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1.
Preprint in English | medRxiv | ID: ppmedrxiv-22274196

ABSTRACT

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics analysis of an immunologically naive SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.

2.
Ho Namkoong; Ryuya Edahiro; Koichi Fukunaga; Yuya Shirai; Kyuto Sonehara; Hiromu Tanaka; Ho Lee; Takanori Hasegawa; Masahiro Kanai; Tatsuhiko Naito; Kenichi Yamamoto; Ryunosuke Saiki; Takayoshi Hyugaji; Eigo Shimizu; Kotoe Katayama; Kazuhisa Takahashi; Norihiro Harada; Toshio Naito; Makoto Hiki; Yasushi Matsushita; Haruhi Takagi; Ryousuke Aoki; Ai Nakamura; Sonoko Harada; Hitoshi Sasano; Hiroki Kabata; Katsunori Masaki; Hirofumi Kamata; Shinnosuke Ikemura; Shotaro Chubachi; Satoshi Okamori; Hideki Terai; Atsuho Morita; Takanori Asakura; Junichi Sasaki; Hiroshi Morisaki; Yoshifumi Uwamino; Kosaku Nanki; Yohei Mikami; Sho Uchida; Shunsuke Uno; Rino Ishihara; Yuta Matsubara; Tomoyasu Nishimura; Takanori Ogawa; Takashi Ishiguro; Taisuke Isono; Shun Shibata; Yuma Matsui; Chiaki Hosoda; Kenji Takano; Takashi Nishida; Yoichi Kobayashi; Yotaro Takaku; Noboru Takayanagi; Soichiro Ueda; Ai Tada; Masayoshi Miyawaki; Masaomi Yamamoto; Eriko Yoshida; Reina Hayashi; Tomoki Nagasaka; Sawako Arai; Yutaro Kaneko; Kana Sasaki; Etsuko Tagaya; Masatoshi Kawana; Ken Arimura; Kunihiko Takahashi; Tatsuhiko Anzai; Satoshi Ito; Akifumi Endo; Yuji Uchimura; Yasunari Miyazaki; Takayuki Honda; Tomoya Tateishi; Shuji Tohda; Naoya Ichimura; Kazunari Sonobe; Chihiro Sassa; Jun Nakajima; Yasushi Nakano; Yukiko Nakajima; Ryusuke Anan; Ryosuke Arai; Yuko Kurihara; Yuko Harada; Kazumi Nishio; Tetsuya Ueda; Masanori Azuma; Ryuichi Saito; Toshikatsu Sado; Yoshimune Miyazaki; Ryuichi Sato; Yuki Haruta; Tadao Nagasaki; Yoshinori Yasui; Yoshinori Hasegawa; Yoshikazu Mutoh; Tomonori Sato; Reoto Takei; Satoshi Hagimoto; Yoichiro Noguchi; Yasuhiko Yamano; Hajime Sasano; Sho Ota; Yasushi Nakamori; Kazuhisa Yoshiya; Fukuki Saito; Tomoyuki Yoshihara; Daiki Wada; Hiromu Iwamura; Syuji Kanayama; Shuhei Maruyama; Takashi Yoshiyama; Ken Ohta; Hiroyuki Kokuto; Hideo Ogata; Yoshiaki Tanaka; Kenichi Arakawa; Masafumi Shimoda; Takeshi Osawa; Hiroki Tateno; Isano Hase; Shuichi Yoshida; Shoji Suzuki; Miki Kawada; Hirohisa Horinouchi; Fumitake Saito; Keiko Mitamura; Masao Hagihara; Junichi Ochi; Tomoyuki Uchida; Rie Baba; Daisuke Arai; Takayuki Ogura; Hidenori Takahashi; Shigehiro Hagiwara; Genta Nagao; Shunichiro Konishi; Ichiro Nakachi; Koji Murakami; Mitsuhiro Yamada; Hisatoshi Sugiura; Hirohito Sano; Shuichiro