19 results on '"Dalgard C"'
Search Results
2. 647: Tensin 1 is a modifier gene for low BMI in homozygous [F508del]CFTR patients
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Walton, N., primary, Zhang, X., additional, Soltis, A., additional, Starr, J., additional, Dalgard, C., additional, Wilkerson, M., additional, Conrad, D., additional, and Pollard, H., additional
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- 2021
- Full Text
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3. Clonal hematopoiesis is not significantly associated with COVID-19 disease severity
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Yifan Zhou, Ruba Shalhoub, Stephanie N. Rogers, Shiqin Yu, Muxin Gu, Margarete A. Fabre, Pedro M. Quiros, Tae-Hoon Shin, Arch Diangson, Wenhan Deng, Shubha Anand, Wenhua Lu, Matthew Cullen, Anna L. Godfrey, Jacobus Preller, Jerome Hadjadj, Emmanuelle Jouanguy, Aurélie Cobat, Laurent Abel, Frederic Rieux-Laucat, Benjamin Terrier, Alain Fischer, Lara Novik, Ingelise J. Gordon, Larisa Strom, Martin R. Gaudinski, Andrea Lisco, Irini Sereti, Thomas J. Gniadek, Andrea Biondi, Paolo Bonfanti, Luisa Imberti, Clifton L. Dalgard, Yu Zhang, Kerry Dobbs, Helen C. Su, Luigi D. Notarangelo, Colin O. Wu, Peter J.M. Openshaw, Malcolm G. Semple, Ziad Mallat, Kenneth Baillie, Cynthia E. Dunbar, George S. Vassiliou, Zhou, Yifan [0000-0002-3538-621X], Rogers, Stephanie N [0000-0002-4563-1899], Gu, Muxin [0000-0003-4376-795X], Fabre, Margarete A [0000-0001-7794-610X], Quiros, Pedro M [0000-0002-7793-6291], Shin, Tae-Hoon [0000-0002-9619-8554], Preller, Jacobus [0000-0001-5706-816X], Cobat, Aurélie [0000-0001-7209-6257], Rieux-Laucat, Frederic [0000-0001-7858-7866], Gaudinski, Martin R [0000-0002-3743-5281], Biondi, Andrea [0000-0002-6757-6173], Bonfanti, Paolo [0000-0001-7289-8823], Imberti, Luisa [0000-0002-2075-8391], Dobbs, Kerry [0000-0002-3432-3137], Notarangelo, Luigi D [0000-0002-8335-0262], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Mallat, Ziad [0000-0003-0443-7878], Baillie, Kenneth [0000-0001-5258-793X], Dunbar, Cynthia E [0000-0002-7645-838X], Vassiliou, George S [0000-0003-4337-8022], Apollo - University of Cambridge Repository, Zhou, Y, Shalhoub, R, Rogers, S, Yu, S, Gu, M, Fabre, M, Quiros, P, Diangson, A, Deng, W, Anand, S, Lu, W, Cullen, M, Godfrey, A, Preller, J, Hadjadj, J, Jouanguy, E, Cobat, A, Abel, L, Rieux-Laucat, F, Terrier, B, Fischer, A, Novik, L, Gordon, I, Strom, L, Gaudinski, M, Lisco, A, Sereti, I, Gniadek, T, Biondi, A, Bonfanti, P, Imberti, L, Zhang, Y, Dalgard, C, Dobbs, K, Su, H, Notarangelo, L, Wu, C, Openshaw, P, Semple, M, Mallat, Z, Baillie, K, Dunbar, C, and Vassiliou, G
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Clonal Evolution ,Immunology ,Mutation ,COVID-19 ,Humans ,Cell Biology ,Hematology ,Clonal Hematopoiesis ,Biochemistry ,Severity of Illness Index ,Hematopoiesis - Abstract
Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stemcell (HSC) and its progeny, in association with leukemia-associated somatic mutations, mostcommonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis forthis increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.
