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  • 1
    Online Resource
    Online Resource
    DOCK2 is involved in the host genetics and biology of severe COVID-19
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . 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.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-022-05163-5
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    A second update on mapping the human genetic architecture of COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 621, No. 7977 ( 2023-09-07), p. E7-E26
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06355-3
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Mapping the human genetic architecture of COVID-19
    Springer Science and Business Media LLC ; 2021
    In:  Nature Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Abstract: The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-021-03767-x
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Benzo[ a ]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor
    Proceedings of the National Academy of Sciences ; 2000
    In:  Proceedings of the National Academy of Sciences Vol. 97, No. 2 ( 2000-01-18), p. 779-782
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 2 ( 2000-01-18), p. 779-782
    Abstract: The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery of xenobiotic-metabolizing enzymes has been studied extensively. However, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumor induction, we have investigated the response of AhR-deficient mice to benzo[ a ]pyrene (B[ a ]P), a widely distributed environmental carcinogen. B[ a ]P treatment induced expression of the cytochrome P450 gene Cyp1a1 in the skin and liver of AhR-positive mice bearing +/+ and +/− genotypes and did not induce expression of the cytochrome P450 gene Cyp1a1 in AhR-null mice in either skin or liver. In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[ a ]P treatment, although its inducibility was lost in the AhR(−/−) mouse. All AhR-positive male mice of both +/+ and +/− genotypes that received subcutaneous injection of B[ a ]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment. In contrast, no tumors were apparent in any of the AhR-deficient mice. Likewise, topical application of B[ a ]P (200 μg) at weekly intervals to the skin of female mice for 25 weeks produced skin tumors only in the AhR-positive mice. Thus the carcinogenic action of B[ a ]P may be determined primarily by AhR, a transcriptional regulator of the gene for CYP1A1. The results of the present study provide direct evidence that AhR is involved in carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.97.2.779
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2000
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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