33 results on '"James, Tojo"'
Search Results
2. Delineating functional and molecular impact of ex vivo sample handling in precision medicine
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Struyf, Nona, Österroos, Albin, Vesterlund, Mattias, Arnroth, Cornelia, James, Tojo, Sunandar, Stephanie, Mermelekas, Georgios, Bohlin, Anna, Hamberg Levedahl, Kerstin, Bengtzén, Sofia, Jafari, Rozbeh, Orre, Lukas M., Lehtiö, Janne, Lehmann, Sören, Östling, Päivi, Kallioniemi, Olli, Seashore-Ludlow, Brinton, and Erkers, Tom
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- 2024
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3. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
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Patsopoulos, Nikolaos A, Baranzini, Sergio E, Santaniello, Adam, Shoostari, Parisa, Cotsapas, Chris, Wong, Garrett, Beecham, Ashley H, James, Tojo, Replogle, Joseph, Vlachos, Ioannis S, McCabe, Cristin, Pers, Tune H, Brandes, Aaron, White, Charles, Keenan, Brendan, Cimpean, Maria, Winn, Phoebe, Panteliadis, Ioannis-Pavlos, Robbins, Allison, Andlauer, Till FM, Zarzycki, Onigiusz, Dubois, Bénédicte, Goris, An, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise Wegner, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusic, Sandra, Berthele, Achim, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Graetz, Christiane, Grummel, Verena, Hemmer, Bernhard, Hoshi, Muni, Knier, Benjamin, Korn, Thomas, Lill, Christina M, Luessi, Felix, Mühlau, Mark, Zipp, Frauke, Dardiotis, Efthimios, Agliardi, Cristina, Amoroso, Antonio, Barizzone, Nadia, Benedetti, Maria D, Bernardinelli, Luisa, Cavalla, Paola, Clarelli, Ferdinando, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Galimberti, Daniela, Guaschino, Clara, Leone, Maurizio A, Martinelli, Vittorio, Moiola, Lucia, Salvetti, Marco, Sorosina, Melissa, Vecchio, Domizia, Zauli, Andrea, Santoro, Silvia, Mancini, Nicasio, Zuccalà, Miriam, Mescheriakova, Julia, van Duijn, Cornelia, Bos, Steffan D, Celius, Elisabeth G, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Bomfim, Izaura L, Gomez-Cabrero, David, Hillert, Jan, Jagodic, Maja, Lindén, Magdalena, Piehl, Fredrik, Jelčić, Ilijas, Martin, Roland, Sospedra, Mirela, Baker, Amie, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Molyneux, Paul, and Neville, Matthew
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Neurosciences ,Brain Disorders ,Multiple Sclerosis ,Human Genome ,Autoimmune Disease ,Clinical Research ,Genetics ,Neurodegenerative ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Neurological ,Case-Control Studies ,Cell Cycle Proteins ,Chromosome Mapping ,Chromosomes ,Human ,X ,GTPase-Activating Proteins ,Gene Frequency ,Genetic Loci ,Genome-Wide Association Study ,Genomics ,Humans ,Inheritance Patterns ,Major Histocompatibility Complex ,Microglia ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,RNA-Seq ,Transcriptome ,International Multiple Sclerosis Genetics Consortium ,General Science & Technology - Abstract
We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.
- Published
- 2019
4. Small noncoding RNA profiling across cellular and biofluid compartments and their implications for multiple sclerosis immunopathology
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Zheleznyakova, Galina Yurevna, Piket, Eliane, Needhamsen, Maria, Hagemann-Jensen, Michael, Ekman, Diana, Han, Yanan, James, Tojo, Khademi, Mohsen, Nimer, Faiez Al, Scicluna, Patrick, Huang, Jesse, Kockum, Ingrid, Faridani, Omid R., Olsson, Tomas, Piehl, Fredrik, and Jagodic, Maja
- Published
- 2021
5. C-type lectin receptors Mcl and Mincle control development of multiple sclerosis-like neuroinflammation
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N'diaye, Marie, Brauner, Susanna, Flytzani, Sevasti, Kular, Lara, Warnecke, Andreas, Adzemovic, Milena Z., Piket, Eliane, Min, Jin-Hong, Edwards, Will, Mela, Filia, Choi, Hoi Ying, Magg, Vera, James, Tojo, Linden, Magdalena, Reichardt, Holger M., Daws, Michael R., van Horssen, Jack, Kockum, Ingrid, Harris, Robert A., Olsson, Tomas, Guerreiro-Cacais, Andre O., and Jagodic, Maja
- Subjects
Lectins -- Analysis -- Health aspects ,Autoimmunity -- Analysis -- Health aspects ,Multiple sclerosis -- Development and progression -- Analysis -- Health aspects ,T cells -- Analysis -- Health aspects ,Brain damage ,Infection ,Central nervous system ,Encephalomyelitis ,Health care industry - Abstract
Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS., Introduction Multiple sclerosis (MS), a leading cause of neurological disability in young adults, is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune destruction of myelin [...]