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- 2022
4. Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
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Carmelo Carmona-Rivera, Yu Zhang, Kerry Dobbs, Tovah E. Markowitz, Clifton L. Dalgard, Andrew J. Oler, Dillon R. Claybaugh, Deborah Draper, Meng Truong, Ottavia M. Delmonte, Francesco Licciardi, Ugo Ramenghi, Nicoletta Crescenzio, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Chiara Fiorini, Valentina Discepolo, Andrea Lo Vecchio, Alfredo Guarino, Luca Pierri, Andrea Catzola, Andrea Biondi, Paolo Bonfanti, Maria C. Poli Harlowe, Yasmin Espinosa, Camila Astudillo, Emma Rey-Jurado, Cecilia Vial, Javiera de la Cruz, Ricardo Gonzalez, Cecilia Pinera, Jacqueline W. Mays, Ashley Ng, Andrew Platt, Beth Drolet, John Moon, Edward W. Cowen, Heather Kenney, Sarah E. Weber, Riccardo Castagnoli, Mary Magliocco, Michael A. Stack, Gina Montealegre, Karyl Barron, Danielle L. Fink, Douglas B. Kuhns, Stephen M. Hewitt, Lisa M. Arkin, Daniel S. Chertow, Helen C. Su, Luigi D. Notarangelo, Mariana J. Kaplan, Carmona-Rivera, C, Zhang, Y, Dobbs, K, Markowitz, T, Dalgard, C, Oler, A, Claybaugh, D, Draper, D, Truong, M, Delmonte, O, Licciardi, F, Ramenghi, U, Crescenzio, N, Imberti, L, Sottini, A, Quaresima, V, Fiorini, C, Discepolo, V, Lo Vecchio, A, Guarino, A, Pierri, L, Catzola, A, Biondi, A, Bonfanti, P, Poli Harlowe, M, Espinosa, Y, Astudillo, C, Rey-Jurado, E, Vial, C, De la Cruz, J, Gonzalez, R, Pinera, C, Mays, J, Ng, A, Platt, A, Drolet, B, Moon, J, Cowen, E, Kenney, H, Weber, S, Castagnoli, R, Magliocco, M, Stack, M, Montealegre Sanchez, G, Barron, K, Fink, D, Kuhns, D, Hewitt, S, Arkin, L, Chertow, D, Su, H, Notarangelo, L, Kaplan, M, Carmona-Rivera, Carmelo, Zhang, Yu, Dobbs, Kerry, Markowitz, Tovah E, Dalgard, Clifton L, Oler, Andrew J, Claybaugh, Dillon R, Draper, Deborah, Truong, Meng, Delmonte, Ottavia M, Licciardi, Francesco, Ramenghi, Ugo, Crescenzio, Nicoletta, Imberti, Luisa, Sottini, Alessandra, Quaresima, Virginia, Fiorini, Chiara, Discepolo, Valentina, Lo Vecchio, Andrea, Guarino, Alfredo, Pierri, Luca, Catzola, Andrea, Biondi, Andrea, Bonfanti, Paolo, Poli Harlowe, Maria C, Espinosa, Yasmin, Astudillo, Camila, Rey-Jurado, Emma, Vial, Cecilia, de la Cruz, Javiera, Gonzalez, Ricardo, Pinera, Cecilia, Mays, Jacqueline W, Ng, Ashley, Platt, Andrew, Drolet, Beth, Moon, John, Cowen, Edward W, Kenney, Heather, Weber, Sarah E, Castagnoli, Riccardo, Magliocco, Mary, Stack, Michael A, Montealegre, Gina, Barron, Karyl, Fink, Danielle L, Kuhns, Douglas B, Hewitt, Stephen M, Arkin, Lisa M, Chertow, Daniel S, Su, Helen C, Notarangelo, Luigi D, and Kaplan, Mariana J
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Adult ,Inflammation ,Infectious disease ,Neutrophils ,SARS-CoV-2 ,Neutrophil ,COVID-19 ,General Medicine ,Actins ,Child ,Deoxyribonuclease I ,Humans ,Systemic Inflammatory Response Syndrome ,Extracellular Traps - Abstract
Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.SummaryNET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.
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- 2022
5. Human genetic and immunological determinants of critical COVID-19 pneumonia
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Zhang, Qian, Bastard, Paul, Karbuz, Adem, Gervais, Adrian, Tayoun, Ahmad Abou, Aiuti, Alessandro, Belot, Alexandre, Bolze, Alexandre, Gaudet, Alexandre, Bondarenko, Anastasiia, Liu, Zhiyong, Spaan, András, Guennoun, Andrea, Arias, Andres Augusto, Planas, Anna, Sediva, Anna, Shcherbina, Anna, Neehus, Anna-Lena, Puel, Anne, Froidure, Antoine, Novelli, Antonio, Parlakay, Aslınur Özkaya, Pujol, Aurora, Yahşi, Aysun, Gülhan, Belgin, Bigio, Benedetta, Boisson, Bertrand, Drolet, Beth, Franco, Carlos Andres Arango, Flores, Carlos, Rodríguez-Gallego, Carlos, Prando, Carolina, Biggs, Catherine, Luyt, Charles-Edouard, Dalgard, Clifton, O’Farrelly, Cliona, Matuozzo, Daniela, Dalmau, David, Perlin, David, Mansouri, Davood, van de Beek, Diederik, Vinh, Donald, Dominguez-Garrido, Elena, Hsieh, Elena, Erdeniz, Emine Hafize, Jouanguy, Emmanuelle, Şevketoglu, Esra, Talouarn, Estelle, Quiros-Roldan, Eugenia, Andreakos, Evangelos, Husebye, Eystein, Alsohime, Fahad, Haerynck, Filomeen, Casari, Giorgio, Novelli, Giuseppe, Aytekin, Gökhan, Morelle, Guillaume, Alkan, Gulsum, Bayhan, Gulsum Iclal, Feldman, Hagit Baris, Su, Helen, von Bernuth, Horst, Resnick, Igor, Bustos, Ingrid, Meyts, Isabelle, Migeotte, Isabelle, Tancevski, Ivan, Bustamante, Jacinta, Fellay, Jacques, El Baghdadi, Jamila, Martinez-Picado, Javier, Casanova, Jean-Laurent, Rosain, Jeremie, Manry, Jeremy, Chen, Jie, Christodoulou, John, Bohlen, Jonathan, Franco, José Luis, Li, Juan, Anaya, Juan