DOCK2 is involved in the host genetics and biology of severe COVID-19

Medientyp: E-Artikel
Titel: DOCK2 is involved in the host genetics and biology of severe COVID-19
Beteiligte: 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; [...]
Erschienen: Springer Science and Business Media LLC, 2022
Erschienen in: Nature
Sprache: Englisch
DOI: 10.1038/s41586-022-05163-5
ISSN: 0028-0836; 1476-4687
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge<jats:sup>1–5</jats:sup>. 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 (<jats:italic>DOCK2</jats:italic>), 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 <jats:italic>DOCK2</jats:italic> associated with the risk allele in these younger patients. <jats:italic>DOCK2</jats:italic> expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (<jats:italic>n</jats:italic> = 61 individuals) identified cell-type-specific downregulation of <jats:italic>DOCK2</jats:italic> and a COVID-19-specific decreasing effect of the risk allele on <jats:italic>DOCK2</jats:italic> 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.</jats:p>

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