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- 2020
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6. Delineating functional and molecular impact of ex vivo sample handling in precision medicine
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Erkers, Tom, primary, Struyf, Nona, additional, Arnroth, Cornelia, additional, Vesterlund, Mattias, additional, James, Tojo, additional, Sunandar, Stephanie, additional, Bohlin, Anna, additional, Hamberg-Levedahl, Kerstin, additional, Bengtzén, Sofia, additional, Jafari, Rozbeh, additional, Orre, Lukas, additional, Lehtiö, Janne, additional, Lehmann, Sören, additional, Ostling, Paivi, additional, Kallioniemi, Olli, additional, and Seashore-Ludlow, Brinton, additional
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- 2023
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7. Data-Driven Molecular Hallmarks of Acute Myeloid Leukemia: Biological, Prognostic and Therapeutic Implications
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Erkers, Tom, primary, Marabita, Francesco, additional, Struyf, Nona, additional, Vesterlund, Mattias, additional, James, Tojo, additional, Arnroth, Cornelia, additional, Bohlin, Anna, additional, Bengtzén, Sofia, additional, Österroos, Albin, additional, Stahl, Matthias, additional, Jafari, Rozbeh, additional, Orre, Lukas, additional, Pawitan, Yudi, additional, Seashore-Ludlow, Brinton, additional, Lehtiö, Janne, additional, Lehmann, Sören, additional, Östling, Päivi, additional, and Kallioniemi, Olli, additional
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- 2022
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8. Implication of DNA methylation changes at chromosome 1q21.1 in the brain pathology of Primary Progressive Multiple Sclerosis
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Pahlevan Kakhki, Majid, primary, Starvaggi Cucuzza, Chiara, additional, Gyllenberg, Alexandra, additional, Badam, Tejaswi Venkata S., additional, Liu, Yun, additional, Boddul, Sanjaykumar, additional, James, Tojo, additional, Wermeling, Fredrik, additional, Gustafsson, Mika, additional, Casaccia, Patrizia, additional, Kockum, Ingrid, additional, Hillert, Jan, additional, Olsson, Tomas, additional, Kular, Lara, additional, and Jagodic, Maja, additional
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- 2022
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9. Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
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Marabita, Francesco, James, Tojo, Karhu, Anu, Virtanen, Heidi, Kettunen, Kaisa, Stenlund, Hans, Boulund, Fredrik, Hellström, Cecilia, Neiman, Maja, Mills, Robert, Perheentupa, Teemu, Laivuori, Hannele, Helkkula, Pyry, Byrne, Myles, Jokinen, Ilkka, Honko, Harri, Kallonen, Antti, Ermes, Miikka, Similä, Heidi, Lindholm, Mikko, Widén, Elisabeth, Ripatti, Samuli, Perälä-Heape, Maritta, Engstrand, Lars, Nilsson, Peter, Moritz, Thomas, Miettinen, Timo, Sallinen, Riitta, Kallioniemi, Olli, Marabita, Francesco, James, Tojo, Karhu, Anu, Virtanen, Heidi, Kettunen, Kaisa, Stenlund, Hans, Boulund, Fredrik, Hellström, Cecilia, Neiman, Maja, Mills, Robert, Perheentupa, Teemu, Laivuori, Hannele, Helkkula, Pyry, Byrne, Myles, Jokinen, Ilkka, Honko, Harri, Kallonen, Antti, Ermes, Miikka, Similä, Heidi, Lindholm, Mikko, Widén, Elisabeth, Ripatti, Samuli, Perälä-Heape, Maritta, Engstrand, Lars, Nilsson, Peter, Moritz, Thomas, Miettinen, Timo, Sallinen, Riitta, and Kallioniemi, Olli
- Abstract
We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.