Matsumoto; Nozomu Kimura; Yoshinao Ono; Hiroaki Baba; Yusuke Suzuki; Sohei Nakayama; Keita Masuzawa; Shinichi Namba; Ken Suzuki; Nobuyuki Hizawa; Takayuki Shiroyama; Satoru Miyawaki; Yusuke Kawamura; Akiyoshi Nakayama; Hirotaka Matsuo; Yuichi Maeda; Takuro Nii; Yoshimi Noda; Takayuki Niitsu; Yuichi Adachi; Takatoshi Enomoto; Saori Amiya; Reina Hara; Toshihiro Kishikawa; Shuhei Yamada; Shuhei Kawabata; Noriyuki Kijima; Masatoshi Takagaki; Noa Sasa; Yuya Ueno; Motoyuki Suzuki; Norihiko Takemoto; Hirotaka Eguchi; Takahito Fukusumi; Takao Imai; Munehisa Fukushima; Haruhiko Kishima; Hidenori Inohara; Kazunori Tomono; Kazuto Kato; Meiko Takahashi; Fumihiko Matsuda; Haruhiko Hirata; Yoshito Takeda; Hidefumi Koh; Tadashi Manabe; Yohei Funatsu; Fumimaro Ito; Takahiro Fukui; Keisuke Shinozuka; Sumiko Kohashi; Masatoshi Miyazaki; Tomohisa Shoko; Mitsuaki Kojima; Tomohiro Adachi; Motonao Ishikawa; Kenichiro Takahashi; Takashi Inoue; Toshiyuki Hirano; Keigo Kobayashi; Hatsuyo Takaoka; Kazuyoshi Watanabe; Naoki Miyazawa; Yasuhiro Kimura; Reiko Sado; Hideyasu Sugimoto; Akane Kamiya; Naota Kuwahara; Akiko Fujiwara; Tomohiro Matsunaga; Yoko Sato; Takenori Okada; Yoshihiro Hirai; Hidetoshi Kawashima; Atsuya Narita; Kazuki Niwa; Yoshiyuki Sekikawa; Koichi Nishi; Masaru Nishitsuji; Mayuko Tani; Junya Suzuki; Hiroki Nakatsumi; Takashi Ogura; Hideya Kitamura; Eri Hagiwara; Kota Murohashi; Hiroko Okabayashi; Takao Mochimaru; Shigenari Nukaga; Ryosuke Satomi; Yoshitaka Oyamada; Nobuaki Mori; Tomoya Baba; Yasutaka Fukui; Mitsuru Odate; Shuko Mashimo; Yasushi Makino; Kazuma Yagi; Mizuha Hashiguchi; Junko Kagyo; Tetsuya Shiomi; Satoshi Fuke; Hiroshi Saito; Tomoya Tsuchida; Shigeki Fujitani; Mumon Takita; Daiki Morikawa; Toru Yoshida; Takehiro Izumo; Minoru Inomata; Naoyuki Kuse; Nobuyasu Awano; Mari Tone; Akihiro Ito; Yoshihiko Nakamura; Kota Hoshino; Junichi Maruyama; Hiroyasu Ishikura; Tohru Takata; Toshio Odani; Masaru Amishima; Takeshi Hattori; Yasuo Shichinohe; Takashi Kagaya; Toshiyuki Kita; Kazuhide Ohta; Satoru Sakagami; Kiyoshi Koshida; Kentaro Hayashi; Tetsuo Shimizu; Yutaka Kozu; Hisato Hiranuma; Yasuhiro Gon; Namiki Izumi; Kaoru Nagata; Ken Ueda; Reiko Taki; Satoko Hanada; Kodai Kawamura; Kazuya Ichikado; Kenta Nishiyama; Hiroyuki Muranaka; Kazunori Nakamura; Naozumi Hashimoto; Keiko Wakahara; Sakamoto Koji; Norihito Omote; Akira Ando; Nobuhiro Kodama; Yasunari Kaneyama; Shunsuke Maeda; Takashige Kuraki; Takemasa Matsumoto; Koutaro Yokote; Taka-Aki Nakada; Ryuzo Abe; Taku Oshima; Tadanaga Shimada; Masahiro Harada; Takeshi Takahashi; Hiroshi