Manuel, Rojas, Julian, Ye, Junqiang, Uddin, K., Yasar, Kadriye Kart, Kisand, Kai, Okamoto, Keisuke, Chaïbi, Khalil, Mironska, Kristina, Maródi, László, Abel, Laurent, Renia, Laurent, Lorenzo, Lazaro, Hammarström, Lennart, Ng, Lisa, Quintana-Murci, Lluis, Erazo, Lucia Victoria, Notarangelo, Luigi, Reyes, Luis Felipe, Allende, Luis, Imberti, Luisa, Renkilaraj, Majistor Raj Luxman Maglorius, Moncada-Velez, Marcela, Materna, Marie, Anderson, Mark, Gut, Marta, Chbihi, Marwa, Ogishi, Masato, Emiroglu, Melike, Seppänen, Mikko, Uddin, Mohammed, Shahrooei, Mohammed, Alexander, Natalie, Hatipoglu, Nevin, Marr, Nico, Akçay, Nihal, Boyarchuk, Oksana, Slaby, Ondrej, Akcan, Ozge Metin, Zhang, Peng, Soler-Palacín, Pere, Gregersen, Peter, Brodin, Petter, Garçon, Pierre, Morange, Pierre-Emmanuel, Pan-Hammarström, Qiang, Zhou, Qinhua, Philippot, Quentin, Halwani, Rabih, de Diego, Rebeca Perez, Levy, Romain, Yang, Rui, Öz, Şadiye Kübra Tüter, Muhsen, Saleh Al, Kanık-Yüksek, Saliha, Espinosa-Padilla, Sara, Ramaswamy, Sathishkumar, Okada, Satoshi, Bozdemir, Sefika Elmas, Aytekin, Selma Erol, Karabela, Şemsi Nur, Keles, Sevgi, Senoglu, Sevtap, Zhang, Shen-Ying, Duvlis, Sotirija, Constantinescu, Stefan, Boisson-Dupuis, Stephanie, Turvey, Stuart, Tangye, Stuart, Asano, Takaki, Ozcelik, Tayfun, Le Voyer, Tom, Maniatis, Tom, Morio, Tomohiro, Mogensen, Trine, Sancho-Shimizu, Vanessa, Beziat, Vivien, Solanich, Xavier, Bryceson, Yenan, Lau, Yu-Lung, Itan, Yuval, Cobat, Aurélie, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, Effort, COVID Human Genetic, Özçelik, Tayfun, Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), National Center for Advancing Translational Sciences (US), George Mason University, National Human Genome Research Institute (US), Yale University, Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, JPB Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, European Commission, Square Foundation, Ministère de l’Enseignement supérieur et de la Recherche (France), Institut National de la Santé et de la Recherche Médicale (France), Université de Paris, Fondation Bettencourt Schueller, Regione Lazio, National Institute of Allergy and Infectious Diseases (US), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR-20-COV6-0001,CRISPR-TARGET-CoV,Cribles CRISPR à l'échelle du génome pour identifier de nouvelles cibles thérapeutiques et inhiber la réplication du SARS-CoV-2(2020), Zhang, Q., Bastard, P., Karbuz, A., Gervais, A., Tayoun, A. A., Aiuti, A., Belot, A., Bolze, A., Gaudet, A., Bondarenko, A., Spaan, A. N., Guennoun, A., Arias, A. A., Planas, A. M., Sediva, A., Shcherbina, A., Neehus, A. -L., Puel, A., Froidure, A., Novelli, A., Parlakay, A. O., Pujol, A., Yahsi, A., Gulhan, B., Bigio, B., Boisson, B., Drolet, B. A., Franco, C. A. A., Flores, C., Rodriguez-Gallego, C., Prando, C., Biggs, C. M., Luyt, C. -E., Dalgard, C. L., O'Farrelly, C., Matuozzo, D., Dalmau, D., Perlin, D. S., Mansouri, D., van de Beek, D., Vinh, D. C., Dominguez-Garrido, E., Hsieh, E. W. Y., Erdeniz, E. H., Jouanguy, E., Sevketoglu, E., Talouarn, E., Quiros-Roldan, E., Andreakos, E., Husebye, E., Alsohime, F., Haerynck, F., Casari, G., Novelli, G., Aytekin, G., Morelle, G., Alkan, G., Bayhan, G. I., Feldman, H. B., Su, H. C., von Bernuth, H., Resnick, I., Bustos, I., Meyts, I., Migeotte, I., Tancevski, I., Bustamantem, J., Fellay, J., El Baghdadi, J., Martinez-Picado, J., Casanova, J. -L., Rosain, J., Manry, J., Chen, J., Christodoulou, J., Bohlen, J., Franco, J. L., Li, J., Anaya, J. M., Rojas, J., Ye, J., Uddin, K. M. F., Yasar, K. K., Kisand, K., Okamoto, K., Chaibi, K., Mironska, K., Marodi, L., Abel, L., Renia, L., Lorenzo, L., Hammarstrom, L., Ng, L. F. P., Quintana-Murci, L., Erazo, L. V., Notarangelo, L. D., Reyes, L. F., Allende, L. M., Imberti, L., Renkilaraj, M. R. L. M., Moncada-Velez, M., Materna, M., Anderson, M. S., Gut, M., Chbihi, M., Ogishi, M., Emiroglu, M., Seppanen, M. R. J., Uddin, M. J., Shahrooei, M., Alexander, N., Hatipoglu, N., Marr, N., Akcay, N., Boyarchuk, O., Slaby, O., Akcan, O. M., Zhang, P., Soler-Palacin, P., Gregersen, P. K., Brodin, P., Garcon, P., Morange, P. -E., Pan-Hammarstrom, Q., Zhou, Q., Philippot, Q., Halwani, R., de Diego, R. P., Levy, R., Yang, R., Oz, S. K. T., Muhsen, S. A., Kanik-Yuksek, S., Espinosa-Padilla, S., Ramaswamy, S., Okada, S., Bozdemir, S. E., Aytekin, S. E., Karabela, S. N., Keles, S., Senoglu, S., Zhang, S. -Y., Duvlis, S., Constantinescu, S. N., Boisson-Dupuis, S., Turvey, S. E., Tangye, S. G., Asano, T., Ozcelik, T., Le Voyer, T., Maniatis, T., Morio, T., Mogensen, T. H., Sancho-Shimizu, V., Beziat, V., Solanich, X., Bryceson, Y., Lau, Y. -L., Itan, Y., and Cobat, A.