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- 2022
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10. Article Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
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Marabita, Francesco, James, Tojo, Karhu, Anu, Virtanen, Heidi, Kettunen, Kaisa, Stenlund, Hans, Boulund, Fredrik, Hellström, Cecilia, Neiman, Maja, Mills, Robert, Perheentupa, Teemu, Laivuori, Hannele, Helkkula, Pyry, Byrne, Myles, Jokinen, Ilkka, Honko, Harri, Kallonen, Antti, Ermes, Miikka, Simila, Heidi, Lindholm, Mikko, Widen, Elisabeth, Ripatti, Samuli, Perala-Heape, Maritta, Engstrand, Lars, Nilsson, Peter, Moritz, Thomas, Miettinen, Timo, Sallinen, Riitta, Kallioniemi, Olli, Marabita, Francesco, James, Tojo, Karhu, Anu, Virtanen, Heidi, Kettunen, Kaisa, Stenlund, Hans, Boulund, Fredrik, Hellström, Cecilia, Neiman, Maja, Mills, Robert, Perheentupa, Teemu, Laivuori, Hannele, Helkkula, Pyry, Byrne, Myles, Jokinen, Ilkka, Honko, Harri, Kallonen, Antti, Ermes, Miikka, Simila, Heidi, Lindholm, Mikko, Widen, Elisabeth, Ripatti, Samuli, Perala-Heape, Maritta, Engstrand, Lars, Nilsson, Peter, Moritz, Thomas, Miettinen, Timo, Sallinen, Riitta, and Kallioniemi, Olli
- Abstract
We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information., QC 20220407
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- 2022
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11. Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
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Marabita, Francesco, primary, James, Tojo, additional, Karhu, Anu, additional, Virtanen, Heidi, additional, Kettunen, Kaisa, additional, Stenlund, Hans, additional, Boulund, Fredrik, additional, Hellström, Cecilia, additional, Neiman, Maja, additional, Mills, Robert, additional, Perheentupa, Teemu, additional, Laivuori, Hannele, additional, Helkkula, Pyry, additional, Byrne, Myles, additional, Jokinen, Ilkka, additional, Honko, Harri, additional, Kallonen, Antti, additional, Ermes, Miikka, additional, Similä, Heidi, additional, Lindholm, Mikko, additional, Widén, Elisabeth, additional, Ripatti, Samuli, additional, Perälä-Heape, Maritta, additional, Engstrand, Lars, additional, Nilsson, Peter, additional, Moritz, Thomas, additional, Miettinen, Timo, additional, Sallinen, Riitta, additional, and Kallioniemi, Olli, additional
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- 2022
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12. Assessing the consistency of public human tissue RNA-seq data sets
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Danielsson, Frida, James, Tojo, Gomez-Cabrero, David, and Huss, Mikael
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- 2015
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13. Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
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Marabita, Francesco, primary, James, Tojo, additional, Karhu, Anu, additional, Virtanen, Heidi, additional, Kettunen, Kaisa, additional, Stenlund, Hans, additional, Boulund, Fredrik, additional, Hellström, Cecilia, additional, Neiman, Maja, additional, Mills, Robert, additional, Perheentupa, Teemu, additional, Laivuori, Hannele, additional, Helkkula, Pyry, additional, Byrne, Myles, additional, Jokinen, Ilkka, additional, Honko, Harri, additional, Kallonen, Antti, additional, Ermes, Miikka, additional, Similä, Heidi, additional, Lindholm, Mikko, additional, Widen, Elisabeth, additional, Ripatti, Samuli, additional, Perälä-Heape, Maritta, additional, Engstrand, Lars, additional, Nilsson, Peter, additional, Moritz, Thomas, additional, Miettinen, Timo, additional, Sallinen, Riitta, additional, and Kallioniemi, Olli, additional