Ono; Toshihiro Sakurai; Takayuki Shibusawa; Yoshifumi Kimizuka; Akihiko Kawana; Tomoya Sano; Chie Watanabe; Ryohei Suematsu; Hisako Sageshima; Ayumi Yoshifuji; Kazuto Ito; Saeko Takahashi; Kota Ishioka; Morio Nakamura; Makoto Masuda; Aya Wakabayashi; Hiroki Watanabe; Suguru Ueda; Masanori Nishikawa; Yusuke Chihara; Mayumi Takeuchi; Keisuke Onoi; Jun Shinozuka; Atsushi Sueyoshi; Yoji Nagasaki; Masaki Okamoto; Sayoko Ishihara; Masatoshi Shimo; Yoshihisa Tokunaga; Yu Kusaka; Takehiko Ohba; Susumu Isogai; Aki Ogawa; Takuya Inoue; Satoru Fukuyama; Yoshihiro Eriguchi; Akiko Yonekawa; Keiko Kan-o; Koichiro Matsumoto; Kensuke Kanaoka; Shoichi Ihara; Kiyoshi Komuta; Yoshiaki Inoue; Shigeru Chiba; Kunihiro Yamagata; Yuji Hiramatsu; Hirayasu Kai; Koichiro Asano; Tsuyoshi Oguma; Yoko Ito; Satoru Hashimoto; Masaki Yamasaki; Yu Kasamatsu; Yuko Komase; Naoya Hida; Takahiro Tsuburai; Baku Oyama; Minoru Takada; Hidenori Kanda; Yuichiro Kitagawa; Tetsuya Fukuta; Takahito Miyake; Shozo Yoshida; Shinji Ogura; Shinji Abe; Yuta Kono; Yuki Togashi; Hiroyuki Takoi; Ryota Kikuchi; Shinichi Ogawa; Tomouki Ogata; Shoichiro Ishihara; Arihiko Kanehiro; Shinji Ozaki; Yasuko Fuchimo; Sae Wada; Nobukazu Fujimoto; Kei Nishiyama; Mariko Terashima; Satoru Beppu; Kosuke Yoshida; Osamu Narumoto; Hideaki Nagai; Nobuharu Ooshima; Mitsuru Motegi; Akira Umeda; Kazuya Miyagawa; Hisato Shimada; Mayu Endo; Yoshiyuki Ohira; Masafumi Watanabe; Sumito Inoue; Akira Igarashi; Masamichi Sato; Hironori Sagara; Akihiko Tanaka; Shin Ohta; Tomoyuki Kimura; Yoko Shibata; Yoshinori Tanino; Takefumi Nikaido; Hiroyuki Minemura; Yuki Sato; Yuichiro Yamada; Takuya Hashino; Masato Shinoki; Hajime Iwagoe; Hiroshi Takahashi; Kazuhiko Fujii; Hiroto Kishi; Masayuki Kanai; Tomonori Imamura; Tatsuya Yamashita; Masakiyo Yatomi; Toshitaka Maeno; Shinichi Hayashi; Mai Takahashi; Mizuki Kuramochi; Isamu Kamimaki; Yoshiteru Tominaga; Tomoo Ishii; Mitsuyoshi Utsugi; Akihiro Ono; Toru Tanaka; Takeru Kashiwada; Kazue Fujita; Yoshinobu Saito; Masahiro Seike; Yosuke Omae; Yasuhito Nannya; Takafumi Ueno; Tomomi Takano; Kazuhiko Katayama; Masumi Ai; Atsushi Kumanogoh; Toshiro Sato; Naoki Hasegawa; Katsushi Tokunaga; Makoto Ishii; Ryuji Koike; Yuko Kitagawa; Akinori Kimura; Seiya Imoto; Satoru Miyano; Seishi Ogawa; Takanori Kanai; Yukinori Okada.
Preprint in English | medRxiv | ID: ppmedrxiv-21256513

ABSTRACT

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5q35 (rs60200309-A at DOCK2) that was associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

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