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Multidisciplinary ,[SDV]Life Sciences [q-bio] ,Critical Illness ,COVID-19 ,Dendritic Cells ,Article ,Toll-Like Receptor 3 ,Basic medicine ,Age Distribution ,Toll-Like Receptor 7 ,Settore MED/03 ,Interferon Type I ,Humans ,Autoantibodies ,Genome-Wide Association Study ,Sex Distribution - Abstract
COVID Human Genetic Effort: Adem Karbuz, Adrian Gervais, Ahmad Abou Tayoun, Alessandro Aiuti, Alexandre Belot, Alexandre Bolze, Alexandre Gaudet, Anastasiia Bondarenko, Zhiyong Liu, András N. Spaan, Andrea Guennoun, Andres Augusto Arias, Anna M. Planas, Anna Sediva, Anna Shcherbina, Anna-Lena Neehus, Anne Puel, Antoine Froidure, Antonio Novelli, Aslınur Özkaya Parlakay, Aurora Pujol, Aysun Yahşi, Belgin Gülhan, Benedetta Bigio, Bertrand Boisson, Beth A. Drolet, Carlos Andres Arango Franco, Carlos Flores, Carlos Rodríguez-Gallego, Carolina Prando, Catherine M. Biggs, Charles-Edouard Luyt, Clifton L. Dalgard, Cliona O’Farrelly, Daniela Matuozzo, David Dalmau, David S. Perlin, Davood Mansouri, Diederik van de Beek, Donald C. Vinh, Elena Dominguez-Garrido, Elena W. Y. Hsieh, Emine Hafize Erdeniz, Emmanuelle Jouanguy, Esra Şevketoglu, Estelle Talouarn, Eugenia Quiros-Roldan, Evangelos Andreakos, Eystein Husebye, Fahad Alsohime, Filomeen Haerynck, Giorgio Casari, Giuseppe Novelli, Gökhan Aytekin, Guillaume Morelle, Gulsum Alkan, Gulsum Iclal Bayhan, Hagit Baris Feldman, Helen C. Su, Horst von Bernuth, Igor Resnick, Ingrid Bustos, Isabelle Meyts, Isabelle Migeotte, Ivan Tancevski, Jacinta Bustamante, Jacques Fellay, Jamila El Baghdadi, Javier Martinez-Picado, Jean-Laurent Casanova, Jeremie Rosain, Jeremy Manry, Jie Chen, John Christodoulou, Jonathan Bohlen, José Luis Franco, Juan Li, Juan Manuel Anaya, Julian Rojas, Junqiang Ye, K. M. Furkan Uddin, Kadriye Kart Yasar, Kai Kisand, Keisuke Okamoto, Khalil Chaïbi, Kristina Mironska, László Maródi, Laurent Abel, Laurent Renia, Lazaro Lorenzo, Lennart Hammarström, Lisa F. P. Ng, Lluis Quintana-Murci, Lucia Victoria Erazo, Luigi D. Notarangelo, Luis Felipe Reyes, Luis M. Allende, Luisa Imberti, Majistor Raj Luxman Maglorius Renkilaraj, Marcela Moncada-Velez, Marie Materna, Mark S. Anderson, Marta Gut, Marwa Chbihi, Masato Ogishi, Melike Emiroglu, Mikko R. J. Seppänen, Mohammed J. Uddin, Mohammed Shahrooei, Natalie Alexander, Nevin Hatipoglu, Nico Marr, Nihal Akçay, Oksana Boyarchuk, Ondrej Slaby, Ozge Metin Akcan, Peng Zhang, Pere Soler-Palacín, Peter K. Gregersen, Petter Brodin, Pierre Garçon, Pierre-Emmanuel Morange, Qiang Pan-Hammarström, Qinhua Zhou, Quentin Philippot, Rabih Halwani, Rebeca Perez de Diego, Romain Levy, Rui Yang, Şadiye Kübra Tüter Öz, Saleh Al Muhsen, Saliha Kanık-Yüksek, Sara Espinosa-Padilla, Sathishkumar Ramaswamy, Satoshi Okada, Sefika Elmas Bozdemir, Selma Erol Aytekin, Şemsi Nur Karabela, Sevgi Keles, Sevtap Senoglu, Shen-Ying Zhang, Sotirija Duvlis, Stefan N. Constantinescu, Stephanie Boisson-Dupuis, Stuart E. Turvey, Stuart G. Tangye, Takaki Asano, Tayfun Ozcelik, Tom Le Voyer, Tom Maniatis, Tomohiro Morio, Trine H. Mogensen, Vanessa Sancho-Shimizu, Vivien Beziat, Xavier Solanich, Yenan Bryceson, Yu-Lung Lau & Yuval Itan, SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation., The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, the Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the ‘Investments for the Future’ program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), ANR grant GENVIR (ANR-20-CE93-003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR MIS-C (ANR 21-COVR-0039, GenMIS-C) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-Genomics), the Square Foundation, Grandir—Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, Fondation du Souffle, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University of Paris. P.B. was supported by the FRM (EA20170638020) and the MD-PhD programme of the Imagine Institute (with the support of the Fondation Bettencourt Schueller). G.N. is supported by Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. H.C.S. and L.D.N. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