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- 2020
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14. C-type lectin receptors Mcl and Mincle control development of multiple sclerosis–like neuroinflammation
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N’diaye, Marie, primary, Brauner, Susanna, additional, Flytzani, Sevasti, additional, Kular, Lara, additional, Warnecke, Andreas, additional, Adzemovic, Milena Z., additional, Piket, Eliane, additional, Min, Jin-Hong, additional, Edwards, Will, additional, Mela, Filia, additional, Choi, Hoi Ying, additional, Magg, Vera, additional, James, Tojo, additional, Linden, Magdalena, additional, Reichardt, Holger M., additional, Daws, Michael R., additional, van Horssen, Jack, additional, Kockum, Ingrid, additional, Harris, Robert A., additional, Olsson, Tomas, additional, Guerreiro-Cacais, Andre O., additional, and Jagodic, Maja, additional
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- 2020
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15. High-Throughput Functional Ex-Vivo Drug Testing and Multi-Omics Profiling in Patients with Acute Myeloid Leukemia
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Erkers, Tom, primary, Seashore-Ludlow, Brinton, additional, Struyf, Nona, additional, Marabita, Francesco, additional, James, Tojo, additional, Malani, Disha, additional, Vesterlund, Mattias, additional, Stalhl, Matthias, additional, Pawitan, Yudi, additional, Lehmann, Sören, additional, Östling, Päivi, additional, Lehtiö, Janne, additional, and Kallioniemi, Olli, additional
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- 2019
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16. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility
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Patsopoulos, Nikolaos A., Baranzini, Sergio E., Santaniello, Adam, Shoostari, Parisa, Cotsapas, Chris, Wong, Garrett, Beecham, Ashley H., James, Tojo, Replogle, Joseph, Vlachos, Ioannis S., McCabe, Cristin, Pers, Tune H., Brandes, Aaron, White, Charles, Keenan, Brendan, Cimpean, Maria, Winn, Phoebe, Panteliadis, Ioannis Pavlos, Robbins, Allison, Andlauer, Till F.M., Zarzycki, Onigiusz, Dubois, Bénédicte, Goris, An, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise Wegner, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusic, Sandra, Berthele, Achim, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Graetz, Christiane, Grummel, Verena, Hemmer, Bernhard, Hoshi, Muni, Knier, Benjamin, Korn, Thomas, Lill, Christina M., Luessi, Felix, Karpe, Fredrik, Lage, Kasper, Oturai, Annette, Patsopoulos, Nikolaos A., Baranzini, Sergio E., Santaniello, Adam, Shoostari, Parisa, Cotsapas, Chris, Wong, Garrett, Beecham, Ashley H., James, Tojo, Replogle, Joseph, Vlachos, Ioannis S., McCabe, Cristin, Pers, Tune H., Brandes, Aaron, White, Charles, Keenan, Brendan, Cimpean, Maria, Winn, Phoebe, Panteliadis, Ioannis Pavlos, Robbins, Allison, Andlauer, Till F.M., Zarzycki, Onigiusz, Dubois, Bénédicte, Goris, An, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise Wegner, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusic, Sandra, Berthele, Achim, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Graetz, Christiane, Grummel, Verena, Hemmer, Bernhard, Hoshi, Muni, Knier, Benjamin, Korn, Thomas, Lill, Christina M., Luessi, Felix, Karpe, Fredrik, Lage, Kasper, and Oturai, Annette
- Abstract
We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.
