLL and the ELN Workpackage 7 on CLL. This work was in part supported by; Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy (Investigator Grant #20246 and Special Program on Metastatic Disease—5 per mille #21198); ERA NET TRANSCAN-2 Joint Transnational Call for Proposals: JTC 2014 (project #143 GCH-CLL) and JTC 2016 (project #179 NOVEL), project code (MIS) 5041673; Bando della Ricerca Finalizzata 2018, Ministero della Salute, Roma, Italy (progetto RF-2018–12368231); “la Caixa” Foundation (Health Research 2017 Program HR17-00221); the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223); the Hellenic Precision Medicine Network in Oncology; project ODYSSEAS (Intelligent and Automated Systems for enabling the Design, Simulation and Development of Integrated Processes and Products) implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462”; MH CZ—DRO (FNBr, 65269705), NV19-03-00091 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next-Generation EU; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes, and Elixir Hungary; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; Fondo di Ateneo per la Ricerca (FAR) 2019, 2020 and 2021 of the University of Ferrara (GMR; AC), Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS Ferrara (AC; GMR), BEAT Leukemia Foundation Milan Italy (AC); the Danish Cancer Society and the CLL-CLUE project under the frame of ERA PerMed; Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669); the Swedish Cancer Society (19 0425 Pj 01 H), the Swedish Research Council (2020-01750), the Knut and Alice Wallenberg Foundation (2016.0373), Region Stockholm (ALF/FoUI-962423), and Radiumhemmets Forskningsfonder (194133), Stockholm; and Lion’s Cancer Research Foundation, Uppsala.

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46. Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions.

Author

Siemelink, Marten A., van der Laan, Sander W., Haitjema, Saskia, van Koeverden, Ian D., Schaap, Jacco, Wesseling, Marian, de Jager, Saskia C.A., Mokry, Michal, van Iterson, Maarten, Dekkers, Koen F., Luijk, René, Foroughi Asl, Hassan, Michoel, Tom, Björkegren, Johan L.M., Aavik, Einari, Ylä-Herttuala, Seppo, de Borst, Gert J., Asselbergs, Folkert W., el Azzouzi, Hamid, and den Ruijter, Hester M.

Abstract

Supplemental Digital Content is available in the text. 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. [ABSTRACT FROM AUTHOR]

Published
2018
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47. 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
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48. 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
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