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- 2022
6. From your nose to your toes: a review of severe acute respiratory syndrome Coronavirus 2 pandemic‒associated pernio
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Tayfun Ozcelik, Mohammed Shahrooei, D. Mansouri, Lisa F.P. Ng, Isabelle Meyts, Pere Soler-Palacín, Aurora Pujol, Samira Asgari, Anne Marie Singh, Saleh Al-Muhsen, Jacques Fellay, Graziano Pesole, Giuseppe Novelli, John J. Moon, Kristina Mironska, Jennifer M Tran, Evangelos Andreakos, Anna Shcherbina, Antonio Condino-Neto, Filomeen Haerynck, Yu-Lung Lau, Sara Espinosa-Padilla, Carlos Flores, Jean-Laurent Casanova, Anna M. Planas, Beth A. Drolet, Donald C. Vinh, Jordi Pérez Tur, Biggs Catherine, Diederik van de Beek, Alexandre Bolze, Kai Kisand, Ahmad Abou Tayoun, Timokratis Karamitros, Colobran Roger, Edward W. Cowen, Elena Hsieh, Carlos Rodríguez-Gallego, Alexandre Belot, Alessandro Aiuti, Anastasiia Bondarenko, Laurent Abel, Anna Sediva, Rebeca Perez de Diego, Rabih Halwani, Petter Brodin, Keisuke Okamoto, Giorgio Casari, Cliona O'Farrelly, Jacqueline W. Mays, Ivan Tancevski, Furkan Uddin, Clifton L. Dalgard, Qiang Pan-Hammarström, Carolina Prando, Satoshi Okada, Trine H. Mogensen, Laurent Renia, Lisa M. Arkin, Özçelik, Tayfun, Arkin, L. M., Moon, J. J., Tran, J. M., Asgari, S., O'Farrelly, C., Casanova, J. -L., Cowen, E. W., Mays, J. W., Singh, A. M., Drolet, B. A., Aiuti, A., Belot, A., Bolze, A., Bondarenko, A., Sediva, A., Shcherbina, A., Planas, A. M., Condino-Neto, A., Pujol, A., Catherine, B., Flores, C., Rodriguez-Gallego, C., Prando, C., Dalgard, C. L., Roger, C., Mansouri, D., van de Beek, D., Vinh, D. C., Hsieh, E., Andreakos, E., Haerynck, F., Uddin, F., Casari, G., Novelli, G., Pesole, G., Meyts, I., Tancevski, I., Fellay, J., Tur, J., Kisand, K., Okamoto, K., Mironska, K., Abel, L., Renia, L., Ng, L. F. P., Shahrooei, M., Soler-Palacin, P., Brodin, P., Pan-Hammarstrom, Q., Halwani, R., Perez de Diego, R., Al-Muhsen, S., Espinosa-Padilla, S., Okada, S., Ozcelik, T., Tayoun, A. A., Karamitros, T., Mogensen, T. H., and Lau, Y. -L.
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Dermatology ,Plasmacytoid dendritic cell ,Review ,Biochemistry ,type 1 interferon, (IFN-1) ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Seroconversion ,Molecular Biology ,Nose ,Pernio ,Innate immune system ,I INTERFERON ,business.industry ,Plasmacytoid Dendritic Cell, (pDC) ,SARS-CoV-2 ,fungi ,COVID-19 ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Pathophysiology ,Innate Immunity ,Immunity, Innate ,Chilblains ,Pneumonia ,medicine.anatomical_structure ,Settore MED/03 ,INFECTIONS ,Immunology ,Interferon Type I ,Eccrine Gland ,business ,Severe Acute Respiratory Syndrome Coronavirus 2, (SARS-CoV-2) - Abstract
Despite thousands of reported patients with pandemic-associated pernio, low rates of seroconversion and PCR positivity have defied causative linkage to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pernio in uninfected children is associated with monogenic disorders of excessive IFN-1 immunity, whereas severe COVID-19 pneumonia can result from insufficient IFN-1. Moreover, SARS-CoV-2 spike protein and robust IFN-1 response are seen in the skin of patients with pandemic-associated pernio, suggesting an excessive innate immune skin response to SARS-CoV-2. Understanding the pathophysiology of this phenomenon may elucidate the host mechanisms that drive a resilient immune response to SARS-CoV-2 and could produce relevant therapeutic targets.