- Published
- 2019
17. Viral antigens elicit augmented immune responses in primary Sjögren’s syndrome
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Björk, Albin, primary, Thorlacius, Gudny Ella, primary, Mofors, Johannes, primary, Richardsdotter Andersson, Elina, primary, Ivanchenko, Margarita, primary, Tingström, Joanna, primary, James, Tojo, primary, Brokstad, Karl A, primary, Cox, Rebecca J, primary, Jonsson, Roland, primary, Kvarnström, Marika, primary, and Wahren-Herlenius, Marie, primary
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- 2019
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18. Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
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James, Tojo, Lindén, Magdalena, Morikawa, Hiromasa, Fernandes, Sunjay Jude, Ruhrmann, Sabrina, Huss, Mikael, Brandi, Maya, Piehl, Fredrik, Jagodic, Maja, Tegnér, Jesper, Khademi, Mohsen, Olsson, Tomas, Gomez-Cabrero, David, Kockum, Ingrid, James, Tojo, Lindén, Magdalena, Morikawa, Hiromasa, Fernandes, Sunjay Jude, Ruhrmann, Sabrina, Huss, Mikael, Brandi, Maya, Piehl, Fredrik, Jagodic, Maja, Tegnér, Jesper, Khademi, Mohsen, Olsson, Tomas, Gomez-Cabrero, David, and Kockum, Ingrid
- Abstract
Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
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- 2018
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19. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
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Kular, Lara, Liu, Yun, Ruhrmann, Sabrina, Zheleznyakova, Galina, Marabita, Francesco, Gomez-Cabrero, David, James, Tojo, Ewing, Ewoud, Lindén, Magdalena, Górnikiewicz, Bartosz, Aeinehband, Shahin, Stridh, Pernilla, Link, Jenny, Andlauer, Till F.M., Gasperi, Christiane, Wiendl, Heinz, Zipp, Frauke, Gold, Ralf, Tackenberg, Björn, Weber, Frank, Hemmer, Bernhard, Strauch, Konstantin, Heilmann-Heimbach, Stefanie, Rawal, Rajesh, Schminke, Ulf, Schmidt, Carsten O., Kacprowski, Tim, Franke, Andre, Laudes, Matthias, Dilthey, Alexander T., Celius, Elisabeth G., Søndergaard, Helle B., Tegnér, Jesper, Harbo, Hanne F., Oturai, Annette B., Olafsson, Sigurgeir, Eggertsson, Hannes P., Halldorsson, Bjarni V., Hjaltason, Haukur, Olafsson, Elias, Jonsdottir, Ingileif, Stefansson, Kari, Olsson, Tomas, Piehl, Fredrik, Ekström, Tomas J., Kockum, Ingrid, Feinberg, Andrew P., Jagodic, Maja, Kular, Lara, Liu, Yun, Ruhrmann, Sabrina, Zheleznyakova, Galina, Marabita, Francesco, Gomez-Cabrero, David, James, Tojo, Ewing, Ewoud, Lindén, Magdalena, Górnikiewicz, Bartosz, Aeinehband, Shahin, Stridh, Pernilla, Link, Jenny, Andlauer, Till F.M., Gasperi, Christiane, Wiendl, Heinz, Zipp, Frauke, Gold, Ralf, Tackenberg, Björn, Weber, Frank, Hemmer, Bernhard, Strauch, Konstantin, Heilmann-Heimbach, Stefanie, Rawal, Rajesh, Schminke, Ulf, Schmidt, Carsten O., Kacprowski, Tim, Franke, Andre, Laudes, Matthias, Dilthey, Alexander T., Celius, Elisabeth G., Søndergaard, Helle B., Tegnér, Jesper, Harbo, Hanne F., Oturai, Annette B., Olafsson, Sigurgeir, Eggertsson, Hannes P., Halldorsson, Bjarni V., Hjaltason, Haukur, Olafsson, Elias, Jonsdottir, Ingileif, Stefansson, Kari, Olsson, Tomas, Piehl, Fredrik, Ekström, Tomas J., Kockum, Ingrid, Feinberg, Andrew P., and Jagodic, Maja
- Abstract
The human leukocyte antigen (HLA) haplotype DRB1 15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1 15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1 15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1 15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10 -8 , odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1 15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
- Published
- 2018
20. Genetic landscape of multiple sclerosis susceptibility by leveraging multi-omics data
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James, Tojo and James, Tojo
- Abstract
The main objective of the research studies presented in this thesis is to study the genetic variants and the expression of genes that relate to Multiple Sclerosis (MS). MS is a polygenic disease with HLA-DRB1*15:01 allele as a strong risk factor. Currently there are more than 200 non-HLA regions identified for MS. However, most of the risk loci identified in those studies are primarily driven by the relapsing-remitting form of MS (RRMS). To identify risk factors specific for the primary progressive form of MS (PPMS) which is a smaller group of MS patients, we have examined the exomes of PPMS and RRMS patients matching to population based controls in a case-control study setting and reported risk variants and mutations that are associated to PPMS and RRMS. The context of this study is during the ‘post-GWAS’ era, when researchers are primarily focused to understand the functional consequences of the genetic risk factors. Using the possibilities of transcriptomic and genotyping data, genes that correlate to the risk loci are identified in relevant cell types of MS. Several statistical methods are implemented to characterize the risk loci and replicate the findings in the context of disease. MicroRNAs (miRNAs), small non-coding RNAs which regulate gene expression at post-transcriptional level, have been identified dysregulated in autoimmune diseases, including MS. We used experimental autoimmune encephalomyelitis (EAE), a commonly used animal model for MS to understand the role of miRNA in the immune activation of EAE. Next generation sequencing (NGS) methods were widely applied in all of these studies specifically at transcriptomic and genomic level of the disease. NGS methods are data intensive but have higher reliability. To test the reliability, we compared reported gene expression measurements for ostensibly similar tissue samples collected from different RNA-seq studies. We found an overall consistency on expression data obtained from different studies and identif
