| 1. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
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| 3. |
- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Chalmers, J. R., et al.
(författare)
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Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)
- 2016
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 175:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmo, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [ including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.
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| 5. |
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| 6. |
- Chalmers, J. R., et al.
(författare)
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Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME)
- 2014
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 1365-2133 .- 0007-0963. ; 171:6, s. 1318-1325
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Tidskriftsartikel (refereegranskat)abstract
- This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.
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| 7. |
- Fung, P. P. L., et al.
(författare)
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Time to onset of bisphosphonate-related osteonecrosis of the jaws : a multicentre retrospective cohort study
- 2017
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Ingår i: Oral Diseases. - : WILEY. - 1354-523X .- 1601-0825. ; 23:4, s. 477-483
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients.Subjects and Methods: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.Results: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n=88) and 2.2years in those treated with zoledronate (n=218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate.Conclusions: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.
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| 8. |
- Takaoka, M, et al.
(författare)
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The home environment of junior high school students in Hyogo, Japan : Associations with asthma, respiratory health and reported allergies
- 2016
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Ingår i: Indoor + Built Environment. - 1420-326X .- 1423-0070. ; 25:1, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- Associations between home environment factors and respiratory symptoms, and reported allergiesamong junior high school students in Kobe, Japan (N¼1048) were investigated in the present study.These were mutually adjusted for age, sex, type of school (private/local) and their significant exposuresto the environment. Totally 13.4% of students reported to have doctor’s diagnosed asthma, 9.9% hadwheeze and 50.1% had attacks of daytime breathlessness during past 12 months, 25.7% of studentsreported that they had pollen allergy, 8.8% had cat allergy and 6.1% had dog allergy. Totally 29.4% ofstudents were living in a wooden house and during past 12 months, 18% of students reported that theirhomes had signs of dampness, 38.2% of homes had window condensation in winter and 7.8% of homeshad indoor painting. Window condensation was associated with wheeze (odds ratio (OR)¼1.54; 95%confidence interval (CI) 1.01–2.34), daytime breathlessness (OR¼2.02; 95% CI 1.56–2.63), airway infec-tion during past 12 months (OR¼1.66; 95% CI 1.17–2.37), cat allergy (OR¼1.63; 95% CI 1.05–2.54);mould allergy (OR¼1.84; 95%CI 1.08–3.12) and pollen allergy (OR¼1.54; 95% CI 1.15–2.06). Recentindoor painting was associated with daytime breathlessness (OR 1.83; 95% CI 1.12–3.00), dog allergy(OR¼2.23; 95% CI 1.02–4.85) and mould allergy (OR¼2.43; 95% CI 1.14–5.17). Living in a wooden housewas associated with dog allergy (OR¼2.17; 95% CI 1.18–4.00) and mould allergy (OR¼1.98; 95% CI1.04–3.76). In conclusion, in Japanese homes, the window condensation in winter, recent indoor paint-ing and living in a wooden house could contribute to the increased risk of respiratory symptoms andallergies for young Japanese school children.
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