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 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

Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease

Abstract Background Pulmonary Mycobacterium avium complex (pMAC) disease is a chronic, slowly progressive disease. The aim of the present study was to determine the association of six-minute walk test (6MWT) parameters with pulmonary function and the health-related quality of life (HRQL) in patients with pMAC disease. Methods This cross-sectional study included adult patients with pMAC and was conducted at Keio University Hospital. We investigated the relationship of 6MWT parameters with clinical parameters, including pulmonary function, and HRQL, which was assessed using the 36-Item Short Form Health Survey (SF-36) and St. George’s Respiratory Questionnaire (SGRQ). Results In total, 103 consecutive patients with pMAC participated in 6MWT (median age, 64 years; 80 women) and completed SF-36 and SGRQ. The six-minute walk distance (6MWD) showed significant negative and positive correlations with all SGRQ domain scores [ρ = (− 0.54)–(− 0.32)] and the physical component summary (PCS) score (ρ = 0.39) in SF-36, respectively; the opposite was observed for the final Borg scale (FBS) score (all SGRQ scores, ρ = 0.34–0.58; PCS score, ρ = − 0.50). The distance-saturation product showed significant negative and positive correlations with all SGRQ scores [ρ = (− 0.29)–(− 0.55)] and the PCS score (ρ = 0.40), respectively. Multivariate analysis revealed that 6MWD and the FBS score were significant predictors of HRQL. Conclusions Our findings suggest that 6MWD and the FBS score are useful parameters for evaluating HRQL in patients with pMAC. Further studies should investigate the impact of 6WMT parameters on disease progression, treatment responses, and prognosis

Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease

Abstract Background In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. Methods This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George’s Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. Results The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). Conclusions MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis

Clinical characteristics of pulmonary Mycobacterium lentiflavum disease in adult patients

Background: Mycobacterium lentiflavum is a slow-growing non-tuberculous Mycobacterium that is often associated with an immunocompromised state and cervical lymphadenitis in young children. However, little is known about the clinical importance of pulmonary infection with M. lentiflavum in adults. Methods: The medical records of all adults who met the diagnostic criteria of pulmonary M. lentiflavum disease at Keio University Hospital and Fukujuji Hospital from 2001 to 2015 were reviewed. In addition, the PubMed database was searched to identify further reported cases in non-HIV adults. Results: Five cases of pulmonary M. lentiflavum disease were identified in the medical records search and 11 additional cases were identified in the literature review. Eleven of the total 16 cases were female, and 15 of 16 cases showed a nodular/bronchiectatic pattern on chest computed tomography imaging. No cases showed an aggressive clinical course of pulmonary M. lentiflavum disease, although one patient died of an exacerbation of underlying vasculitis and bacterial pneumonia. Conclusions: The clinical characteristics of pulmonary M. lentiflavum disease in adult patients were identified. This disease mainly affects females, displays a nodular/bronchiectatic pattern on chest computed tomography imaging, and does not demonstrate an aggressive clinical course. Further larger studies are needed to reveal detailed clinical features

Longitudinal significance of six-minute walk test in patients with nontuberculous mycobacterial pulmonary disease: an observational study

Abstract Background The long-term exercise tolerance changes in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) are of great interest because of its chronic course. This study aimed to characterize the associations between changes over time in six-minute walking test (6MWT) parameters and clinical parameters in patients with NTM-PD. Methods Overall, 188 patients with NTM-PD, visiting outpatient clinics at Keio University Hospital from April 2012 to March 2020 were included in the study. Data were collected using the St. George’s Respiratory Questionnaire (SGRQ), pulmonary function test (PFT), blood tests, and the 6MWT at registration and at least once after that. The association of the anchors and clinical indicators with the 6MWT parameters was assessed. Results The median age [interquartile range] of the patients was 67 [63–74] years. The median baseline six-minute walk distance (6MWD) and final Borg scale (FBS) were 413 [361–470] m and 1 [0–2], respectively. In the correlation analysis, ΔSGRQ total/year (yr), Δforced vital capacity (FVC, % predicted)/yr, Δforced expiratory volume in 1 s (FEV1, % predicted)/yr, and Δdiffusing capacity for carbon monoxide (DLCO, % predicted)/yr correlated with both Δ6MWD/yr and ΔFBS/yr in the longitudinal analysis (|Rho| > 0.20). When stratified into three quantiles of changes in each anchor, the 6MWT parameters worsened over time in the bottom 25% group by mixed-effects model. Specifically, Δ6MWD was affected by SGRQ activity, SGRQ impacts, PFT (FVC, FEV1, and DLCO), and C-reactive protein (CRP). ΔFBS was affected by all SGRQ components, total score, and PFT. Anchor scores and variables at baseline that worsened Δ6MWD were higher SGRQ scores, lower FVC (% predicted), lower DLCO (% predicted), higher Krebs von den Lungen-6, old age, and undergoing treatment at registration. Similarly, these clinical parameters and elevated CRP, excluding undergoing treatment at registration, worsened ΔFBS. Conclusions The decreased walking distance and exacerbation of dyspnea on exertion over time in patients with NTM-PD may reflect a deterioration of health-related quality of life and pulmonary function. Thus, the change in 6MWT over time can be used as an indicator to accurately assess the patient’s condition and tailor their healthcare environment

Additional file 1: of Association between six-minute walk test parameters and the health-related quality of life in patients with pulmonary Mycobacterium avium complex disease

Supplemental analyses. Table S1. Clinical characteristics of patients with pulmonary Mycobacterium avium complex disease in the never smoker group (n = 92). Table S2. Results of the six-minute walk test for patients with pulmonary Mycobacterium avium complex disease in the never smoker group (n = 92). Table S3. Spearman’s correlations among six-minute walk test parameters and clinical parameters for patients with pulmonary Mycobacterium avium complex disease in the never smoker group (n = 92). Table S4. Spearman’s correlations among six-minute walk test parameters and 36-Item Short Form Health Survey and St George’s Respiratory Questionnaire scores for patients with pulmonary Mycobacterium avium complex disease in the never smoker group (n = 92). Table S5. Multivariate analysis for predictors of 36-Item Short Form Health Survey and St George’s Respiratory Questionnaire scores for patients with pulmonary Mycobacterium avium complex disease in the never smoker group (n = 92). Table S6. Comparisons of six-minute walk test parameters and 36-Item Short Form Health Survey and St George’s Respiratory Questionnaire scores with or without cavitary lesions (n = 103). Table S7. Comparisons of clinical characteristics in pulmonary Mycobacterium avium complex disease patients between male and female (n = 103). Table S8. Multivariate analysis for predictors of 36-Item Short Form Health Survey and St George’s Respiratory Questionnaire scores for patients with pulmonary Mycobacterium avium complex disease in female alone (n = 80). Table S9. Comparisons of 36-Item Short Form Health Survey and St George’s Respiratory Questionnaire scores with or without several clinical parameters (n = 103). (DOCX 55 kb