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- 2018
21. Viral antigens elicit augmented immune responses in primary Sjögren's syndrome.
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Björk, Albin, Thorlacius, Gudny Ella, Mofors, Johannes, Andersson, Elina Richardsdotter, Ivanchenko, Margarita, Tingström, Joanna, James, Tojo, Brokstad, Karl A, Cox, Rebecca J, Jonsson, Roland, Kvarnström, Marika, and Wahren-Herlenius, Marie
- Subjects
CHLOROQUINE ,ENZYME-linked immunosorbent assay ,GENE expression ,IMMUNIZATION ,IMMUNOGLOBULINS ,INFLUENZA ,LONGITUDINAL method ,MONOCYTES ,PROTEINS ,QUESTIONNAIRES ,SEROLOGY ,SJOGREN'S syndrome ,VIRAL antigens ,ROUTINE diagnostic tests - Abstract
Objectives Infections have been suggested in the pathogenesis of primary SS (pSS). Systematic studies of immune responses to microbial antigens in vivo may be performed during vaccination. In the present study, we therefore longitudinally followed patients with pSS and controls during split-virion influenza vaccination to identify pSS-specific cellular, transcriptomic and serological responses. Methods Patients without treatment (pSS
Untr , n = 17), on hydroxychloroquine-treatment (pSSHCQ , n = 8), and healthy controls (n = 16) were included. Antibody titres were determined by ELISA. Plasma proteins were measured by proximity extension assay. Monocyte gene expression was assessed by Nanostring. Routine laboratory tests were performed and clinical disease symptoms were registered by questionnaires. Results pSSUntr developed higher vaccine-specific IgG titres compared with controls. Notably, anti-Ro52 autoantibody titres increased in pSSUntr but remained unchanged in pSSHCQ . No changes in disease symptoms including EULAR Sjögren's Syndrome Patient Reported Index score were registered. Twenty-four hours after vaccination, the leucocyte count in pSSUntr decreased, with a concomitant increase of CCL7 in plasma. Transcriptomic analysis in monocytes revealed differential vaccination-related expression of the NEMO/IKBKG gene, and its higher induced expression in pSSUntr associated with higher serological vaccine responses. Moreover, titres of vaccine-specific antibodies were associated with higher vaccination-induced NF-κB signalling and higher steady-state IFN signatures in monocytes, and with the levels of several plasma proteins with soluble PD-1 displaying the strongest association. Conclusion We observed augmented innate and adaptive immune responses in pSS following viral antigen exposure suggesting an underlying hyper-responsiveness to immune challenges, supporting a role for infections driving the immunopathology and acting as environmental risk factor for pSS. [ABSTRACT FROM AUTHOR]- Published
- 2020
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22. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
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Kular, Lara, primary, Liu, Yun, additional, Ruhrmann, Sabrina, additional, Zheleznyakova, Galina, additional, Marabita, Francesco, additional, Gomez-Cabrero, David, additional, James, Tojo, additional, Ewing, Ewoud, additional, Lindén, Magdalena, additional, Górnikiewicz, Bartosz, additional, Aeinehband, Shahin, additional, Stridh, Pernilla, additional, Link, Jenny, additional, Andlauer, Till F. M., additional, Gasperi, Christiane, additional, Wiendl, Heinz, additional, Zipp, Frauke, additional, Gold, Ralf, additional, Tackenberg, Björn, additional, Weber, Frank, additional, Hemmer, Bernhard, additional, Strauch, Konstantin, additional, Heilmann-Heimbach, Stefanie, additional, Rawal, Rajesh, additional, Schminke, Ulf, additional, Schmidt, Carsten O., additional, Kacprowski, Tim, additional, Franke, Andre, additional, Laudes, Matthias, additional, Dilthey, Alexander T., additional, Celius, Elisabeth G., additional, Søndergaard, Helle B., additional, Tegnér, Jesper, additional, Harbo, Hanne F., additional, Oturai, Annette B., additional, Olafsson, Sigurgeir, additional, Eggertsson, Hannes P., additional, Halldorsson, Bjarni V., additional, Hjaltason, Haukur, additional, Olafsson, Elias, additional, Jonsdottir, Ingileif, additional, Stefansson, Kari, additional, Olsson, Tomas, additional, Piehl, Fredrik, additional, Ekström, Tomas J., additional, Kockum, Ingrid, additional, Feinberg, Andrew P., additional, and Jagodic, Maja, additional
- Published
- 2018
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23. Author Correction: Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship
