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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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Background Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. Methods This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. Results Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11–0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43–4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. Conclusions Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Aim Diabetes mellitus (DM) is a known risk factor for severe coronavirus disease 2019 (COVID‐19), but the clinical impact of undiagnosed diabetes and prediabetes in COVID‐19 are unclear particularly in Japan. We clarify the difference in clinical characteristics, including age, sex, body mass index and co‐morbidities, laboratory findings and critical outcomes, in a large Japanese COVID‐19 cohort without diabetes, with prediabetes, undiagnosed diabetes and diagnosed diabetes, and to identify associated risk factors. Materials and Methods This multicentre, retrospective cohort study used the Japan COVID‐19 Task Force database, which included data on 2430 hospitalized COVID‐19 patients from over 70 hospitals from February 2020 to October 2021. The prevalence of prediabetes, undiagnosed diabetes and diagnosed diabetes were estimated based on HbA1c levels or a clinical diabetes history. Critical outcomes were defined as the use of high‐flow oxygen, invasive positive‐pressure ventilation or extracorporeal membrane oxygenation, or death during hospitalization. Results Prediabetes, undiagnosed diabetes and diagnosed diabetes were observed in 40.9%, 10.0% and 23.0%, respectively. Similar to diagnosed diabetes, prediabetes and undiagnosed diabetes were risk factors for critical COVID‐19 outcomes (adjusted odds ratio [aOR] [95% CI]: 2.13 [1.31‐3.48] and 4.00 [2.19‐7.28], respectively). HbA1c was associated with COVID‐19 severity in prediabetes patients (aOR [95% CI]: 11.2 [3.49‐36.3]), but not other groups. Conclusions We documented the clinical characteristics and outcomes of Japanese COVID‐19 patients according to HbA1c levels or diabetes co‐morbidity. As well as undiagnosed and diagnosed diabetes, physicians should be aware of prediabetes related to COVID‐19 severity.