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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.

Objective/HypothesisMeniere's disease (MD) is a common inner ear disease characterized by repeated episodic vertigo, fluctuating sensorineural hearing loss, and tinnitus. Its pathology is defined as endolymphatic hydrops (EH) in the inner ear and EH has been hypothesized to correlate with the clinical symptoms of MD. We presented the dynamics of in vivo EH in MD patients during medical treatments.Study DesignProspective, single‐arm repeated measuresMethodsEleven MD patients were enrolled. All subjects prospectively underwent gadolinium‐enhanced inner ear magnetic resonance (MR) imaging and neuro‐otological testing before and after medical treatment. The volume of EH was quantitatively evaluated by processing MR images. All MD patients were administered continuous medication and followed up for more than 12 months.ResultsThe frequency of vertigo episodes decreased in all patients and vestibular function decreased to 13–91% of the pre‐treatment level. The volume ratio of post‐treatment EH‐to‐pre‐treatment EH ranged from 1.01–3.22. The total volume of pre‐treatment EH was significantly correlated with cochlear symptom disease duration and the affected ear's hearing level.ConclusionEH in MD patients developed longitudinally with deterioration of inner ear function during medical treatment. The natural course of MD may progress with development of EH at least for a certain period.Level of Evidence2b.

Although steroid treatment is generally administered for patients with inner ear disorders, including Meniere's disease, the mechanism via which steroids exert their effects remains to be clarified. The aquaporins (AQPs) are a family of small transmembrane water transporters, and it has recently been revealed that they play a role in regulating homeostasis in the inner ear fluids. In order to elucidate the action points of steroids in the inner ear, we firstly identified AQPI, 2, 3, 4, 5 and 6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 in the rat endolymphatic sac by means of reverse transcription-polymerase chain reaction. Subsequently, we found that intratympanic injections of steroids upregulated AQPI mRNA of the rat cochlea in a dose-dependent manner. These results suggest that steroids may affect water homeostasis in the rat inner ear mainly via AQP1.

Objectives/Hypothesis: Meniere's disease (MD) patients can show normal head impulses despite poor caloric test results. This study aimed to investigate the discrepancy in the vestibulo-ocular reflex (VOR) in MD patients and whether endolymphatic hydrops (EH) influence the VOR.Study Design: Prospective, cross-sectional observational study. Methods: Ninety MD patients were enrolled. Neuro-otological testing, including a video head impulse test (vHIT) of all semicircular canals (SCs), and gadolinium-enhanced inner ear magnetic resonance imaging were performed. The vestibular EH volume was quantitatively evaluated by processing magnetic resonance images.Results: Abnormal vHIT results in MD patients were found most frequently in the posterior (44.4%) SCs, followed by the horizontal (13.3%) and anterior (10%) SCs. Canal paresis (CP) was assessed using the vHIT and the caloric test, and results were not significant when vHIT responses were assessed as CP only using the horizontal SC. The difference in the vestibular EH between the presence and absence of CP was not significant if assessed using the vHIT (P = .5591), but it was statistically different if assessed using the caloric test (P = .0467).Conclusions: The contradictory reaction of VOR in MD patients may result from the high specificity but low sensitivity of CP in the horizontal vHIT. EH volume in the vestibule affects the caloric response but does not affect the vHIT response.