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Marabita, Francesco, primary, Almgren, Malin, additional, Sjöholm, Louise K., additional, Kular, Lara, additional, Liu, Yun, additional, James, Tojo, additional, Kiss, Nimrod B., additional, Feinberg, Andrew P., additional, Olsson, Tomas, additional, Kockum, Ingrid, additional, Alfredsson, Lars, additional, Ekström, Tomas J., additional, and Jagodic, Maja, additional
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- 2018
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24. Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
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James, Tojo, primary, Lindén, Magdalena, additional, Morikawa, Hiromasa, additional, Fernandes, Sunjay Jude, additional, Ruhrmann, Sabrina, additional, Huss, Mikael, additional, Brandi, Maya, additional, Piehl, Fredrik, additional, Jagodic, Maja, additional, Tegnér, Jesper, additional, Khademi, Mohsen, additional, Olsson, Tomas, additional, Gomez-Cabrero, David, additional, and Kockum, Ingrid, additional
- Published
- 2018
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25. Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship
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Marabita, Francesco, primary, Almgren, Malin, additional, Sjöholm, Louise K., additional, Kular, Lara, additional, Liu, Yun, additional, James, Tojo, additional, Kiss, Nimrod B., additional, Feinberg, Andrew P., additional, Olsson, Tomas, additional, Kockum, Ingrid, additional, Alfredsson, Lars, additional, Ekström, Tomas J., additional, and Jagodic, Maja, additional
- Published
- 2017
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26. Sex influences eQTL effects of SLE and Sjögren’s syndrome-associated genetic polymorphisms
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Lindén, Magdalena, primary, Ramírez Sepúlveda, Jorge I., additional, James, Tojo, additional, Thorlacius, Gudny Ella, additional, Brauner, Susanna, additional, Gómez-Cabrero, David, additional, Olsson, Tomas, additional, Kockum, Ingrid, additional, and Wahren-Herlenius, Marie, additional
- Published
- 2017
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27. Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
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Jan Ernerudh, Jordi Serra-Musach, Núria Bonifaci, Mika Gustafsson, James Tojo, Fredrik Barrenäs, Colm E. Nestor, Tomas Olsson, Måns Edström, Ingrid Kockum, Huan Zhang, Miguel Angel Pujana, Hui Wang, Mikael Benson, and Danuta R. Gawel
- Subjects
Medicinska och farmaceutiska grundvetenskaper ,Systems biology ,Hay fever ,Genome-wide association study ,Translational research ,Esclerosi múltiple ,Computational biology ,Biology ,Bioinformatics ,Proteomics ,Multiple sclerosis ,03 medical and health sciences ,0302 clinical medicine ,Pleiotropy ,Genetics ,Genetics(clinical) ,Molecular Biology ,Gene ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Research ,Klinisk medicin ,Basic Medicine ,Human genetics ,Febre del fenc ,3. Good health ,Gene expression profiling ,030220 oncology & carcinogenesis ,Molecular Medicine ,Clinical Medicine - Abstract
Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.
- Published
- 2014
28. TGFβ regulates persistent neuroinflammation by controlling Th1 polarization and ROS production via monocyte-derived dendritic cells
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Parsa, Roham, primary, Lund, Harald, additional, Tosevski, Ivana, additional, Zhang, Xing-Mei, additional, Malipiero, Ursula, additional, Beckervordersandforth, Jan, additional, Merkler, Doron, additional, Prinz, Marco, additional, Gyllenberg, Alexandra, additional, James, Tojo, additional, Warnecke, Andreas, additional, Hillert, Jan, additional, Alfredsson, Lars, additional, Kockum, Ingrid, additional, Olsson, Tomas, additional, Fontana, Adriano, additional, Suter, Tobias, additional, and Harris, Robert A., additional
- Published
- 2016
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29. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis
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Bergman, Petra, primary, Piket, Eliane, additional, Khademi, Mohsen, additional, James, Tojo, additional, Brundin, Lou, additional, Olsson, Tomas, additional, Piehl, Fredrik, additional, and Jagodic, Maja, additional
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- 2016
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30. Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats.
