Association of
| العنوان: | Association of |
|---|---|
| المؤلفون: | Junke Wang, Yulin Dai, Peilin Jia, Zhongming Zhao, Wenhao Chen, Hyun-Hwan Jeong |
| المصدر: | Human Genetics bioRxiv article-version (status) pre article-version (number) 2 |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Quantitative Trait Loci, TWAS, Genome-wide association study, Locus (genetics), CD8-Positive T-Lymphocytes, Biology, Quantitative trait locus, Severity of Illness Index, Article, colocalization, Transcriptome, Receptors, CCR, 03 medical and health sciences, Immune system, Risk Factors, single cell RNA sequencing, Genetics, medicine, Humans, Lung, Genetics (clinical), Receptors, CXCR6, 030304 developmental biology, Genetic association, Original Investigation, 0303 health sciences, medicine.diagnostic_test, SARS-CoV-2, 030305 genetics & heredity, COVID-19, CXCR6, Human genetics, Host genetics, Bronchoalveolar lavage, Immunology, lung resident memory CD8+ T (TRM) cell, Female, Immunologic Memory, CD8, Genome-Wide Association Study |
| الوصف: | BackgroundThe 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.MethodsWe 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.ResultsWe discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on the 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 3.32-fold decrease of cell proportion and lower expression of CXCR6 in the severe than moderate patients using the BALF transcriptomic dataset. Pro-inflammatory transcriptional programs were highlighted in TRM cells trajectory from moderate to severe patients.ConclusionsCXCR6 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. We illustrate one potential mechanism of host genetic factor impacting the severity of COVID-19 through regulating the expression of CXCR6 and TRM cell proportion and stability. Our results shed light on potential therapeutic targets for severe COVID-19. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::554ad2711fd42782e618ba5451f6baac https://pubmed.ncbi.nlm.nih.gov/34155559 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....554ad2711fd42782e618ba5451f6baac |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |