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

Effects of an Artificial Intelligence–Assisted Health Program on Workers With Neck/Shoulder Pain/Stiffness and Low Back Pain: Randomized Controlled Trial

BackgroundMusculoskeletal symptoms such as neck and shoulder pain/stiffness and low back pain are common health problems in the working population. They are the leading causes of presenteeism (employees being physically present at work but unable to be fully engaged). Recently, digital interventions have begun to be used to manage health but their effectiveness has not yet been fully verified, and adherence to such programs is always a problem. ObjectiveThis study aimed to evaluate the improvements in musculoskeletal symptoms in workers with neck/shoulder stiffness/pain and low back pain after the use of an exercise-based artificial intelligence (AI)–assisted interactive health promotion system that operates through a mobile messaging app (the AI-assisted health program). We expected that this program would support participants’ adherence to exercises. MethodsWe conducted a two-armed, randomized, controlled, and unblinded trial in workers with either neck/shoulder stiffness/pain or low back pain or both. We recruited participants with these symptoms through email notifications. The intervention group received the AI-assisted health program, in which the chatbot sent messages to users with the exercise instructions at a fixed time every day through the smartphone’s chatting app (LINE) for 12 weeks. The program was fully automated. The control group continued with their usual care routines. We assessed the subjective severity of the neck and shoulder pain/stiffness and low back pain of the participants by using a scoring scale of 1 to 5 for both the intervention group and the control group at baseline and after 12 weeks of intervention by using a web-based form. We used a logistic regression model to calculate the odds ratios (ORs) of the intervention group to achieve to reduce pain scores with those of the control group, and the ORs of the subjective assessment of the improvement of the symptoms compared to the intervention and control groups, which were performed using Stata software (version 16, StataCorp LLC). ResultsWe analyzed 48 participants in the intervention group and 46 participants in the control group. The adherence rate was 92% (44/48) during the intervention. The participants in the intervention group showed significant improvements in the severity of the neck/shoulder pain/stiffness and low back pain compared to those in the control group (OR 6.36, 95% CI 2.57-15.73; P<.001). Based on the subjective assessment of the improvement of the pain/stiffness at 12 weeks, 36 (75%) out of 48 participants in the intervention group and 3 (7%) out of 46 participants in the control group showed improvements (improved, slightly improved) (OR 43.00, 95% CI 11.25-164.28; P<.001). ConclusionsThis study shows that the short exercises provided by the AI-assisted health program improved both neck/shoulder pain/stiffness and low back pain in 12 weeks. Further studies are needed to identify the elements contributing to the successful outcome of the AI-assisted health program. Trial RegistrationUniversity hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) 000033894; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000038307

Fulvestrant with or without anti‐HER2 therapy in patients in a postmenopausal hormonal state and with ER‐positive HER2‐positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG‐C06)

Abstract Background The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)‐positive, human epidermal growth factor receptor 2 (HER2)‐positive advanced or metastatic breast cancer (AMBC) is unclear. Methods We analyzed the data from 94 patients with ER‐positive HER2‐positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER‐positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first‐line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. Results The TTF was longer in the patients treated with F500 as first‐ or second‐line therapy (n = 20) than in those who received later‐line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti‐HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. Conclusions In patients with ER‐positive HER2‐positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first‐ or second‐line therapy. In patients who received chemotherapy‐free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut‐off for indicating clinical outcomes

Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with post-menopausal estrogen receptor-positive advanced breast cancer: a sub-group analysis of the JBCRG-C06 Safari study

<p><b>Objective:</b> The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2−) cases.</p> <p><b>Methods:</b> The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (<i>n</i> = 960). Of these, 828 patients were HER2−.</p> <p><b>Results</b> Multivariate analysis showed that advanced age (≥65 years; <i>p</i> = .035), longer time (≥3 years) from ABC diagnosis to F500 use (<i>p</i> < .001), no prior chemotherapy (<i>p</i> < .001), and F500 treatment line (<i>p</i> < .001) were correlated with prolonged TTF (median = 5.39 months).</p> <p><b>Conclusions:</b> In ER+/HER2− patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.</p