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1. Circulating proteins to predict COVID-19 severity

Author

Chen-Yang Su, Sirui Zhou, Edgar Gonzalez-Kozlova, Guillaume Butler-Laporte, Elsa Brunet-Ratnasingham, Tomoko Nakanishi, Wonseok Jeon, David R. Morrison, Laetitia Laurent, Jonathan Afilalo, Marc Afilalo, Danielle Henry, Yiheng Chen, Julia Carrasco-Zanini, Yossi Farjoun, Maik Pietzner, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Meriem Bouab, Louis Petitjean, Charlotte Guzman, Xiaoqing Xue, Chris Tselios, Branka Vulesevic, Olumide Adeleye, Tala Abdullah, Noor Almamlouk, Yara Moussa, Chantal DeLuca, Naomi Duggan, Erwin Schurr, Nathalie Brassard, Madeleine Durand, Diane Marie Del Valle, Ryan Thompson, Mario A. Cedillo, Eric Schadt, Kai Nie, Nicole W. Simons, Konstantinos Mouskas, Nicolas Zaki, Manishkumar Patel, Hui Xie, Jocelyn Harris, Robert Marvin, Esther Cheng, Kevin Tuballes, Kimberly Argueta, Ieisha Scott, The Mount Sinai COVID-19 Biobank Team, Celia M. T. Greenwood, Clare Paterson, Michael A. Hinterberg, Claudia Langenberg, Vincenzo Forgetta, Joelle Pineau, Vincent Mooser, Thomas Marron, Noam D. Beckmann, Seunghee Kim-schulze, Alexander W. Charney, Sacha Gnjatic, Daniel E. Kaufmann, Miriam Merad, and J. Brent Richards

Subjects
Medicine, Science
Abstract

Abstract Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Published
2023
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2. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Author

David R. Morrison, Elsa Brunet-Ratnasingham, Marc Afilalo, Nardin Rezk, Michael Hultström, Maik Pietzner, Hugo Zeberg, Tala Abdullah, Nicola D. Kerrison, Daniel Kaufmann, Celia M. T. Greenwood, Tomoko Nakanishi, Guillaume Butler-Laporte, Elin Thysell, Claudia Langenberg, Kaiqiong Zhao, Danielle Henry, Michaël Chassé, Vincenzo Forgetta, Madeleine Durand, Miklos Lipcsey, Clare Paterson, Michael Pollak, Jonathan Afilalo, Yiheng Chen, Vincent Mooser, Xiaoqing Xue, Zaman Afrasiabi, Louis Petitjean, Meriem Bouab, J. Brent Richards, Johan Normark, Branka Vulesevic, Nofar Kimchi, Charlotte Guzman, Noor Almamlouk, Chris Tselios, Sirui Zhou, Robert Frithiof, Olumide Adeleye, and Laetitia Laurent

Subjects
0301 basic medicine, Innate immune system, business.industry, Confounding, Case-control study, Mendelian Randomization Analysis, General Medicine, Odds ratio, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Severity of illness, Mendelian randomization, Immunology, Medicine, business
Abstract

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.

Published
2021

3. Circulating proteins to predict adverse COVID-19 outcomes

Author

Edgar Gonzalez-Kozlova, David R. Morrison, Branka Vulesevic, Nofar Kimchi, Robert Marvin, Maik Pietzner, Zaman Afrasiabi, Kimberly Argueta, Louis Petitjean, Naomi Duggan, Ryan Thompson, Meriem Bouab, Manishkumar Patel, Kevin Tuballes, Ieisha Scott, J. Brent Richards, Mario A. Cedillo, Nicole W. Simons, Jocelyn Harris, Tala Abdullah, Claudia Langenberg, Danielle Henry, Vincenzo Forgetta, Daniel Kaufmann, Madeleine Durand, Chen-Yang Su Mr., Michael A Hinterberg, Elsa Brunet-Ratnasingham, Celia M. T. Greenwood, Miriam Merad, Wonseok Jeon, Alexander W. Charney, Sacha Gnjatic, Noam D. Beckmann, Xiaoqing Xue, Nicolas Zaki, Julia Carrasco-Zanini, Diane Marie Del Valle, Joelle Pineau, Esther Cheng, Tomoko Nakanishi, Olumide Adeleye, Kai Nie, Chantal DeLuca, Konstantinos Mouskas, Thomas U. Marron, Marc Afilalo, Guillaume Butler-Laporte, Yiheng Chen, Yossi Farjoun, Yara Moussa, Vincent Mooser, Eric E. Schadt, Clare Paterson, Noor Almamlouk, Chris Tselios, Nathalie Brassard, Sirui Zhou, Hui Xie, Ephraim Kenigsberg, Nardin Rezk, Seunghee Kim-Schulze, Laetitia Laurent, Charlotte Guzman, Erwin Schurr, and Joanthan Afilalo

