DOCK2 is involved in the host genetics and biology of severe COVID-19.
DOCK2 is involved in the host genetics and biology of severe COVID-19.
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DOI：
10.1038/s41586-022-05163-5
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发表时间：
2022-09
期刊：
影响因子：
64.8
通讯作者：
Okada, Yukinori
中科院分区：
文献类型：
--
作者：
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;Sasaki, Junichi;Morisaki, Hiroshi;Uwamino, Yoshifumi;Nanki, Kosaku;Uchida, Sho;Uno, Shunsuke;Nishimura, Tomoyasu;Ishiguro, Takashi;Isono, Taisuke;Shibata, Shun;Matsui, Yuma;Hosoda, Chiaki;Takano, Kenji;Nishida, Takashi;Kobayashi, Yoichi;Takaku, Yotaro;Takayanagi, Noboru;Ueda, Soichiro;Tada, Ai;Miyawaki, Masayoshi;Yamamoto, Masaomi;Yoshida, Eriko;Hayashi, Reina;Nagasaka, Tomoki;Arai, Sawako;Kaneko, Yutaro;Sasaki, Kana;Tagaya, Etsuko;Kawana, Masatoshi;Arimura, Ken;Takahashi, Kunihiko;Anzai, Tatsuhiko;Ito, Satoshi;Endo, Akifumi;Uchimura, Yuji;Miyazaki, Yasunari;Honda, Takayuki;Tateishi, Tomoya;Tohda, Shuji;Ichimura, Naoya;Sonobe, Kazunari;Sassa, Chihiro Tani;Nakajima, Jun;Nakano, Yasushi;Nakajima, Yukiko;Anan, Ryusuke;Arai, Ryosuke;Kurihara, Yuko;Harada, Yuko;Nishio, Kazumi;Ueda, Tetsuya;Azuma, Masanori;Saito, Ryuichi;Sado, Toshikatsu;Miyazaki, Yoshimune;Sato, Ryuichi;Haruta, Yuki;Nagasaki, Tadao;Yasui, Yoshinori;Hasegawa, Yoshinori;Mutoh, Yoshikazu;Kimura, Tomoki;Sato, Tomonori;Takei, Reoto;Hagimoto, Satoshi;Noguchi, Yoichiro;Yamano, Yasuhiko;Sasano, Hajime;Ota, Sho;Nakamori, Yasushi;Yoshiya, Kazuhisa;Saito, Fukuki;Yoshihara, Tomoyuki;Wada, Daiki;Iwamura, Hiromu;Kanayama, Syuji;Maruyama, Shuhei;Yoshiyama, Takashi;Ohta, Ken;Kokuto, Hiroyuki;Ogata, Hideo;Tanaka, Yoshiaki;Arakawa, Kenichi;Shimoda, Masafumi;Osawa, Takeshi;Tateno, Hiroki;Hase, Isano;Yoshida, Shuichi;Suzuki, Shoji;Kawada, Miki;Horinouchi, Hirohisa;Saito, Fumitake;Mitamura, Keiko;Hagihara, Masao;Ochi, Junichi;Uchida, Tomoyuki;Baba, Rie;Arai, Daisuke;Ogura, Takayuki;Takahashi, Hidenori;Hagiwara, Shigehiro;Nagao, Genta;Konishi, Shunichiro;Nakachi, Ichiro;Murakami, Koji;Yamada, Mitsuhiro;Sugiura, Hisatoshi;Sano, Hirohito;Matsumoto, Shuichiro;Kimura, Nozomu;Ono, Yoshinao;Baba, Hiroaki;Suzuki, Yusuke;Nakayama, Sohei;Masuzawa, Keita;Namba, Shinichi;Suzuki, Ken;Naito, Yoko;Liu, Yu-Chen;Takuwa, Ayako;Sugihara, Fuminori;Wing, James B.;Sakakibara, Shuhei;Hizawa, Nobuyuki;Shiroyama, Takayuki;Miyawaki, Satoru;Kawamura, Yusuke;Nakayama, Akiyoshi;Matsuo, Hirotaka;Maeda, Yuichi;Nii, Takuro;Noda, Yoshimi;Niitsu, Takayuki;Adachi, Yuichi;Enomoto, Takatoshi;Amiya, Saori;Hara, Reina;Yamaguchi, Yuta;Murakami, Teruaki;Kuge, Tomoki;Matsumoto, Kinnosuke;Yamamoto, Yuji;Yamamoto, Makoto;Yoneda, Midori;Kishikawa, Toshihiro;Yamada, Shuhei;Kawabata, Shuhei;Kijima, Noriyuki;Takagaki, Masatoshi;Sasa, Noah;Ueno, Yuya;Suzuki, Motoyuki;Takemoto, Norihiko;Eguchi, Hirotaka;Fukusumi, Takahito;Imai, Takao;Fukushima, Munehisa;Kishima, Haruhiko;Inohara, Hidenori;Tomono, Kazunori;Kato, Kazuto;Takahashi, Meiko;Matsuda, Fumihiko;Hirata, Haruhiko;Takeda, Yoshito;Koh, Hidefumi;Manabe, Tadashi;Funatsu, Yohei;Ito, Fumimaro;Fukui, Takahiro;Shinozuka, Keisuke;Kohashi, Sumiko;Miyazaki, Masatoshi;Shoko, Tomohisa;Kojima, Mitsuaki;Adachi, Tomohiro;Ishikawa, Motonao;Takahashi, Kenichiro;Inoue, Takashi;Hirano, Toshiyuki;Kobayashi, Keigo;Takaoka, Hatsuyo;Watanabe, Kazuyoshi;Miyazawa, Naoki;Kimura, Yasuhiro;Sado, Reiko;Sugimoto, Hideyasu;Kamiya, Akane;Kuwahara, Naota;Fujiwara, Akiko;Matsunaga, Tomohiro;Sato, Yoko;Okada, Takenori;Hirai, Yoshihiro;Kawashima, Hidetoshi;Narita, Atsuya;Niwa, Kazuki;Sekikawa, Yoshiyuki;Nishi, Koichi;Nishitsuji, Masaru;Tani, Mayuko;Suzuki, Junya;Nakatsumi, Hiroki;Ogura, Takashi;Kitamura, Hideya;Hagiwara, Eri;Murohashi, Kota;Okabayashi, Hiroko;Mochimaru, Takao;Nukaga, Shigenari;Satomi, Ryosuke;Oyamada, Yoshitaka;Mori, Nobuaki;Baba, Tomoya;Fukui, Yasutaka;Odate, Mitsuru;Mashimo, Shuko;Makino, Yasushi;Yagi, Kazuma;Hashiguchi, Mizuha;Kagyo, Junko;Shiomi, Tetsuya;Fuke, Satoshi;Saito, Hiroshi;Tsuchida, Tomoya;Fujitani, Shigeki;Takita, Mumon;Morikawa, Daiki;Yoshida, Toru;Izumo, Takehiro;Inomata, Minoru;Kuse, Naoyuki;Awano, Nobuyasu;Tone, Mari;Ito, Akihiro;Nakamura, Yoshihiko;Hoshino, Kota;Maruyama, Junichi;Ishikura, Hiroyasu;Takata, Tohru;Odani, Toshio;Amishima, Masaru;Hattori, Takeshi;Shichinohe, Yasuo;Kagaya, Takashi;Kita, Toshiyuki;Ohta, Kazuhide;Sakagami, Satoru;Koshida, Kiyoshi;Hayashi, Kentaro;Shimizu, Tetsuo;Kozu, Yutaka;Hiranuma, Hisato;Gon, Yasuhiro;Izumi, Namiki;Nagata, Kaoru;Ueda, Ken;Taki, Reiko;Hanada, Satoko;Kawamura, Kodai;Ichikado, Kazuya;Nishiyama, Kenta;Muranaka, Hiroyuki;Nakamura, Kazunori;Hashimoto, Naozumi;Wakahara, Keiko;Sakamoto, Koji;Omote, Norihito;Ando, Akira;Kodama, Nobuhiro;Kaneyama, Yasunari;Maeda, Shunsuke;Kuraki, Takashige;Matsumoto, Takemasa;Yokote, Koutaro;Nakada, Taka-Aki;Abe, Ryuzo;Oshima, Taku;Shimada, Tadanaga;Harada, Masahiro;Takahashi, Takeshi;Ono, Hiroshi;Sakurai, Toshihiro;Shibusawa, Takayuki;Kimizuka, Yoshifumi;Kawana, Akihiko;Sano, Tomoya;Watanabe, Chie;Suematsu, Ryohei;Sageshima, Hisako;Yoshifuji, Ayumi;Ito, Kazuto;Takahashi, Saeko;Ishioka, Kota;Nakamura, Morio;Masuda, Makoto;Wakabayashi, Aya;Watanabe, Hiroki;Ueda, Suguru;Nishikawa, Masanori;Chihara, Yusuke;Takeuchi, Mayumi;Onoi, Keisuke;Shinozuka, Jun;Sueyoshi, Atsushi;Nagasaki, Yoji;Okamoto, Masaki;Ishihara, Sayoko;Shimo, Masatoshi;Tokunaga, Yoshihisa;Kusaka, Yu;Ohba, Takehiko;Isogai, Susumu;Ogawa, Aki;Inoue, Takuya;Fukuyama, Satoru;Eriguchi, Yoshihiro;Yonekawa, Akiko;Kan-o, Keiko;Matsumoto, Koichiro;Kanaoka, Kensuke;Ihara, Shoichi;Komuta, Kiyoshi;Inoue, Yoshiaki;Chiba, Shigeru;Yamagata, Kunihiro;Hiramatsu, Yuji;Kai, Hirayasu;Asano, Koichiro;Oguma, Tsuyoshi;Ito, Yoko;Hashimoto, Satoru;Yamasaki, Masaki;Kasamatsu, Yu;Komase, Yuko;Hida, Naoya;Tsuburai, Takahiro;Oyama, Baku;Takada, Minoru;Kanda, Hidenori;Kitagawa, Yuichiro;Fukuta, Tetsuya;Miyake, Takahito;Yoshida, Shozo;Ogura, Shinji;Abe, Shinji;Kono, Yuta;Togashi, Yuki;Takoi, Hiroyuki;Kikuchi, Ryota;Ogawa, Shinichi;Ogata, Tomouki;Ishihara, Shoichiro;Kanehiro, Arihiko;Ozaki, Shinji;Fuchimoto, Yasuko;Wada, Sae;Fujimoto, Nobukazu;Nishiyama, Kei;Terashima, Mariko;Beppu, Satoru;Yoshida, Kosuke;Narumoto, Osamu;Nagai, Hideaki;Ooshima, Nobuharu;Motegi, Mitsuru;Umeda, Akira;Miyagawa, Kazuya;Shimada, Hisato;Endo, Mayu;Ohira, Yoshiyuki;Watanabe, Masafumi;Inoue, Sumito;Igarashi, Akira;Sato, Masamichi;Sagara, Hironori;Tanaka, Akihiko;Ohta, Shin;Kimura, Tomoyuki;Shibata, Yoko;Tanino, Yoshinori;Nikaido, Takefumi;Minemura, Hiroyuki;Sato, Yuki;Yamada, Yuichiro;Hashino, Takuya;Shinoki, Masato;Iwagoe, Hajime;Takahashi, Hiroshi;Fujii, Kazuhiko;Kishi, Hiroto;Kanai, Masayuki;Imamura, Tomonori;Yamashita, Tatsuya;Yatomi, Masakiyo;Maeno, Toshitaka;Hayashi, Shinichi;Takahashi, Mai;Kuramochi, Mizuki;Kamimaki, Isamu;Tominaga, Yoshiteru;Ishii, Tomoo;Utsugi, Mitsuyoshi;Ono, Akihiro;Tanaka, Toru;Kashiwada, Takeru;Fujita, Kazue;Saito, Yoshinobu;Seike, Masahiro;Watanabe, Hiroko;Matsuse, Hiroto;Kodaka, Norio;Nakano, Chihiro;Oshio, Takeshi;Hirouchi, Takatomo;Makino, Shohei;Egi, Moritoki;Omae, Yosuke;Nannya, Yasuhito;Ueno, Takafumi;Katayama, Kazuhiko;Ai, Masumi;Fukui, Yoshinori;Kumanogoh, Atsushi;Sato, Toshiro;Hasegawa, Naoki;Tokunaga, Katsushi;Ishii, Makoto;Koike, Ryuji;Kitagawa, Yuko;Kimura, Akinori;Imoto, Seiya;Miyano, Satoru;Ogawa, Seishi;Kanai, Takanori;Fukunaga, Koichi;Okada, Yukinori
确定导致严重COVID-19的宿主遗传因素是一个新出现的挑战。在这里，我们进行了一项全基因组关联研究（GWAS），涉及在大流行最初几波期间收集的一组日本人中的2，393例COVID-19病例，其中3，289例未受影响的对照。我们在5号染色体5 q35（rs60200309-A）上发现了一个变异体，该变异体靠近胞质分裂2基因（DOCK 2）的贡献者，与65岁以下患者的严重COVID-19相关。这种风险等位基因在东亚个体中普遍存在，但在欧洲人中很少见，这突出了在非欧洲人群中进行全基因组关联研究的价值。对473份外周血样本进行RNA测序分析，发现这些年轻患者中与危险等位基因相关的DOCK 2表达降低。DOCK 2表达在COVID-19重症患者中受到抑制。单细胞RNA测序分析（n = 61人）确定了DOCK 2的细胞类型特异性下调和COVID-19风险等位基因对非经典单核细胞中DOCK 2表达的特异性降低效应。来自严重COVID-19肺炎患者的肺标本的免疫组织化学显示DOCK 2表达受到抑制。此外，用CPYPP抑制DOCK 2功能增加了SARS-CoV-2感染的叙利亚仓鼠模型中肺炎的严重程度，其特征在于体重减轻、肺水肿、病毒载量增加、巨噬细胞募集受损和I型干扰素反应失调。我们的结论是DOCK 2在宿主对SARS-CoV-2感染的免疫应答和严重COVID-19的发展中具有重要作用，并且可以进一步探索作为潜在的生物标志物和/或治疗靶点。一项全基因组关联研究强调了DOCK 2的一种变异，这种变异在东亚人群中很常见，但在欧洲人中很罕见，是严重COVID-19的宿主遗传风险因素。
Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. 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. A genome-wide association study highlights a variant in DOCK2, which is common in East Asian populations but rare in Europeans, as a host genetic risk factor for severe COVID-19.
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早发作感染患者的遗传DOCK2缺乏。
DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
通讯作者：
Notarangelo LD
影响因子：
8.8
作者：
Ebisudani T;Sugimoto S;Haga K;Mitsuishi A;Takai-Todaka R;Fujii M;Toshimitsu K;Hamamoto J;Sugihara K;Hishida T;Asamura H;Fukunaga K;Yasuda H;Katayama K;Sato T
通讯作者：
Sato T
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
12.3
作者：
Lun AT;Bach K;Marioni JC
通讯作者：
Marioni JC
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S