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DOCK2 is involved in the host genetics and biology of severe COVID-19.
Namkoong, Ho; Edahiro, Ryuya; Takano, Tomomi; Nishihara, Hiroshi; Shirai, Yuya; Sonehara, Kyuto; Tanaka, Hiromu; Azekawa, Shuhei; Mikami, Yohei; Lee, Ho; Hasegawa, Takanori; Okudela, Koji; Okuzaki, Daisuke; Motooka, Daisuke; Kanai, Masahiro; Naito, Tatsuhiko; Yamamoto, Kenichi; Wang, Qingbo S; Saiki, Ryunosuke; Ishihara, Rino; Matsubara, Yuta; Hamamoto, Junko; Hayashi, Hiroyuki; Yoshimura, Yukihiro; Tachikawa, Natsuo; Yanagita, Emmy; Hyugaji, Takayoshi; Shimizu, Eigo; Katayama, Kotoe; Kato, Yasuhiro; Morita, Takayoshi; Takahashi, Kazuhisa; Harada, Norihiro; Naito, Toshio; Hiki, Makoto; Matsushita, Yasushi; Takagi, Haruhi; Aoki, Ryousuke; Nakamura, Ai; Harada, Sonoko; Sasano, Hitoshi; Kabata, Hiroki; Masaki, Katsunori; Kamata, Hirofumi; Ikemura, Shinnosuke; Chubachi, Shotaro; Okamori, Satoshi; Terai, Hideki; Morita, Atsuho; Asakura, Takanori.
  • Namkoong H; Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.
  • Edahiro R; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Takano T; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Nishihara H; Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
  • Shirai Y; Genomics Unit, Keio Cancer Center, Keio University Hospital, Tokyo, Japan.
  • Sonehara K; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Tanaka H; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Azekawa S; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Mikami Y; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
  • Lee H; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Hasegawa T; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Okudela K; Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Okuzaki D; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Motooka D; M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan.
  • Kanai M; Department of Pathology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
  • Naito T; Single Cell Genomics, Human Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
  • Yamamoto K; Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
  • Wang QS; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
  • Saiki R; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Ishihara R; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Matsubara Y; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Hamamoto J; Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
  • Hayashi H; Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Yoshimura Y; Division of Gastroenterology and Hepatology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Tachikawa N; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Yanagita E; Division of Pathology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
  • Hyugaji T; Division of Infectious Disease, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
  • Shimizu E; Division of Infectious Disease, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
  • Katayama K; Genomics Unit, Keio Cancer Center, Keio University Hospital, Tokyo, Japan.
  • Kato Y; Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
  • Morita T; Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
  • Takahashi K; Division of Health Medical Intelligence, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
  • Harada N; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Naito T; Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
  • Hiki M; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
  • Matsushita Y; Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
  • Takagi H; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Aoki R; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Nakamura A; Department of General Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Harada S; Department of Emergency and Disaster Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Sasano H; Department of Cardiovascular Biology and Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Kabata H; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Masaki K; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Kamata H; Department of Nephrology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Ikemura S; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Chubachi S; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Okamori S; Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • Terai H; Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo, Japan.
  • Morita A; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • Asakura T; Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Nature ; 609(7928): 754-760, 2022 09.
Статья в английский | MEDLINE | ID: covidwho-1984401
ABSTRACT
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: GTPase-Activating Proteins / Guanine Nucleotide Exchange Factors / Genome-Wide Association Study / Host Microbial Interactions / SARS-CoV-2 / COVID-19 Тип исследования: Когортное исследование / Наблюдательное исследование / Прогностическое исследование Темы: Длинный Ковид / Варианты Пределы темы: Животные / Люди / Middle aged Страна как тема: Азия Язык: английский Журнал: Nature Год: 2022 Тип: Статья Аффилированная страна: S41586-022-05163-5

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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: GTPase-Activating Proteins / Guanine Nucleotide Exchange Factors / Genome-Wide Association Study / Host Microbial Interactions / SARS-CoV-2 / COVID-19 Тип исследования: Когортное исследование / Наблюдательное исследование / Прогностическое исследование Темы: Длинный Ковид / Варианты Пределы темы: Животные / Люди / Middle aged Страна как тема: Азия Язык: английский Журнал: Nature Год: 2022 Тип: Статья Аффилированная страна: S41586-022-05163-5