Subjects
Oncology, medicine.medical_specialty, Receiver operating characteristic, Coronavirus disease 2019 (COVID-19), business.industry, medicine.medical_treatment, Disease progression, Age and sex, Cytokine, Internal medicine, Cohort, Medicine, Generalizability theory, business, Predictive modelling
Abstract

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Published
2021

4. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Published
2022

5. A Neanderthal OAS1 isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies

Author

Daniel Kaufmann, Celia M. T. Greenwood, Laetitia Laurent, Danielle Henry, Zaman Afrasiabi, Clare Paterson, Louis Petitjean, Meriem Bouab, David R. Morrison, Brent Richards, Kaiqiong Zhao, Michaël Chassé, Vincenzo Forgetta, Maik Pietzner, Michael Hultström, Robert Frithiof, Yiheng Chen, Elin Thysell, Vincent Mooser, Xiaoqing Xue, Nicola D. Kerrison, Jonathan Afilalo, Olumide Adeleye, Elsa Brunet-Ratnasingham, Miklos Lipcsey, Nardin Rezk, Guillaume Butler-Laporte, Claudia Langenberg, Hugo Zeberg, Tala Abdullah, Charlotte Guzman, Michael Pollak, Noor Almamlouk, Chris Tselios, Branka Vulesevic, Nofar Kimchi, Sirui Zhou, Marc Afilalo, Johan Normark, Madeleine Durand, and Tomoko Nakanishi

Subjects
Gene isoform, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Confounding, Immunology, Mendelian randomization, Breathing, Medicine, Single-nucleotide polymorphism, business, Gene
Abstract

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7×10−8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8×10−8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8×10−6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.

Published
2020

6. A multicenter prospective study of risk factors and treatment of unusual site thrombosis

Author

Alejandro Lazo-Langner, Michael J. Kovacs, Kim Ma, David Anderson, Vicky Tagalakis, Susan R. Kahn, P. S. Wells, Marc A. Rodger, Charlotte Guzman, Andrew Hirsch, and Mark Blostein

Subjects
Adult, Male, Canada, medicine.medical_specialty, medicine.drug_class, Deep vein, medicine.medical_treatment, Low molecular weight heparin, 030204 cardiovascular system & hematology, Thrombophilia, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Aged, Venous Thrombosis, business.industry, Renal vein thrombosis, Anticoagulants, Hematology, Middle Aged, medicine.disease, Thrombosis, Portal vein thrombosis, Surgery, Discontinuation, medicine.anatomical_structure, Female, business, Central venous catheter, Follow-Up Studies
Abstract

Unusual site deep vein thrombosis (USDVT) is an uncommon form of venous thromboembolism (VTE) with heterogeneity in pathophysiology and clinical features. While the need for anticoagulation treatment is generally accepted, there is little data on optimal USDVT treatment. The TRUST study aimed to characterize the epidemiology, treatment and outcomes of USDVT. From 2008 to 2012, 152 patients were prospectively enrolled at 4 Canadian centers. After baseline, patients were followed at 6, 12 and 24months. There were 97 (64%) cases of splanchnic, 33 (22%) cerebral, 14 (9%) jugular, 6 (4%) ovarian and 2 (1%) renal vein thrombosis. Mean age was 52.9years and 113 (74%) cases were symptomatic. Of 72 (47%) patients tested as part of clinical care, 22 (31%) were diagnosed with new thrombophilia. Of 138 patients evaluated in follow-up, 66 (48%) completed at least 6months of anticoagulation. Estrogen exposure or inflammatory conditions preceding USDVT were commonly associated with treatment discontinuation before 6months, while previous VTE was associated with continuing anticoagulation beyond 6months. During follow-up, there were 22 (16%) deaths (20 from cancer), 4 (3%) cases of recurrent VTE and no fatal bleeding events. Despite half of USDVT patients receiving6months of anticoagulation, the rate of VTE recurrence was low and anticoagulant treatment appears safe. Thrombophilia testing was common and thrombophilia prevalence was high. Further research is needed to determine the optimal investigation and management of USDVT.

