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

The usefulness of a computer-aided diagnosis scheme for improving the performance of clinicians to diagnose non-mass lesions on breast ultrasonographic images

application/pdfPurpose The purpose of this study was to evaluate the usefulness of a computer-aided diagnosis (CAD) scheme for improving the performance of clinicians to diagnose non-mass lesions appearing as hypoechoic areas on breast ultrasonographic images. Methods The database included 97 ultrasonographic images with hypoechoic areas: 48 benign cases [benign lesion with benign mammary tissue or fibrocystic disease (n = 20), fibroadenoma (n = 11), and intraductal papilloma (n = 17)] and 49 malignant cases [ductal carcinoma in situ (n = 17) and invasive ductal carcinoma (n = 32)]. Seven clinicians, three expert breast surgeons, and four general surgeons participated in the observer study. They were asked their confidence level concerning the possibility of malignancy in all 97 cases with and without the use of the CAD scheme. Receiver operating characteristic (ROC) analysis was performed to evaluate the usefulness of the CAD scheme. Results The areas under the ROC curve (AUC) improved for all observers when they used the CAD scheme and increased from 0.649 to 0.783 (P = 0.0167). Notably, the AUC for the general surgeon group increased from 0.625 to 0.793 (P = 0.045). Conclusions This study showed that the performance of clinicians to diagnose non-mass lesions appearing as hypoechoic areas on breast ultrasonographic images was improved by the use of a CAD scheme.本文 / Department of Breast Surgery, Mie University Hospital21

The usefulness of a computer-aided diagnosis scheme for improving the performance of clinicians to diagnose non-mass lesions on breast ultrasonographic images

application/pdf内容の要旨・審査結果の要旨 / 三重大学大学院医学系研究科 生命医科学専攻 臨床医学系講座 乳腺外科学分

Strategy for the accurate preoperative evaluation of the number of metastatic axillary lymph nodes in breast cancer

Summary: Background: After the ACOSOG Z0011 trial, it became important to evaluate the number of metastatic axillary lymph nodes (LNs) preoperatively. The purpose of this paper is to confirm whether the number of metastases can be accurately diagnosed by preoperative computed tomography (CT), ultrasound sonography (US), and US-guided fine-needle aspiration cytology (FNAC). Methods: We retrospectively analyzed the axillary LNs finding of preoperative CT/US of 470 breast cancer patients. Metastasis was suspected based on the following findings: LNs with a long-axis diameter of ≥10 mm or a short-axis diameter of ≥5 mm on CT, and LNs with the absence of a fatty hilum, focal cortical thickness or a cortical thickness ≥2 mm on US. We also examined the results of FNAC making a rapid bedside diagnosis (bedside-FNAC) of 162 LNs that were suspected to metastatic based on the US findings. Results: On CT, all cases with ≥3 LNs with a long-axis diameter of ≥10 mm and a short-axis diameter of ≥5 mm had metastasis. However, there was no relationship between the number of detected LNs and the number of metastases. On US, 75.7% of LNs with the absence of a fatty hilum and all LNs with cortical thickness ≥6 mm had metastasis. The accuracy of bedside-FNAC for suspicious LNs was 100%. Conclusions: Although we can pick up LNs that are likely to have metastasis on CT/US, it was impossible to accurately predict the number of metastases on CT/US. However, bedside-FNAC of suspicious LNs could accurately predict the number of metastases. Keywords: Bedside fine-needle aspiration cytology, Computed tomography, Lymph node metastasis, Rapid diagnosis, Ultrasound sonograph