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

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.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

Incidence and Outcomes of Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Registry-based Descriptive Trial in Kobe City

The current study aims to evaluate the incidence and results of aneurysmal subarachnoid hemorrhage (aSAH) throughout Kobe City. Based on a multicenter retrospective registry-based descriptive trial involving all 13 primary stroke centers in Kobe City, patients with aSAH treated between October 2017 and September 2019 were studied. A total of 334 patients were included, with an estimated age-adjusted incidence of 11.12 per 100,000 person-years. Curative treatment was given to 94% of patients, with endovascular treatment (51%) preferred over surgical treatment (43%). Of the patients, 12% were treated by shunt surgery for sequential hydrocephalus with a worse outcome at 30 days or discharge (14% vs. 46%, odds ratio (OR): 0.19, 95% confidence interval (CI): 0.088-0.39, p-value <0.001). As for vasospasm and delayed cerebral ischemia, most patients were given intravenous fasudil infusion (73%), with endovascular treatment for vasospasm in 24 cases (7.2%). The fasudil group had more good outcomes (42% vs. 30%, OR: 1.64, 95% CI: 0.95-2.87, p-value = 0.075) and significantly less death (3.3% vs. 35%, OR: 0.064, 95% CI: 0.024-0.15, p-value <0.001) at 30 days or discharge. Mortality rose from 12% at 30 days or discharge to 17% at 1 year, but neurological function distribution improved over time (modified Rankin Scale 0-2 was 39% at 30 days or discharge, 53% at 60 days, and 63% at 1 year). Our retrospective registered trial presented various statistics on aSAH, summarizing the current treatment status and prognosis