Published
2016

7. Association Between Patient Knowledge of Anticoagulation, INR Control, and Warfarin-Related Adverse Events

Author

Charlotte Guzman, Abbas Kezouh, Mark Blostein, Poupak Rahmani, and Susan R. Kahn

Subjects
medicine.medical_specialty, Pediatrics, business.industry, education, Warfarin, Pharmaceutical Science, Articles, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Emergency medicine, Medicine, 030212 general & internal medicine, business, Adverse effect, Association (psychology), medicine.drug, Patient education
Abstract

Background: Whether the level of patient’s knowledge about warfarin plays any role in maintenance of therapeutic international normalized ratio (INR) is controversial. Several studies have looked at patients’ warfarin knowledge and the level of patients’ anticoagulation control (AC). Most studies had small numbers and did not use validated questionnaires. Objectives: To use the Oral Anticoagulation Knowledge (OAK) test to assess patients’ knowledge of AC and to examine associations between knowledge, INR, and adverse events. Methods: In this cross-sectional study, patients were asked to complete the OAK test. Data on clinical and demographic characteristics, INR values, and thrombosis or bleeding events during the preceding 1 year period were collected. Associations between OAK scores, patient characteristics, proportion of therapeutic INRs, and bleeding/thrombosis events were assessed. Results: A total of 225 patients completed the OAK test. Mean (SD) age was 70 (13.4) years, 53% were male, and 75% were on warfarin for >3 years. Over the preceding year, 57.3% of INRs were therapeutic, and there were 22 bleeding and 6 thrombotic events. The mean OAK score was 12/20 (passing score = 15/20); 64% of patients failed the OAK test. Predictors of passing the OAK test were younger age ( P = .01) and higher level of education ( P = .03). There was no association between OAK score and proportion of therapeutic INRs, or OAK score and bleeding or thrombosis events. Conclusion: We used the OAK test to assess patients’ AC knowledge. Results suggests that while younger and more educated patients were more likely to pass the OAK test, the OAK test results may not predict INR control or occurrence of bleeding or thrombotic events.

Published
2016

8. Patients’ Knowledge Of Anticoagulation and Its Association With Clinical Characteristics, INR Control and Warfarin-Related Adverse Events

Author

Poupak Rahmani, Mark Blostein, Charlotte Guzman, Ashley Tabah, Alla Muladzanov, and Susan R. Kahn

Subjects
medicine.medical_specialty, Pediatrics, business.industry, education, Immunology, Warfarin, Atrial fibrillation, Cell Biology, Hematology, medicine.disease, Biochemistry, Thrombosis, Tertiary care, Test (assessment), Sample size determination, Internal medicine, medicine, Thrombus, business, Adverse effect, medicine.drug
Abstract

Background Whether level of knowledge of anticoagulation (AC) among patients on warfarin plays a role in maintenance of therapeutic INR or in warfarin-related adverse events is controversial. Most studies conducted on this subject had small patient sample sizes and did not use validated questionnaires to assess patients’ knowledge of AC. Objectives To use the validated Oral Anticoagulation Knowledge (OAK) test (Zeolla MM, 2006) to assess knowledge of AC among patients attending a busy AC clinic, and to examine associations between level of knowledge, INR control and adverse events. We hypothesized that patients with higher OAK test scores (i.e. greater knowledge) would have better INR control (primary outcome) and fewer bleeding and thrombosis events (secondary outcomes). Methods Consecutive patients who had been followed in our AC clinic (tertiary care, university-affiliated hospital, 20,000 patient-visits per year) for at least one year and consented to participate were asked to complete the OAK test. The OAK test is a 20-question multiple-choice questionnaire that assesses patients’ knowledge of warfarin AC. A passing score is ≥15 correct responses. Patient charts were reviewed to obtain data on clinical and demographic characteristics, and information on INR values and any thrombosis or bleeding events during the preceding 1 year period. Associations between OAK scores and patient characteristics, INR control and bleeding/thrombosis events were assessed by chi-square and t-tests, as appropriate. Results Among 252 patients screened for participation, 225 met the inclusion criteria and completed the OAK test. Mean (SD) age was 70 (13.4) years, 53% were male and 75% were on warfarin for >3 years. Indications for AC were atrial fibrillation in 65%, VTE in 8%, mechanical heart valve in 10%, and other in 19%. The mean OAK score was 12/20, and 64% failed the OAK test. Predictors of a pass score on the OAK test were younger age (p= 0.01) and higher level of education (p=0.03). Over the preceding year, 57.3% of INRs were therapeutic, 25.1% subtherapeutic and 17.4% supratherapeutic, and there were 22 bleeding events and 5 thrombosis events. There was no association between OAK score and INR control, or OAK score and bleeding or thrombosis events. Conclusion To our knowledge, this is the first study to use the validated OAK test to assess patients’ AC knowledge. We found that younger and more educated patients were more likely to pass the OAK test; however, OAK test result did not predict INR control or occurrence of bleeding or thrombotic events. The OAK test may not be sensitive enough to capture the standard of care practiced in different anticoagulation clinics (e.g. differences in teaching material, frequency of INR checks in stable patients). Also, for some patients, AC knowledge among their caretakers may be more important than self-knowledge. Further research is needed to assess the relationship between AC knowledge, INR control and adverse clinical outcomes. Disclosures: No relevant conflicts of interest to declare.

Published
2013

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