- Published
- 2021
7. ImmunoTyper-SR: A computational approach for genotyping immunoglobulin heavy chain variable genes using short-read data
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Michael K.B. Ford, Ananth Hari, Oscar Rodriguez, Junyan Xu, Justin Lack, Cihan Oguz, Yu Zhang, Andrew J. Oler, Ottavia M. Delmonte, Sarah E. Weber, Mary Magliocco, Jason Barnett, Sandhya Xirasagar, Smilee Samuel, Luisa Imberti, Paolo Bonfanti, Andrea Biondi, Clifton L. Dalgard, Stephen Chanock, Lindsey B. Rosen, Steven M. Holland, Helen C. Su, Luigi D. Notarangelo, Uzi Vishkin, Corey T. Watson, S. Cenk Sahinalp, Kerry Dobbs, Elana Shaw, Miranda F. Tompkins, Camille Alba, Adelani Adeleye, Samuel Li, Jingwen Gu, Ford, M, Hari, A, Rodriguez, O, Xu, J, Lack, J, Oguz, C, Zhang, Y, Weber, S, Magliocco, M, Barnett, J, Xirasagar, S, Samuel, S, Imberti, L, Bonfanti, P, Biondi, A, Dalgard, C, Chanock, S, Rosen, L, Holland, S, Su, H, Notarangelo, L, Vishkin, U, Watson, C, and Sahinalp, S
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genomic ,ILP ,next generation sequencing ,algorithm ,computational biology ,Histology ,genotyping ,immunogenomic ,Cell Biology ,immunoglobulin ,optimization ,WGS ,Pathology and Forensic Medicine - Abstract
Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which are critical for the structure of antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype when using standard short-read sequencing technologies. Here, we introduce ImmunoTyper-SR, an algorithmic tool for the genotyping and CNV analysis of the germline IGHV genes on Illumina whole-genome sequencing (WGS) data using a combinatorial optimization formulation that resolves ambiguous read mappings. We have validated ImmunoTyper-SR on 12 individuals, whose IGHV allele composition had been independently validated, as well as concordance between WGS replicates from nine individuals. We then applied ImmunoTyper-SR on 585 COVID patients to investigate the associations between IGHV alleles and anti-type I IFN autoantibodies, which were previously associated with COVID-19 severity.
- Published
- 2022
8. Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis.
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Grassano M, Canosa A, D'Alfonso S, Corrado L, Brodini G, Koumantakis E, Cugnasco P, Manera U, Vasta R, Palumbo F, Mazzini L, Gallone S, Moglia C, Dewan R, Chia R, Ding J, Dalgard C, Gibbs RJ, Scholz S, Calvo A, Traynor B, and Chio A
- Abstract
Competing Interests: Competing interests: AChio serves on scientific advisory boards for Mitsubishi Tanabe, Roche, Biogen, Denali Pharma, AC Immune, Biogen, Lilly, and Cytokinetics and has received a research grant from Biogen. BT holds the US, Canadian and European patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion in C9orf72. BT and SS received research support from Cerevel Therapeutics. ACalvo has received a research grant from Cytokinetics. MG has received grants from the American Academy of Neurology, the American Brain Foundation and the ALS Association.
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- 2024
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9. Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease.
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Gunasekaran TI, Reyes-Dumeyer D, Faber KM, Goate A, Boeve B, Cruchaga C, Pericak-Vance M, Haines JL, Rosenberg R, Tsuang D, Mejia DR, Medrano M, Lantigua RA, Sweet RA, Bennett DA, Wilson RS, Alba C, Dalgard C, Foroud T, Vardarajan BN, and Mayeux R
- Abstract
Background: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling., Methods: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study., Results: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci., Discussion: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants., Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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10. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.
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Wang H, Chang TS, Dombroski BA, Cheng PL, Patil V, Valiente-Banuet L, Farrell K, Mclean C, Molina-Porcel L, Rajput A, De Deyn PP, Le Bastard N, Gearing M, Kaat LD, Van Swieten JC, Dopper E, Ghetti BF, Newell KL, Troakes C, de Yébenes JG, Rábano-Gutierrez A, Meller T, Oertel WH, Respondek G, Stamelou M, Arzberger T, Roeber S, Müller U, Hopfner F, Pastor P, Brice A, Durr A, Le Ber I, Beach TG, Serrano GE, Hazrati LN, Litvan I, Rademakers R, Ross OA, Galasko D, Boxer AL, Miller BL, Seeley WW, Van Deerlin VM, Lee EB, White CL 3rd, Morris H, de Silva R, Crary JF, Goate AM, Friedman JS, Leung YY, Coppola G, Naj AC, Wang LS, Dalgard C, Dickson DW, Höglinger GU, Schellenberg GD, Geschwind DH, and Lee WP
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- Humans, Male, Female, Aged, Middle Aged, Aged, 80 and over, Supranuclear Palsy, Progressive genetics, Genetic Predisposition to Disease genetics, Whole Genome Sequencing, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs)., Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed., Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10
-3 ) in PSP., Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions., (© 2024. The Author(s).)- Published
- 2024
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11. SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma.
