The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Risk of myocardial infarction in patients with psoriasis: A cross-sectional patient-population study in a Japanese hospital

[Background]Some epidemiological studies have demonstrated the association between psoriasis vulgaris and coronary artery disease (CAD). However, there is a lack of specific data regarding the association between psoriasis vulgaris and myocardial infarction (MI), the more severe and critical presentation of CAD, in the Japanese population. [Methods and results]We retrospectively analyzed 113, 065 patients of all ages at our hospital from January 1, 2011 to January 1, 2013. We extracted the data of patients with psoriasis vulgaris, diabetes mellitus, dyslipidemia, or MI (acute, sub-acute, or old), including sex and age from the electronic medical record database. The prevalence of MI in patients with hypertension, dyslipidemia, diabetes mellitus, and psoriasis vulgaris were 4.8% (794/16, 476), 5.0% (459/9236), 4.6% (531/11, 555), and 2.7% (32/1197), respectively. Multivariate analysis showed that psoriasis vulgaris was significantly associated with MI [adjusted odds ratio (OR): 1.87; 95% confidence interval (CI): 1.26–2.68; p = 0.0022]. In a subgroup analysis of 24, 069 patients who had one or more comorbidities including diabetes mellitus, dyslipidemia, and hypertension, psoriasis vulgaris was still independently associated with MI after adjusting for sex and age (adjusted OR, 1.49; 95% CI: 1.02–2.18; p = 0.0358) in adults. [Conclusion]Psoriasis vulgaris was significantly associated with MI in a Japanese hospital-based population

Association between atrial fibrillation, atrial enlargement, and left ventricular geometric remodeling

This study investigated the relationship between atrial fibrillation (AF) and left ventricular (LV) geometric patterns in a hospital-based population in Japan. We retrospectively analyzed 4444 patients who had undergone simultaneous scheduled transthoracic echocardiography (TTE) and electrocardiography during 2013. A total of 430 patients who had findings of previous myocardial infarctions (n = 419) and without the data on body surface area (n = 11) were excluded from the study. We calculated the LV mass index (LVMI) and relative wall (RWT) and categorized 4014 patients into four groups as follows: normal geometry (n = 3046); concentric remodeling (normal LVMI and high RWT, n = 437); concentric hypertrophy (high LVMI and high RWT, n = 149); and eccentric remodeling (high LVMI and normal RWT, n = 382). The mean left atrial volume indices (LAVI) were 22.5, 23.8, 33.3, and 37.0 mm/m^2 in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. The mean LV ejection fractions (LVEF) were 62.7, 62.6, 60.8, and 53.8%, respectively, whereas the prevalence of AF was 10.4%, 10.5%, 14.8%, and 16.8% in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. In conclusion, the prevalence of AF was increasing according to LV geometric remodeling patterns in association with LA size and LVEF

The Differential Diagnosis of Two Cases of Chronic Periaortitis

The imaging features of chronic periaortitis resemble those of infected aneurysms. Two illustrative cases of chronic periaortitis, in which the etiologies were caused by IgG4-related disease, are presented. The first case involved a 68-year-old man who presented with vague discomfort in his lower abdomen. The second case was a 42-year-old man who presented with a fever of 38°C and persistent, vague chest discomfort. Both cases demonstrated an increased amount of connective tissue around the aorta in computed tomography images and low intensity in the T2-weighed sequence and high intensity in the diffusion-weighed sequence, suggesting the presence of inflammation, in the magnetic resonance imaging. Negative blood cultures, elevated IgG4 levels, and pathological findings confirmed the diagnosis as chronic periaortitis due to IgG4-related disease. This is a newly recognized syndrome of unknown etiology, characterized by a fibroinflammatory condition, tumefactive lesions, and a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells. Both cases were successfully treated with corticosteroids. Infected aneurysms need to be carefully differentiated from this syndrome in view of the similar imaging features