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Bergman, Petra, James, Tojo, Kular, Lara, Ruhrmann, Sabrina, Kramarova, Tatiana, Kvist, Anders, Supic, Gordana, Gillett, Alan, Pivarcsi, Andor, Jagodic, Maja, Bergman, Petra, James, Tojo, Kular, Lara, Ruhrmann, Sabrina, Kramarova, Tatiana, Kvist, Anders, Supic, Gordana, Gillett, Alan, Pivarcsi, Andor, and Jagodic, Maja
- Abstract
MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
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- 2013
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31. Next-Generation Sequencing Identifies MicroRNAs that Associate with Pathogenic Autoimmune Neuroinflammation in Rats
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Bergman, Petra, primary, James, Tojo, additional, Kular, Lara, additional, Ruhrmann, Sabrina, additional, Kramarova, Tatiana, additional, Kvist, Anders, additional, Supic, Gordana, additional, Gillett, Alan, additional, Pivarcsi, Andor, additional, and Jagodic, Maja, additional
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- 2013
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32. Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
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Marabita, Francesco, James, Tojo, Karhu, Anu, Virtanen, Heidi, Kettunen, Kaisa, Stenlund, Hans, Boulund, Fredrik, Hellström, Cecilia, Neiman, Maja, Mills, Robert, Perheentupa, Teemu, Laivuori, Hannele, Helkkula, Pyry, Byrne, Myles, Jokinen, Ilkka, Honko, Harri, Kallonen, Antti, Ermes, Miikka, Similä, Heidi, Lindholm, Mikko, Widén, Elisabeth, Ripatti, Samuli, Perälä-Heape, Maritta, Engstrand, Lars, Nilsson, Peter, Moritz, Thomas, Miettinen, Timo, Sallinen, Riitta, and Kallioniemi, Olli
- Abstract
We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper’s transparent peer review process is included in the supplemental information.
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- 2021
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33. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis.
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Bergman P, Piket E, Khademi M, James T, Brundin L, Olsson T, Piehl F, and Jagodic M
- Abstract
Objective: To explore circulating microRNAs (miRNAs) in cell-free CSF as novel biomarkers for multiple sclerosis (MS)., Methods: Profiling of miRNAs in CSF of pooled patients with clinically isolated syndrome (CIS), patients with relapsing-remitting MS, and inflammatory and noninflammatory neurologic disease controls was performed using TaqMan miRNA arrays. Two independent patient cohorts (n = 142 and n = 430) were used for validation with real-time PCR., Results: We reliably detected 88 CSF miRNAs in the exploratory cohort. Subsequent validation in 2 cohorts demonstrated significantly higher levels of miR-150 in patients with MS. Higher miR-150 levels were also observed in patients with CIS who converted to MS compared to nonconverters, and in patients initiating natalizumab treatment. Levels of miR-150 correlated with immunologic parameters including CSF cell count, immunoglobulin G index, and presence of oligoclonal bands, and with candidate protein biomarkers C-X-C motif chemokine 13, matrix metallopeptidase 9, and osteopontin. Correlation with neurofilament light chain (NFL) was observed only when NFL was adjusted for age using a method that requires further validation. Additionally, miR-150 discriminated MS from controls and CIS converters from nonconverters equally well as the most informative protein biomarkers. Following treatment with natalizumab, but not fingolimod, CSF levels of miR-150 decreased, while plasma levels increased with natalizumab and decreased with fingolimod, suggesting immune cells as a source of miR-150., Conclusions: Our findings demonstrate miR-150 as a putative novel biomarker of inflammatory active disease with the potential to be used for early diagnosis of MS., Classification of Evidence: This study provides Class II evidence that CSF miR-150 distinguishes patients with MS from patients with other neurologic conditions.
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- 2016
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