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Daley BR, Sealover NE, Sheffels E, Hughes JM, Gerlach D, Hofmann MH, Kostyrko K, Mair B, Linke A, Beckley Z, Frank A, Dalgard C, and Kortum RL
- Abstract
Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ . SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.
- Published
- 2023
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12. Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis.
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Chiò A, Moglia C, Canosa A, Manera U, Grassano M, Vasta R, Palumbo F, Gallone S, Brunetti M, Barberis M, De Marchi F, Dalgard C, Chia R, Mora G, Iazzolino B, Peotta L, Traynor BJ, Corrado L, D'Alfonso S, Mazzini L, and Calvo A
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- Humans, C9orf72 Protein genetics, Alleles, Phenotype, Prognosis, Amyotrophic Lateral Sclerosis epidemiology
- Abstract
Background and Objectives: Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease., Methods: The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A ( UNC13A ) (rs12608932), calmodulin binding transcription activator 1 ( CAMTA1 ) (rs2412208), solute carrier family 11 member 2 ( SLC11A2 ) (rs407135), and zinc finger protein 512B ( ZNF512B ) (rs2275294) variants, as well as ataxin-2 ( ATXN2 ) polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 ( C9orf72 ) GGGGCC intronic expansions (≥30)., Results: The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only C9orf72 (2.51 years, IQR 1.74-3.82; p = 0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p < 0.001), and UNC13A
C/C (2.3 years, IQR 1.3-3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, p = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1G/G+G/T and UNC13AC/C alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants ( p < 0.001); the survival of patients with CAMTA1G/G+G/T alleles and ATXN2≥31 intermediate polyQ repeats was 1.75 years (0.84-2.18) ( p < 0.001); the survival of patients with ATXN2≥31 polyQ repeats and UNC13AC/C allele was 1.33 years (0.84-1.75) ( p < 0.001); the survival of patients with C9ORF72≥30 and UNC13AC/C allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes., Discussion: We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)- Published
- 2023
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13. Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.
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Zanovello M, Ibáñez K, Brown AL, Sivakumar P, Bombaci A, Santos L, van Vugt JJFA, Narzisi G, Karra R, Scholz SW, Ding J, Gibbs JR, Chiò A, Dalgard C, Weisburd B, Hanna MG, Greensmith L, Phatnani H, Veldink JH, Traynor BJ, Polke J, Houlden H, Fratta P, and Tucci A
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- Humans, Male, Muscular Atrophy, Polymerase Chain Reaction, Trinucleotide Repeat Expansion genetics, Receptors, Androgen genetics, Muscular Atrophy, Spinal genetics
- Abstract
CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8-100%], specificity of 99% (95% CI 94.2-99.7%), and a positive predictive value of 97.4% (95% CI 84.4-99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309-1:4386, n = 117 734) X chromosomes-10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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14. Transcriptomic Profiling and Pathway Analysis of Mesenchymal Stem Cells Following Low Dose-Rate Radiation Exposure.
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Slaven JE, Wilkerson M, Soltis AR, Rittase WB, Bradfield DT, Bylicky M, Cary L, Tsioplaya A, Bouten R, Dalgard C, and Day RM
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Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h,
60 Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.- Published
- 2023
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15. Clinical and Metabolic Signature of UNC13A rs12608932 Variant in Amyotrophic Lateral Sclerosis.
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Calvo A, Canosa A, Moglia C, Manera U, Grassano M, Vasta R, Palumbo F, Cugnasco P, Gallone S, Brunetti M, De Marchi F, Arena V, Pagani M, Dalgard C, Scholz SW, Chia R, Corrado L, Dalfonso S, Mazzini L, Traynor BJ, and Chio A
- Abstract
Background and Objectives: To characterize the clinical and cognitive behavioral phenotype and brain
18 F-2-fluoro-2-deoxy-d-glucose-PET (18 F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene., Methods: The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP , and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent18 F-FDG-PET., Results: The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18-2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33-3.92; A/A + C/C: 2.90 years, IQR 1.74-5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain18 F-FDG-PET extending to frontal and precentral areas of the right hemisphere., Discussion: C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on18 F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2022
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16. ATXN2 intermediate expansions in amyotrophic lateral sclerosis.
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Glass JD, Dewan R, Ding J, Gibbs JR, Dalgard C, Keagle PJ, Shankaracharya, García-Redondo A, Traynor BJ, Chia R, and Landers JE
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- Ataxin-2, Humans, Phenotype, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Lewy Body Disease
- Abstract
Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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17. Exploring the phenotype of Italian patients with ALS with intermediate ATXN2 polyQ repeats.
