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Association of CXCR6 with COVID-19 severity: delineating the host genetic factors in transcriptomic regulation.
Dai, Yulin; Wang, Junke; Jeong, Hyun-Hwan; Chen, Wenhao; Jia, Peilin; Zhao, Zhongming.
  • Dai Y; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 600, Houston, TX, 77030, USA.
  • Wang J; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
  • Jeong HH; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 600, Houston, TX, 77030, USA.
  • Chen W; Immunobiology and Transplant Science Center, Department of Surgery, Houston Methodist Research Institute and Institute for Academic Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA.
  • Jia P; Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA.
  • Zhao Z; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 600, Houston, TX, 77030, USA.
Hum Genet ; 140(9): 1313-1328, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1279450
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ABSTRACT
The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ~ 80% asymptomatic or mild cases and ~ 5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis, and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single-cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on lung, and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis-expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung-resident memory CD8+ T (TRM) cells, we found a 2.24-fold decrease of cell proportion among CD8+ T cells and lower expression of CXCR6 in the severe patients than moderate patients. Pro-inflammatory transcriptional programs were highlighted in the TRM cellular trajectory from moderate to severe patients. CXCR6 from the 3p21.31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung TRM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Quantitative Trait Loci / Transcriptome / Receptors, CXCR6 / SARS-CoV-2 / COVID-19 / Immunologic Memory / Lung Type of study: Prognostic study Topics: Variants Limits: Female / Humans / Male Language: English Journal: Hum Genet Year: 2021 Document Type: Article Affiliation country: S00439-021-02305-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: CD8-Positive T-Lymphocytes / Quantitative Trait Loci / Transcriptome / Receptors, CXCR6 / SARS-CoV-2 / COVID-19 / Immunologic Memory / Lung Type of study: Prognostic study Topics: Variants Limits: Female / Humans / Male Language: English Journal: Hum Genet Year: 2021 Document Type: Article Affiliation country: S00439-021-02305-z