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Chio A, Moglia C, Canosa A, Manera U, Grassano M, Vasta R, Palumbo F, Gallone S, Brunetti M, Barberis M, De Marchi F, Dalgard C, Chia R, Mora G, Iazzolino B, Peotta L, Traynor B, Corrado L, D'Alfonso S, Mazzini L, and Calvo A
- Abstract
Objective: To detect the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) carrying an intermediate ATXN2 polyQ number of repeats in a large population-based series of Italian patients with ALS., Methods: The study population includes 1330 patients with ALS identified through the Piemonte and Valle d'Aosta Register for ALS, diagnosed between 2007 and 2019 and not carrying C9orf72, SOD1, TARDBP and FUS mutations. Controls were 1274 age, sex and geographically matched Italian subjects, identified through patients' general practitioners., Results: We found 42 cases and 4 controls with≥31 polyQ repeats, corresponding to an estimated OR of 10.4 (95% CI 3.3 to 29.0). Patients with≥31 polyQ repeats (ATXN2+) compared with those without repeat expansion (ATXN2-) had more frequently a spinal onset (p=0.05), a shorter diagnostic delay (p=0.004), a faster rate of ALSFRS-R progression (p=0.004) and King's progression (p=0.004), and comorbid frontotemporal dementia (7 (28.0%) vs 121 (13.4%), p=0.037). ATXN2+ patients had a 1-year shorter survival (ATXN2+ patients 1.82 years, 95% CI 1.08 to 2.51; ATXN2- 2.84 years, 95% CI 1.67 to 5.58, p=0.0001). ATXN2 polyQ intermediate repeats was independently related to a worse outcome in Cox multivariable analysis (p=0.006)., Conclusions: In our population-based cohort, ATXN2+ patients with ALS have a distinctive phenotype, characterised by a more rapid disease course and a shorter survival. In addition, ATXN2+ patients have a more severe impairment of cognitive functions. These findings have relevant implications on clinical practice, including the possibility of refining the individual prognostic prediction and improving the design of ALS clinical trials, in particular as regards as those targeted explicitly to ATXN2 ., Competing Interests: Competing interests: Adriano Chiò serves on scientific advisory boards for Mitsubishi Tanabe, Biogen, Roche, Denali Pharma, Cytokinetics, Lilly, and Amylyx Pharmaceuticals and has received a research grant from Biogen. Cristina Moglia, Antonio Canosa, Umberto Manera, Maurizio Grassano, Rosario Vasta, Francesca Palumbo, Salvatore Gallone, Maura Brunetti, Fabiola De Marchi, Clifton L. Dalgard, Ruth Chia, Gabriele Mora, Lucia Corrado, Sandra D’Alfonso, Letizia Mazzini no disclosures. Dr Traynor holds the US, Canadian, and European patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion in C9orf72. Andrea Calvo has received a research grant from Cytokinetics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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- 2022
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18. Systematic evaluation of genetic mutations in ALS: a population-based study.
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Grassano M, Calvo A, Moglia C, Sbaiz L, Brunetti M, Barberis M, Casale F, Manera U, Vasta R, Canosa A, D'Alfonso S, Corrado L, Mazzini L, Dalgard C, Karra R, Chia R, Traynor B, and Chiò A
- Abstract
Background: A genetic diagnosis in Amyotrophic Lateral Sclerosis (ALS) can inform genetic counselling, prognosis and, in the light of incoming gene-targeted therapy, management. However, conventional genetic testing strategies are often costly and time-consuming., Objective: To evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS., Methods: In this population-based cohort study, 1043 ALS patients from the Piemonte and Valle d'Aosta Register for ALS and 755 healthy individuals were screened by WGS for variants in 42 ALS-related genes and for repeated-expansions in C9orf72 and ATXN2., Results: A total of 279 ALS cases (26.9%) received a genetic diagnosis, namely 75.2% of patients with a family history of ALS and 21.5% of sporadic cases. The mutation rate among early-onset ALS patients was 43.9%, compared with 19.7% of late-onset patients. An additional 14.6% of the cohort carried a genetic factor that worsen prognosis., Conclusions: Our results suggest that, because of its high diagnostic yield and increasingly competitive costs, along with the possibility of retrospectively reassessing newly described genes, WGS should be considered as standard genetic testing for all ALS patients. Additionally, our results provide a detailed picture of the genetic basis of ALS in the general population., Competing Interests: Competing interests: MG, CM, LS, MBr, MBa, FC, UM, RV, AC, SD'A, LC, LM, CD, RK and RC report no disclosures. AC has received research grant from Cytokinetics. BT holds European, Canadian and American patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. AC serves on scientific advisory boards for Mitsubishi Tanabe, Roche and Cytokinetics, and has received a research grant from Italfarmaco., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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- 2022
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19. Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.
- Author
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Kohaar I, Zhang X, Tan SH, Nousome D, Babcock K, Ravindranath L, Sukumar G, Mcgrath-Martinez E, Rosenberger J, Alba C, Ali A, Young D, Chen Y, Cullen J, Rosner IL, Sesterhenn IA, Dobi A, Chesnut G, Turner C, Dalgard C, Wilkerson MD, Pollard HB, Srivastava S, and Petrovics G
- Subjects
- DNA Damage genetics, Germ-Line Mutation, Humans, Male, Mutation, Black or African American genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2022
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